Embryology - User contributions [en-gb]

User:Z3331330

2012-10-16T23:50:00Z

Z3331330: /* Lab Attendance */

==Lab Attendance==

Lab 1--[[User:Z3331330|Z3331330]] 11:49, 25 July 2012 (EST)
Lab 2--[[User:Z3331330|Z3331330]] 10:41, 1 August 2012 (EST)
Lab 3--[[User:Z3331330|Z3331330]] 13:00, 8 August 2012 (EST)
Lab 4--[[User:Z3331330|Z3331330]] 10:07, 15 August 2012 (EST)
Lab 5--[[User:Z3331330|Z3331330]] 10:08, 22 August 2012 (EST)
Lab 6--[[User:Z3331330|Z3331330]] 10:10, 29 August 2012 (EST)
Lab 7--[[User:Z3331330|Z3331330]] 10:05, 12 September 2012 (EST)
Lab 8--[[User:Z3331330|Z3331330]] 10:03, 19 September 2012 (EST)
Lab 9--[[User:Z3331330|Z3331330]] 10:08, 26 September 2012 (EST)
Lab 10--[[User:Z3331330|Z3331330]] 10:10, 3 October 2012 (EST)
Lab 11--[[User:Z3331330|Z3331330]] 10:07, 10 October 2012 (EST)
Lab 12--[[User:Z3331330|Z3331330]] 10:49, 17 October 2012 (EST)

==Lab 1 Assessment==
(1)Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.

Many studies and experiments were conducted and they all contributed to the development of In Vitro Fertilization as it is today. Some early studies have used hamster gametes to prove the possibility of mammalian gametes being fertilized in vitro, done by Yanagimachi and Chang in1963. Chang, in 1959 has also done a study that demonstrated the normal development of a rabbit egg that was fertilized in vitro. Numerous experiments were done using different animals and species which proved the success of in vitro fertilization. Capacitation of the sperm in the uterus of the mother was a significant discovery to in vitro fertilisation. On July 25, 1978, the first successful 'test-tube' baby was born. Dr. Patrick Steptoe, a gynecologist and Dr. Robert Edwards, a physiologist, the team who pioneered the IVF were accredited for their contribution to IVF.

In 2010, Robert Edwards was awarded the 'Nobel prize in physiology or medicine' for his contribution in the development of "In Vitro Fertilization", see [http://www.nobelprize.org/]

(2)Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).

'Genes required for the common miracle of fertilization in Caenorhabditis Elegans' <ref><pubmed>18649278</pubmed></ref>

Fertilization is a result of various sperm-egg interactions and together these interactions lead to gamete fusions and egg activation.This paper describes the identity of genes that are responsible for the interactions between gametes during ferilization and the function of protein products that are produced by these specific genes. The paper focuses on the fertilization process in Caenorhabditis Elegans which is a type of worm. There are two main types of molecules that are essential in fertilization and they are sperm function molecules and egg function molecules. Spe-9 gene produces a single-pass transmembrane molecules with extracellular domain that contain 10 epidermal growth factor and it is responsible for adhesion or ligand receptor functions. Its critical presence on the surface of the sperm allow the sperm to bind to the oocytes during fertilization. Other genes such as Spe-38 is also identified with similar function.

Egg function genes such as egg-1 and egg-2 genes lead to the production of type II transmembrane molecules. Loss of these gene can lead to complete hermaphrodite fertility. Sperms will not be able to enter the oocytes.The main function of these genes is to act as oocyte surface receptor for sperms during fertilization. These discoveries and results in C.elegans provide a blueprint of the genetic control involved in the process of fertilization and encouraged discoveries of similar genes that are involved in fertilization in humans.

--[[User:Z8600021|Mark Hill]] 16:30, 11 September 2012 (EST) Question 1 is answered well and I like that you have discussed earlier research. Question 1 is also answered well, though a 2008 paper is not as recent as I was seeking as an answer. You will need to fix your referencing (ref 1 is blank because it is incorrectly formatted and should only contain the PMID (not PMC number) number without text)'''10/10'''

==lab 2 assessment==
===Degradation of ooctyes by sperm proteasomes===
--[[User:Z8600021|Mark Hill]] 16:49, 11 September 2012 (EST) This should be a sub-heading.

(1)[[File:Degradation_of_oocytes_by_sperm_proteasomes.png‎]]

(2) Rac-1 is a member of the Rho GTPases family of proteins. It was discovered that with the activation of the Rac-1 gene, its protein product can regulate the motility of the human endometrial stromal cells (HESCs) in reponse to the implantation of the embryo in the uterine wall. Rac-1 promotes the lamellipodial protrusion at front of the migrating cells. This protein also encourage the migration of HESCs away from the implantation site which then facilitate the invasion of trophoblast and lead to the inplantation of the embryo into the stromal compartment. <ref><pubmed>PMC2562412</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:32, 11 September 2012 (EST) Question 1 image is well named and contains all the requested information. Though the image is quite small 320 × 399 pixels and a larger version should have been sourced, also png files are quite large 125 KB, jpg are smaller). You have also misinterpreted my request as the file name should be a sub-heading on the file summary page, not here. Question 2 is also relevant to implantation. Rac proteins regulate the actin cytoskeleton and this is further explored in the 3rd year Cell Biology course. '''10/10'''

==Lab 3 assessment==

(1)Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

Answer: Gestational age is classified as the time elapsed from the first day of a women's last menstrual period, and the post-fertilization age is referred as the time since the fertilzation of the egg in the woman's uterus. The main difference is their starting date and gestational age is often two weeks earlier than the post-fertilization age. Clinically, gestational age is often used in describing human development because the start date of the gestational age can be clearly defined while the exact time of fertilization can be confusing. It is also essential for predicting consequences to the development of fetus from toxin exposure of infection during the gestational age.It is also important for evaluation of physical findings such as fetal growth and screening markers.

(2)Identify using histological descriptions at least 3 different types of tissues formed from somites.

3 types of tissues formed from somites:
- dermatome --> Skin are formed from dermatome. There are 3 layers to skin, epidermis which contain stratified squamous cells with epidermal ridges with thick layer of keratin. Dermis layer contain a lot of the vasculature such as blood vessels and glands, there are also dense collagen and irregular elastic fibres. Usually, this layer contains a lot of type I collagen fibre. The last layer is the hypodermis layer where its mainly adipose tissue.

- myotome--> skeletal muscle are developed from myotome. Skeletal muscle has a lot of myocytes and they are long and elongated with multiple nucleus. Their nucleus are often pushed to the periphery of the cells. They also contain myosin and actin which are called the thick and thin filament which cause striation appearance of the muscle cells.

- Sclerotome--> vertebrae and rib cartilages are developed from it, where different type of bone cells are present. The extracellular matrix of bone is formed through inorganic material such as phosphate along with some organic component being collagen fibres and ground substance.

--[[User:Z8600021|Mark Hill]] 16:41, 11 September 2012 (EST) Question 1 has been clearly and correctly answered. Question 2 the somite compartments and major tissues correctly identified. The one error is the answer for dermatome suggests that the epidermis is also a component of this compartment, while it is ectodermal in origin. '''9/10'''

==Lab 4 assessment==

(1)Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

The first invasive prenatal diagnostic techniques is called "chorionic villus sampling" and it involves a catheter passed via the vagina through the cervix and into the uterus to the placenta, under the guidance of ultrasound. There can be other approaches as well such as transvaginal and transabdominal. The catheter will then collect sample of the chorionic villus which is placental tissue. The sample will then be analyse for any chromosomal abnormalities or genetic disorders, and the karotype of the fetus will be determined.

The second technique is "Placental biopsy", it is similiar to the chorionic villus sampling, but it has a transabdominal approach to it. It can be performed at a later stage of the pregnancy. It is used to obtain a rapid result. The karyotype of the fetus can be determined and genetic disorders can be detected such as trisomy 21 and monosomy X.

(2)Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

"Transplantation of microencapsulated umbilical-cord-bloodderived hepatic-like cells for treatment of hepatic failure" [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3051145/?tool=pmcentrez]

The paper aim to investigate intraperitoneal transplantation of microencapsulated hepatic-like cells from human umbilical cord blood for treatment of hepatic failure in rats. There are a few candidates for this experiment but human umbilical cord blood (UCB) cells were thought to be the best as they have some advantages that other cells do not have. The frequencies of UCB hematopoietic stem or progenitor cells is much higher than those from bone marrow and peripheral blood. The paper also mentioned that there are three ways of inducing the UCB cells into hepatocytes-like cells and they are Co-culture with injured liver cell, growth factor-assisted and MNC transplantation.

In the experiment, CD34 cells are isolated from the UCB cells and through the combination of fibroblast growth factor and hepatocyte growth factor, the CD34 cells are induced to hepatocytes-like cells.
It was found that in the cultured cells, the level of human albumin, alpha-fetoprotein and GATA-4 mRNA and albumin positive cells have increased significantly suggesting the transformation of the CD34 cells into hepatic-like cells. The cultured system with growth factors have the ability to convert these UCB cells into hepatocytes phenotype and it is confirmed through PCR and immunohistochemcial staining. Then these hepatic-like cells are encapsulated and transplanted into the abdominal cavity of rats with acute hepatic failure. The transplantation occurs 48 hours after the onset of an acute hepatic failure.The microencapsulation of the cells provide a possibility to overcome the immuno-rejection from the AHF rats.

The result obtained from this experiment was that CD34 cells from the UCB cells can be converted into hepatic-like cells under suitable conditions with appropriate growth factors. The transplantation of these encapsulated hepatic-like cells have resulted in decreased mortality of the AHF rats. But these hepatic-like cells can only offer short term metabolic effect to these AHF rats and cannot interrupt or repair the damaged hepatocytes. Therefore the conclusion of this paper suggests the possibility of UCB cells used in conversion to hepatic-like cells that can temporarily alleviate the symptoms of Acute hepatic failure in rats bur not regenerating healthy hepatocytes. <ref><pubmed>PMC3051145</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:46, 11 September 2012 (EST) Question 1 You have clearly identified 2 invasive techniques diagnostic techniques. I would have liked specific disorders for the first technique, as you have for the second technique. Question 2 this is an excellent description of the paper and technique. You have used the UCB acronym correctly (citing in full the first time), though you still have problems in formatting your reference links, which only require the PMID number to link correctly. '''10/10'''

==Lab 7 assessment==
(1) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?

It is a mononuclear stem cell that are found in mature skeletal muscle fibres and promote their growth, repair and regeneration, they are usually situated between sarcolemma and basement membrane of muscle fibres.

Satellite cells are activated after muscle strains such as trauma, where myogenic regulatory factors will be expressed and they are similar to those produced by muscle precursor cells during muscle development. These cells proliferate and fuse with each other to form myotubes and slowly mature into myofibres. They can also fuse with damaged segments of muscle fibres. These cells can also give rise to new satellite cells. Heavy exercise can induce muscle hypertrophy which also encourage the growth and proliferation of these muscle satellite cells.

(2)In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?

In situations of long term motor nerve damage, since skeletal muscles are activated by these motor nerves, when they are damaged, the muscles will often lose their function and movement. There can be a complete loss of function or only a part of, depending on the severity of the damage to the nerve. When the muscle lose their initiation, they can present symptoms such as muscle twitching, cramping and muscle can become stiff due to the lack of movement. Muscles paralysed by spinal cord injury are usually atrophic, possesses lower tension generating capacity and is less fatigue resistant compared to normal muscles. Upper motor neuron paralysed muscles lose the normal type I (slow) and II (fast) fibre and become predominantly composed of type II (fast glycolytic) fibres. A transitional period can be seen ranging from 1 to 20 months after the injury where there is usually drop in the proportion of slow muscle fibres and a rise in the development of fast fibres.

==Lab 8 assessment==

''Vision''

I really liked the eye image at the top of the project page, it automatically drags my attention towards the page and it clearly shows what the project is going to be focused on. The introduction was good, its not too long but provide sufficient information about the project and as reader, we know what we can expect from the project page. The image used there is very good as well but maybe more labelling and explanation can be included.

Images from the textbook, Atlas of the development of men, both on the development of lens and the formation of optic vesicle, they are really good. I understand that the page is not complete yet, but just looking at these images, a lot of explanation and labelling need to be put in to ensure that readers know what is going on and actually learn from those images. The development of the optic nerve is good. Information provided is clear and precise. The whole process of the development was explained well and used simple terms so that it is very easy to follow and understand but maybe the images need to be labelled more? I saw that this section of the project, only 1-2 references is used? Maybe try to expand the research and include more information from different sources. I really liked the way that most of the images are hand-drawn, this really shows that you understand the process yourself and able to interpret all the knowledge you gathered from resources and produce something that is easy to understand and can actually teach readers about vision development.

There is a glossary at the end of the page which includes all the scientific terms, maybe expand this section a little bit more. Some scientific words are not included such as mesenchyme, as a science student, maybe we will understand these words but for the general public, they may not. That's why it is essential to have a glossary. I thought having an image gallery was a good idea, in that way, people can concentrate on only the image aspect of the project without all the text in between, allowing a different approach in looking at this project. Referencing of the project overall was good, except there is one citing error, no.13? But this should be quite easy to fix. In terms of variety of resources used, i thought was quite narrow, with the majority resources being websites and lab material from the course. Maybe use more journal articles and reviews to expand the depth of the information presented. The structure and the lay out of the page is very clear with consistent headings and sub-headings, which makes the page very easy to read and follow.

Overall, the project page is looking good.There are just some minor parts to be completed and maybe a little bit more research needs to be done. :) hope this helps.
--Z3331330 18:35, 23 September 2012 (EST)

''Somatosensory''

The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?
The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

''Taste''

The introduction is very detailed but did not mention anything about the development of the taste. But I thought the mechanisms behind sweet and salty tastes are very interesting. Maybe do the same for the other 3 tastes? The image of the basic 5 tastes is a bit small, maybe upload a bigger version of the image. Also, the image is lacking some reference, copyright information and a student image template.

The type II receptor section is pretty good and descriptive but it does not really relate to the development of the taste. The taste map is a very eye-catchy image and it would be really useful if it had all the needed information such as the copyright notice. The timeline of the gustatory system is very well-presented and easy to read. I understand the project is not completed yet, therefore more images are still to be put in. Only 2 references have been used in the timeline section, maybe try to research more and use different resources. There are some citing error but it should be quite easy to fix.

Histories of discoveries section is very detailed and easy to read but the referencing needs to be fixed. The adult tongue and taste bud section is very clear and precise and contain a lot of useful information but it does not really relate to the research topic, should beware of going off-track. The hand-drawn diagram of the taste bud is impressive and easy to understand but again lacking in some referencing information such as who drew it. The abnormalities section is good and well-researched and it is interesting to know about which gene or receptors will effect the development of taste and sensation. Maybe the abnormalities section can be included into the current research section because abnormalities are repeated in the current research section below. There are detailed definitions of terms in the glossary which is good because it really helps the reader to understand more about the research topic.

Overall, the page is looking good. The main thing that needs to be fixed will be the images that are already on the page, they need the correct and essential information with them when uploaded on the page or else, they will get deleted and there will be no images on the page and the nice balance of images and text now will be gone. There seem to be a lot of anatomy and biology of the taste system but not a lot of information about their development. Although there is a timeline of development but i think more information is needed. Referencing is pretty good with only one or two minor citing error but it should be easy to fix. Structure of the page is clear and simple with headings and sub-headings being consistent, making the page easy to read and follow. Hope this helps :)

''Olfaction''

The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.
The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

''Hearing''

Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

==Lab 9 assessment==

(1)Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

'Stam2 expression pattern during embryo development.'

Signal transduction adaptor molecules 1 and 2 (STAM1 and STAM2). They are both involved in the endosomal sorting of the cargo proteins for trafficking towards the lysosome. STAM2 is activated by tyrosine phosphorylation and can also be stimulated by various cytokines and growth factors. It is involved in the regulation of endocytosis and also regulation of intracellular signal transduction for DNA synthesis through JAK2 and JAK3 tyrosine kinases.

In the paper, a mouse line have been created to enable the expression of STAM2 to be observed by X-gal histochemistry. At around embryonic day 16.5, it is evident that STAM2 is expressed in the heart, testes, olfactory bulbs, trigeminal and dorsal root ganglia, pituitary and medulla of the adrenal glands. Around embryonic day 18.5, the expression of STAM2 become much stronger, especially in areas of testes, ovaries, lungs, kidneys, urogenital sinus, pituitary and adrenal glands. Near the end of gestation, STAM2 expression is confined to regions such as nervous tissue, and endocrine organs like pituitary and adrenal glands and they are already highly secretory active at this stage of embryonic development. This paper demonstrates a very strong correlation between the development of the adrenal glands and the expression of STAM2. <ref><pubmed>22143071</pubmed></ref>

(2)Identify the embryonic layers and tissues that contribute to the developing teeth.

Teeth are formed from cells that derived from the ectoderm of the first branchial arch and the ectomesenchyme of the neural crest and also mesoderm.It is organized into 3 parts, the enamel organ, the dental papilla and the dental follicle. The enamel organ give rise to ameloblasts which produce enamel and the reduced enamel epithelium and ultimately determines the root shape of the tooth.The dental papilla contains cells that develop into odontoblasts which determines the crown shape of a tooth. Mesenchymal cells in the dental papilla are for the formation of tooth pulp. The dental follicle contribute to cementoblasts which form the cementum of the tooth, osteoblasts which give rise to the alveolar bone and fibroblasts give rise to periodontal ligamtns.

==Lab 11 assessment==

(1)Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.

'Two-step differentiation of mast cells from induced pluripotent stem cells.'

Mast cells are responsible for the pathogenesis of many allergic diseases in the human body. There are mainly two types of mast cells and they are connective tissue type mast cells (CTMCs) and mucosal-type mast cells. This study aim to report on the generation and characterisation of connective tissue type mast cells that are derived from induced pluripotent stem cells (iPS cells) that originated from mouse. Mast cells are generated from mouse iPS cells and are characterised from several aspects including morphology, function and gene expression.

The study generated mast cells and differentiated them from mouse iPS cells from two major methods. The first one is by co-culturing the mouse iPS cells with OP9 stromal cells and the second one is the embryoid body formation method. With these two methods, they were able to produce mast cells that have characteristics similiar to CTMCs. When mouse iPS cells were generated with the OP9 stromal cells and also co-cultured with Swiss 3T3 fibroblasts, the result of the generation was that the mast cells exhibit even more of a functional phenotype. Therefore, the study provided a protocol with two step differentiation which allows the transformation of mouse iPS cells to mast cells. The two differentiation method was co-culture with OP9 stromal cells and co-culture with Swiss 3T3 fibroblasts.

The protocol provided by this study consist of mesoderm induction, mast cell specification, differentiation and maturation of mast cells from mouse iPS cells. The study also suggested a few cytokines and feeder cells that were essential for the development of iPS cells to mast cells. Interleukin-3 has been recgonised and considered to play a very important role in the differentiation of mast cells. OP9 cells may not be necessary for the specification of mast cells but it promotes the maturation of them. Swiss 3T3 fibroblasts have been proved to be essential for the maturation of the mast cells from mouse iPS cells. The successful protocol generated from the study has provided a novel method for more efficient generation of mast cells from mouse iPS cells, with the production of more mature mast cells. <ref><pubmed>23045993</pubmed></ref>

===References===
<references/>

User:Z3331330

2012-10-16T23:49:29Z

Z3331330: /* Lab Attendance */

==Lab Attendance==

Lab 1--[[User:Z3331330|Z3331330]] 11:49, 25 July 2012 (EST)
Lab 2--[[User:Z3331330|Z3331330]] 10:41, 1 August 2012 (EST)
Lab 3--[[User:Z3331330|Z3331330]] 13:00, 8 August 2012 (EST)
Lab 4--[[User:Z3331330|Z3331330]] 10:07, 15 August 2012 (EST)
Lab 5--[[User:Z3331330|Z3331330]] 10:08, 22 August 2012 (EST)
Lab 6--[[User:Z3331330|Z3331330]] 10:10, 29 August 2012 (EST)
Lab 7--[[User:Z3331330|Z3331330]] 10:05, 12 September 2012 (EST)
Lab 8--[[User:Z3331330|Z3331330]] 10:03, 19 September 2012 (EST)
Lab 9--[[User:Z3331330|Z3331330]] 10:08, 26 September 2012 (EST)
Lab 10--[[User:Z3331330|Z3331330]] 10:10, 3 October 2012 (EST)
Lab 11--[[User:Z3331330|Z3331330]] 10:07, 10 October 2012 (EST)
--[[User:Z3331330|Z3331330]] 10:49, 17 October 2012 (EST)

==Lab 1 Assessment==
(1)Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.

Many studies and experiments were conducted and they all contributed to the development of In Vitro Fertilization as it is today. Some early studies have used hamster gametes to prove the possibility of mammalian gametes being fertilized in vitro, done by Yanagimachi and Chang in1963. Chang, in 1959 has also done a study that demonstrated the normal development of a rabbit egg that was fertilized in vitro. Numerous experiments were done using different animals and species which proved the success of in vitro fertilization. Capacitation of the sperm in the uterus of the mother was a significant discovery to in vitro fertilisation. On July 25, 1978, the first successful 'test-tube' baby was born. Dr. Patrick Steptoe, a gynecologist and Dr. Robert Edwards, a physiologist, the team who pioneered the IVF were accredited for their contribution to IVF.

In 2010, Robert Edwards was awarded the 'Nobel prize in physiology or medicine' for his contribution in the development of "In Vitro Fertilization", see [http://www.nobelprize.org/]

(2)Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).

'Genes required for the common miracle of fertilization in Caenorhabditis Elegans' <ref><pubmed>18649278</pubmed></ref>

Fertilization is a result of various sperm-egg interactions and together these interactions lead to gamete fusions and egg activation.This paper describes the identity of genes that are responsible for the interactions between gametes during ferilization and the function of protein products that are produced by these specific genes. The paper focuses on the fertilization process in Caenorhabditis Elegans which is a type of worm. There are two main types of molecules that are essential in fertilization and they are sperm function molecules and egg function molecules. Spe-9 gene produces a single-pass transmembrane molecules with extracellular domain that contain 10 epidermal growth factor and it is responsible for adhesion or ligand receptor functions. Its critical presence on the surface of the sperm allow the sperm to bind to the oocytes during fertilization. Other genes such as Spe-38 is also identified with similar function.

Egg function genes such as egg-1 and egg-2 genes lead to the production of type II transmembrane molecules. Loss of these gene can lead to complete hermaphrodite fertility. Sperms will not be able to enter the oocytes.The main function of these genes is to act as oocyte surface receptor for sperms during fertilization. These discoveries and results in C.elegans provide a blueprint of the genetic control involved in the process of fertilization and encouraged discoveries of similar genes that are involved in fertilization in humans.

--[[User:Z8600021|Mark Hill]] 16:30, 11 September 2012 (EST) Question 1 is answered well and I like that you have discussed earlier research. Question 1 is also answered well, though a 2008 paper is not as recent as I was seeking as an answer. You will need to fix your referencing (ref 1 is blank because it is incorrectly formatted and should only contain the PMID (not PMC number) number without text)'''10/10'''

==lab 2 assessment==
===Degradation of ooctyes by sperm proteasomes===
--[[User:Z8600021|Mark Hill]] 16:49, 11 September 2012 (EST) This should be a sub-heading.

(1)[[File:Degradation_of_oocytes_by_sperm_proteasomes.png‎]]

(2) Rac-1 is a member of the Rho GTPases family of proteins. It was discovered that with the activation of the Rac-1 gene, its protein product can regulate the motility of the human endometrial stromal cells (HESCs) in reponse to the implantation of the embryo in the uterine wall. Rac-1 promotes the lamellipodial protrusion at front of the migrating cells. This protein also encourage the migration of HESCs away from the implantation site which then facilitate the invasion of trophoblast and lead to the inplantation of the embryo into the stromal compartment. <ref><pubmed>PMC2562412</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:32, 11 September 2012 (EST) Question 1 image is well named and contains all the requested information. Though the image is quite small 320 × 399 pixels and a larger version should have been sourced, also png files are quite large 125 KB, jpg are smaller). You have also misinterpreted my request as the file name should be a sub-heading on the file summary page, not here. Question 2 is also relevant to implantation. Rac proteins regulate the actin cytoskeleton and this is further explored in the 3rd year Cell Biology course. '''10/10'''

==Lab 3 assessment==

(1)Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

Answer: Gestational age is classified as the time elapsed from the first day of a women's last menstrual period, and the post-fertilization age is referred as the time since the fertilzation of the egg in the woman's uterus. The main difference is their starting date and gestational age is often two weeks earlier than the post-fertilization age. Clinically, gestational age is often used in describing human development because the start date of the gestational age can be clearly defined while the exact time of fertilization can be confusing. It is also essential for predicting consequences to the development of fetus from toxin exposure of infection during the gestational age.It is also important for evaluation of physical findings such as fetal growth and screening markers.

(2)Identify using histological descriptions at least 3 different types of tissues formed from somites.

3 types of tissues formed from somites:
- dermatome --> Skin are formed from dermatome. There are 3 layers to skin, epidermis which contain stratified squamous cells with epidermal ridges with thick layer of keratin. Dermis layer contain a lot of the vasculature such as blood vessels and glands, there are also dense collagen and irregular elastic fibres. Usually, this layer contains a lot of type I collagen fibre. The last layer is the hypodermis layer where its mainly adipose tissue.

- myotome--> skeletal muscle are developed from myotome. Skeletal muscle has a lot of myocytes and they are long and elongated with multiple nucleus. Their nucleus are often pushed to the periphery of the cells. They also contain myosin and actin which are called the thick and thin filament which cause striation appearance of the muscle cells.

- Sclerotome--> vertebrae and rib cartilages are developed from it, where different type of bone cells are present. The extracellular matrix of bone is formed through inorganic material such as phosphate along with some organic component being collagen fibres and ground substance.

--[[User:Z8600021|Mark Hill]] 16:41, 11 September 2012 (EST) Question 1 has been clearly and correctly answered. Question 2 the somite compartments and major tissues correctly identified. The one error is the answer for dermatome suggests that the epidermis is also a component of this compartment, while it is ectodermal in origin. '''9/10'''

==Lab 4 assessment==

(1)Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

The first invasive prenatal diagnostic techniques is called "chorionic villus sampling" and it involves a catheter passed via the vagina through the cervix and into the uterus to the placenta, under the guidance of ultrasound. There can be other approaches as well such as transvaginal and transabdominal. The catheter will then collect sample of the chorionic villus which is placental tissue. The sample will then be analyse for any chromosomal abnormalities or genetic disorders, and the karotype of the fetus will be determined.

The second technique is "Placental biopsy", it is similiar to the chorionic villus sampling, but it has a transabdominal approach to it. It can be performed at a later stage of the pregnancy. It is used to obtain a rapid result. The karyotype of the fetus can be determined and genetic disorders can be detected such as trisomy 21 and monosomy X.

(2)Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

"Transplantation of microencapsulated umbilical-cord-bloodderived hepatic-like cells for treatment of hepatic failure" [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3051145/?tool=pmcentrez]

The paper aim to investigate intraperitoneal transplantation of microencapsulated hepatic-like cells from human umbilical cord blood for treatment of hepatic failure in rats. There are a few candidates for this experiment but human umbilical cord blood (UCB) cells were thought to be the best as they have some advantages that other cells do not have. The frequencies of UCB hematopoietic stem or progenitor cells is much higher than those from bone marrow and peripheral blood. The paper also mentioned that there are three ways of inducing the UCB cells into hepatocytes-like cells and they are Co-culture with injured liver cell, growth factor-assisted and MNC transplantation.

In the experiment, CD34 cells are isolated from the UCB cells and through the combination of fibroblast growth factor and hepatocyte growth factor, the CD34 cells are induced to hepatocytes-like cells.
It was found that in the cultured cells, the level of human albumin, alpha-fetoprotein and GATA-4 mRNA and albumin positive cells have increased significantly suggesting the transformation of the CD34 cells into hepatic-like cells. The cultured system with growth factors have the ability to convert these UCB cells into hepatocytes phenotype and it is confirmed through PCR and immunohistochemcial staining. Then these hepatic-like cells are encapsulated and transplanted into the abdominal cavity of rats with acute hepatic failure. The transplantation occurs 48 hours after the onset of an acute hepatic failure.The microencapsulation of the cells provide a possibility to overcome the immuno-rejection from the AHF rats.

The result obtained from this experiment was that CD34 cells from the UCB cells can be converted into hepatic-like cells under suitable conditions with appropriate growth factors. The transplantation of these encapsulated hepatic-like cells have resulted in decreased mortality of the AHF rats. But these hepatic-like cells can only offer short term metabolic effect to these AHF rats and cannot interrupt or repair the damaged hepatocytes. Therefore the conclusion of this paper suggests the possibility of UCB cells used in conversion to hepatic-like cells that can temporarily alleviate the symptoms of Acute hepatic failure in rats bur not regenerating healthy hepatocytes. <ref><pubmed>PMC3051145</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:46, 11 September 2012 (EST) Question 1 You have clearly identified 2 invasive techniques diagnostic techniques. I would have liked specific disorders for the first technique, as you have for the second technique. Question 2 this is an excellent description of the paper and technique. You have used the UCB acronym correctly (citing in full the first time), though you still have problems in formatting your reference links, which only require the PMID number to link correctly. '''10/10'''

==Lab 7 assessment==
(1) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?

It is a mononuclear stem cell that are found in mature skeletal muscle fibres and promote their growth, repair and regeneration, they are usually situated between sarcolemma and basement membrane of muscle fibres.

Satellite cells are activated after muscle strains such as trauma, where myogenic regulatory factors will be expressed and they are similar to those produced by muscle precursor cells during muscle development. These cells proliferate and fuse with each other to form myotubes and slowly mature into myofibres. They can also fuse with damaged segments of muscle fibres. These cells can also give rise to new satellite cells. Heavy exercise can induce muscle hypertrophy which also encourage the growth and proliferation of these muscle satellite cells.

(2)In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?

In situations of long term motor nerve damage, since skeletal muscles are activated by these motor nerves, when they are damaged, the muscles will often lose their function and movement. There can be a complete loss of function or only a part of, depending on the severity of the damage to the nerve. When the muscle lose their initiation, they can present symptoms such as muscle twitching, cramping and muscle can become stiff due to the lack of movement. Muscles paralysed by spinal cord injury are usually atrophic, possesses lower tension generating capacity and is less fatigue resistant compared to normal muscles. Upper motor neuron paralysed muscles lose the normal type I (slow) and II (fast) fibre and become predominantly composed of type II (fast glycolytic) fibres. A transitional period can be seen ranging from 1 to 20 months after the injury where there is usually drop in the proportion of slow muscle fibres and a rise in the development of fast fibres.

==Lab 8 assessment==

''Vision''

I really liked the eye image at the top of the project page, it automatically drags my attention towards the page and it clearly shows what the project is going to be focused on. The introduction was good, its not too long but provide sufficient information about the project and as reader, we know what we can expect from the project page. The image used there is very good as well but maybe more labelling and explanation can be included.

Images from the textbook, Atlas of the development of men, both on the development of lens and the formation of optic vesicle, they are really good. I understand that the page is not complete yet, but just looking at these images, a lot of explanation and labelling need to be put in to ensure that readers know what is going on and actually learn from those images. The development of the optic nerve is good. Information provided is clear and precise. The whole process of the development was explained well and used simple terms so that it is very easy to follow and understand but maybe the images need to be labelled more? I saw that this section of the project, only 1-2 references is used? Maybe try to expand the research and include more information from different sources. I really liked the way that most of the images are hand-drawn, this really shows that you understand the process yourself and able to interpret all the knowledge you gathered from resources and produce something that is easy to understand and can actually teach readers about vision development.

There is a glossary at the end of the page which includes all the scientific terms, maybe expand this section a little bit more. Some scientific words are not included such as mesenchyme, as a science student, maybe we will understand these words but for the general public, they may not. That's why it is essential to have a glossary. I thought having an image gallery was a good idea, in that way, people can concentrate on only the image aspect of the project without all the text in between, allowing a different approach in looking at this project. Referencing of the project overall was good, except there is one citing error, no.13? But this should be quite easy to fix. In terms of variety of resources used, i thought was quite narrow, with the majority resources being websites and lab material from the course. Maybe use more journal articles and reviews to expand the depth of the information presented. The structure and the lay out of the page is very clear with consistent headings and sub-headings, which makes the page very easy to read and follow.

Overall, the project page is looking good.There are just some minor parts to be completed and maybe a little bit more research needs to be done. :) hope this helps.
--Z3331330 18:35, 23 September 2012 (EST)

''Somatosensory''

The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?
The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

''Taste''

The introduction is very detailed but did not mention anything about the development of the taste. But I thought the mechanisms behind sweet and salty tastes are very interesting. Maybe do the same for the other 3 tastes? The image of the basic 5 tastes is a bit small, maybe upload a bigger version of the image. Also, the image is lacking some reference, copyright information and a student image template.

The type II receptor section is pretty good and descriptive but it does not really relate to the development of the taste. The taste map is a very eye-catchy image and it would be really useful if it had all the needed information such as the copyright notice. The timeline of the gustatory system is very well-presented and easy to read. I understand the project is not completed yet, therefore more images are still to be put in. Only 2 references have been used in the timeline section, maybe try to research more and use different resources. There are some citing error but it should be quite easy to fix.

Histories of discoveries section is very detailed and easy to read but the referencing needs to be fixed. The adult tongue and taste bud section is very clear and precise and contain a lot of useful information but it does not really relate to the research topic, should beware of going off-track. The hand-drawn diagram of the taste bud is impressive and easy to understand but again lacking in some referencing information such as who drew it. The abnormalities section is good and well-researched and it is interesting to know about which gene or receptors will effect the development of taste and sensation. Maybe the abnormalities section can be included into the current research section because abnormalities are repeated in the current research section below. There are detailed definitions of terms in the glossary which is good because it really helps the reader to understand more about the research topic.

Overall, the page is looking good. The main thing that needs to be fixed will be the images that are already on the page, they need the correct and essential information with them when uploaded on the page or else, they will get deleted and there will be no images on the page and the nice balance of images and text now will be gone. There seem to be a lot of anatomy and biology of the taste system but not a lot of information about their development. Although there is a timeline of development but i think more information is needed. Referencing is pretty good with only one or two minor citing error but it should be easy to fix. Structure of the page is clear and simple with headings and sub-headings being consistent, making the page easy to read and follow. Hope this helps :)

''Olfaction''

The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.
The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

''Hearing''

Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

==Lab 9 assessment==

(1)Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

'Stam2 expression pattern during embryo development.'

Signal transduction adaptor molecules 1 and 2 (STAM1 and STAM2). They are both involved in the endosomal sorting of the cargo proteins for trafficking towards the lysosome. STAM2 is activated by tyrosine phosphorylation and can also be stimulated by various cytokines and growth factors. It is involved in the regulation of endocytosis and also regulation of intracellular signal transduction for DNA synthesis through JAK2 and JAK3 tyrosine kinases.

In the paper, a mouse line have been created to enable the expression of STAM2 to be observed by X-gal histochemistry. At around embryonic day 16.5, it is evident that STAM2 is expressed in the heart, testes, olfactory bulbs, trigeminal and dorsal root ganglia, pituitary and medulla of the adrenal glands. Around embryonic day 18.5, the expression of STAM2 become much stronger, especially in areas of testes, ovaries, lungs, kidneys, urogenital sinus, pituitary and adrenal glands. Near the end of gestation, STAM2 expression is confined to regions such as nervous tissue, and endocrine organs like pituitary and adrenal glands and they are already highly secretory active at this stage of embryonic development. This paper demonstrates a very strong correlation between the development of the adrenal glands and the expression of STAM2. <ref><pubmed>22143071</pubmed></ref>

(2)Identify the embryonic layers and tissues that contribute to the developing teeth.

Teeth are formed from cells that derived from the ectoderm of the first branchial arch and the ectomesenchyme of the neural crest and also mesoderm.It is organized into 3 parts, the enamel organ, the dental papilla and the dental follicle. The enamel organ give rise to ameloblasts which produce enamel and the reduced enamel epithelium and ultimately determines the root shape of the tooth.The dental papilla contains cells that develop into odontoblasts which determines the crown shape of a tooth. Mesenchymal cells in the dental papilla are for the formation of tooth pulp. The dental follicle contribute to cementoblasts which form the cementum of the tooth, osteoblasts which give rise to the alveolar bone and fibroblasts give rise to periodontal ligamtns.

==Lab 11 assessment==

(1)Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.

'Two-step differentiation of mast cells from induced pluripotent stem cells.'

Mast cells are responsible for the pathogenesis of many allergic diseases in the human body. There are mainly two types of mast cells and they are connective tissue type mast cells (CTMCs) and mucosal-type mast cells. This study aim to report on the generation and characterisation of connective tissue type mast cells that are derived from induced pluripotent stem cells (iPS cells) that originated from mouse. Mast cells are generated from mouse iPS cells and are characterised from several aspects including morphology, function and gene expression.

The study generated mast cells and differentiated them from mouse iPS cells from two major methods. The first one is by co-culturing the mouse iPS cells with OP9 stromal cells and the second one is the embryoid body formation method. With these two methods, they were able to produce mast cells that have characteristics similiar to CTMCs. When mouse iPS cells were generated with the OP9 stromal cells and also co-cultured with Swiss 3T3 fibroblasts, the result of the generation was that the mast cells exhibit even more of a functional phenotype. Therefore, the study provided a protocol with two step differentiation which allows the transformation of mouse iPS cells to mast cells. The two differentiation method was co-culture with OP9 stromal cells and co-culture with Swiss 3T3 fibroblasts.

The protocol provided by this study consist of mesoderm induction, mast cell specification, differentiation and maturation of mast cells from mouse iPS cells. The study also suggested a few cytokines and feeder cells that were essential for the development of iPS cells to mast cells. Interleukin-3 has been recgonised and considered to play a very important role in the differentiation of mast cells. OP9 cells may not be necessary for the specification of mast cells but it promotes the maturation of them. Swiss 3T3 fibroblasts have been proved to be essential for the maturation of the mast cells from mouse iPS cells. The successful protocol generated from the study has provided a novel method for more efficient generation of mast cells from mouse iPS cells, with the production of more mature mast cells. <ref><pubmed>23045993</pubmed></ref>

===References===
<references/>

User:Z3331330

2012-10-14T06:35:32Z

Z3331330: /* Lab 9 assessment */

==Lab Attendance==

Lab 1--[[User:Z3331330|Z3331330]] 11:49, 25 July 2012 (EST)
Lab 2--[[User:Z3331330|Z3331330]] 10:41, 1 August 2012 (EST)
Lab 3--[[User:Z3331330|Z3331330]] 13:00, 8 August 2012 (EST)
Lab 4--[[User:Z3331330|Z3331330]] 10:07, 15 August 2012 (EST)
Lab 5--[[User:Z3331330|Z3331330]] 10:08, 22 August 2012 (EST)
Lab 6--[[User:Z3331330|Z3331330]] 10:10, 29 August 2012 (EST)
Lab 7--[[User:Z3331330|Z3331330]] 10:05, 12 September 2012 (EST)
Lab 8--[[User:Z3331330|Z3331330]] 10:03, 19 September 2012 (EST)
Lab 9--[[User:Z3331330|Z3331330]] 10:08, 26 September 2012 (EST)
Lab 10--[[User:Z3331330|Z3331330]] 10:10, 3 October 2012 (EST)
Lab 11--[[User:Z3331330|Z3331330]] 10:07, 10 October 2012 (EST)

==Lab 1 Assessment==
(1)Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.

Many studies and experiments were conducted and they all contributed to the development of In Vitro Fertilization as it is today. Some early studies have used hamster gametes to prove the possibility of mammalian gametes being fertilized in vitro, done by Yanagimachi and Chang in1963. Chang, in 1959 has also done a study that demonstrated the normal development of a rabbit egg that was fertilized in vitro. Numerous experiments were done using different animals and species which proved the success of in vitro fertilization. Capacitation of the sperm in the uterus of the mother was a significant discovery to in vitro fertilisation. On July 25, 1978, the first successful 'test-tube' baby was born. Dr. Patrick Steptoe, a gynecologist and Dr. Robert Edwards, a physiologist, the team who pioneered the IVF were accredited for their contribution to IVF.

In 2010, Robert Edwards was awarded the 'Nobel prize in physiology or medicine' for his contribution in the development of "In Vitro Fertilization", see [http://www.nobelprize.org/]

(2)Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).

'Genes required for the common miracle of fertilization in Caenorhabditis Elegans' <ref><pubmed>18649278</pubmed></ref>

Fertilization is a result of various sperm-egg interactions and together these interactions lead to gamete fusions and egg activation.This paper describes the identity of genes that are responsible for the interactions between gametes during ferilization and the function of protein products that are produced by these specific genes. The paper focuses on the fertilization process in Caenorhabditis Elegans which is a type of worm. There are two main types of molecules that are essential in fertilization and they are sperm function molecules and egg function molecules. Spe-9 gene produces a single-pass transmembrane molecules with extracellular domain that contain 10 epidermal growth factor and it is responsible for adhesion or ligand receptor functions. Its critical presence on the surface of the sperm allow the sperm to bind to the oocytes during fertilization. Other genes such as Spe-38 is also identified with similar function.

Egg function genes such as egg-1 and egg-2 genes lead to the production of type II transmembrane molecules. Loss of these gene can lead to complete hermaphrodite fertility. Sperms will not be able to enter the oocytes.The main function of these genes is to act as oocyte surface receptor for sperms during fertilization. These discoveries and results in C.elegans provide a blueprint of the genetic control involved in the process of fertilization and encouraged discoveries of similar genes that are involved in fertilization in humans.

--[[User:Z8600021|Mark Hill]] 16:30, 11 September 2012 (EST) Question 1 is answered well and I like that you have discussed earlier research. Question 1 is also answered well, though a 2008 paper is not as recent as I was seeking as an answer. You will need to fix your referencing (ref 1 is blank because it is incorrectly formatted and should only contain the PMID (not PMC number) number without text)'''10/10'''

==lab 2 assessment==
===Degradation of ooctyes by sperm proteasomes===
--[[User:Z8600021|Mark Hill]] 16:49, 11 September 2012 (EST) This should be a sub-heading.

(1)[[File:Degradation_of_oocytes_by_sperm_proteasomes.png‎]]

(2) Rac-1 is a member of the Rho GTPases family of proteins. It was discovered that with the activation of the Rac-1 gene, its protein product can regulate the motility of the human endometrial stromal cells (HESCs) in reponse to the implantation of the embryo in the uterine wall. Rac-1 promotes the lamellipodial protrusion at front of the migrating cells. This protein also encourage the migration of HESCs away from the implantation site which then facilitate the invasion of trophoblast and lead to the inplantation of the embryo into the stromal compartment. <ref><pubmed>PMC2562412</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:32, 11 September 2012 (EST) Question 1 image is well named and contains all the requested information. Though the image is quite small 320 × 399 pixels and a larger version should have been sourced, also png files are quite large 125 KB, jpg are smaller). You have also misinterpreted my request as the file name should be a sub-heading on the file summary page, not here. Question 2 is also relevant to implantation. Rac proteins regulate the actin cytoskeleton and this is further explored in the 3rd year Cell Biology course. '''10/10'''

==Lab 3 assessment==

(1)Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

Answer: Gestational age is classified as the time elapsed from the first day of a women's last menstrual period, and the post-fertilization age is referred as the time since the fertilzation of the egg in the woman's uterus. The main difference is their starting date and gestational age is often two weeks earlier than the post-fertilization age. Clinically, gestational age is often used in describing human development because the start date of the gestational age can be clearly defined while the exact time of fertilization can be confusing. It is also essential for predicting consequences to the development of fetus from toxin exposure of infection during the gestational age.It is also important for evaluation of physical findings such as fetal growth and screening markers.

(2)Identify using histological descriptions at least 3 different types of tissues formed from somites.

3 types of tissues formed from somites:
- dermatome --> Skin are formed from dermatome. There are 3 layers to skin, epidermis which contain stratified squamous cells with epidermal ridges with thick layer of keratin. Dermis layer contain a lot of the vasculature such as blood vessels and glands, there are also dense collagen and irregular elastic fibres. Usually, this layer contains a lot of type I collagen fibre. The last layer is the hypodermis layer where its mainly adipose tissue.

- myotome--> skeletal muscle are developed from myotome. Skeletal muscle has a lot of myocytes and they are long and elongated with multiple nucleus. Their nucleus are often pushed to the periphery of the cells. They also contain myosin and actin which are called the thick and thin filament which cause striation appearance of the muscle cells.

- Sclerotome--> vertebrae and rib cartilages are developed from it, where different type of bone cells are present. The extracellular matrix of bone is formed through inorganic material such as phosphate along with some organic component being collagen fibres and ground substance.

--[[User:Z8600021|Mark Hill]] 16:41, 11 September 2012 (EST) Question 1 has been clearly and correctly answered. Question 2 the somite compartments and major tissues correctly identified. The one error is the answer for dermatome suggests that the epidermis is also a component of this compartment, while it is ectodermal in origin. '''9/10'''

==Lab 4 assessment==

(1)Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

The first invasive prenatal diagnostic techniques is called "chorionic villus sampling" and it involves a catheter passed via the vagina through the cervix and into the uterus to the placenta, under the guidance of ultrasound. There can be other approaches as well such as transvaginal and transabdominal. The catheter will then collect sample of the chorionic villus which is placental tissue. The sample will then be analyse for any chromosomal abnormalities or genetic disorders, and the karotype of the fetus will be determined.

The second technique is "Placental biopsy", it is similiar to the chorionic villus sampling, but it has a transabdominal approach to it. It can be performed at a later stage of the pregnancy. It is used to obtain a rapid result. The karyotype of the fetus can be determined and genetic disorders can be detected such as trisomy 21 and monosomy X.

(2)Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

"Transplantation of microencapsulated umbilical-cord-bloodderived hepatic-like cells for treatment of hepatic failure" [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3051145/?tool=pmcentrez]

The paper aim to investigate intraperitoneal transplantation of microencapsulated hepatic-like cells from human umbilical cord blood for treatment of hepatic failure in rats. There are a few candidates for this experiment but human umbilical cord blood (UCB) cells were thought to be the best as they have some advantages that other cells do not have. The frequencies of UCB hematopoietic stem or progenitor cells is much higher than those from bone marrow and peripheral blood. The paper also mentioned that there are three ways of inducing the UCB cells into hepatocytes-like cells and they are Co-culture with injured liver cell, growth factor-assisted and MNC transplantation.

In the experiment, CD34 cells are isolated from the UCB cells and through the combination of fibroblast growth factor and hepatocyte growth factor, the CD34 cells are induced to hepatocytes-like cells.
It was found that in the cultured cells, the level of human albumin, alpha-fetoprotein and GATA-4 mRNA and albumin positive cells have increased significantly suggesting the transformation of the CD34 cells into hepatic-like cells. The cultured system with growth factors have the ability to convert these UCB cells into hepatocytes phenotype and it is confirmed through PCR and immunohistochemcial staining. Then these hepatic-like cells are encapsulated and transplanted into the abdominal cavity of rats with acute hepatic failure. The transplantation occurs 48 hours after the onset of an acute hepatic failure.The microencapsulation of the cells provide a possibility to overcome the immuno-rejection from the AHF rats.

The result obtained from this experiment was that CD34 cells from the UCB cells can be converted into hepatic-like cells under suitable conditions with appropriate growth factors. The transplantation of these encapsulated hepatic-like cells have resulted in decreased mortality of the AHF rats. But these hepatic-like cells can only offer short term metabolic effect to these AHF rats and cannot interrupt or repair the damaged hepatocytes. Therefore the conclusion of this paper suggests the possibility of UCB cells used in conversion to hepatic-like cells that can temporarily alleviate the symptoms of Acute hepatic failure in rats bur not regenerating healthy hepatocytes. <ref><pubmed>PMC3051145</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:46, 11 September 2012 (EST) Question 1 You have clearly identified 2 invasive techniques diagnostic techniques. I would have liked specific disorders for the first technique, as you have for the second technique. Question 2 this is an excellent description of the paper and technique. You have used the UCB acronym correctly (citing in full the first time), though you still have problems in formatting your reference links, which only require the PMID number to link correctly. '''10/10'''

==Lab 7 assessment==
(1) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?

It is a mononuclear stem cell that are found in mature skeletal muscle fibres and promote their growth, repair and regeneration, they are usually situated between sarcolemma and basement membrane of muscle fibres.

Satellite cells are activated after muscle strains such as trauma, where myogenic regulatory factors will be expressed and they are similar to those produced by muscle precursor cells during muscle development. These cells proliferate and fuse with each other to form myotubes and slowly mature into myofibres. They can also fuse with damaged segments of muscle fibres. These cells can also give rise to new satellite cells. Heavy exercise can induce muscle hypertrophy which also encourage the growth and proliferation of these muscle satellite cells.

(2)In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?

In situations of long term motor nerve damage, since skeletal muscles are activated by these motor nerves, when they are damaged, the muscles will often lose their function and movement. There can be a complete loss of function or only a part of, depending on the severity of the damage to the nerve. When the muscle lose their initiation, they can present symptoms such as muscle twitching, cramping and muscle can become stiff due to the lack of movement. Muscles paralysed by spinal cord injury are usually atrophic, possesses lower tension generating capacity and is less fatigue resistant compared to normal muscles. Upper motor neuron paralysed muscles lose the normal type I (slow) and II (fast) fibre and become predominantly composed of type II (fast glycolytic) fibres. A transitional period can be seen ranging from 1 to 20 months after the injury where there is usually drop in the proportion of slow muscle fibres and a rise in the development of fast fibres.

==Lab 8 assessment==

''Vision''

I really liked the eye image at the top of the project page, it automatically drags my attention towards the page and it clearly shows what the project is going to be focused on. The introduction was good, its not too long but provide sufficient information about the project and as reader, we know what we can expect from the project page. The image used there is very good as well but maybe more labelling and explanation can be included.

Images from the textbook, Atlas of the development of men, both on the development of lens and the formation of optic vesicle, they are really good. I understand that the page is not complete yet, but just looking at these images, a lot of explanation and labelling need to be put in to ensure that readers know what is going on and actually learn from those images. The development of the optic nerve is good. Information provided is clear and precise. The whole process of the development was explained well and used simple terms so that it is very easy to follow and understand but maybe the images need to be labelled more? I saw that this section of the project, only 1-2 references is used? Maybe try to expand the research and include more information from different sources. I really liked the way that most of the images are hand-drawn, this really shows that you understand the process yourself and able to interpret all the knowledge you gathered from resources and produce something that is easy to understand and can actually teach readers about vision development.

There is a glossary at the end of the page which includes all the scientific terms, maybe expand this section a little bit more. Some scientific words are not included such as mesenchyme, as a science student, maybe we will understand these words but for the general public, they may not. That's why it is essential to have a glossary. I thought having an image gallery was a good idea, in that way, people can concentrate on only the image aspect of the project without all the text in between, allowing a different approach in looking at this project. Referencing of the project overall was good, except there is one citing error, no.13? But this should be quite easy to fix. In terms of variety of resources used, i thought was quite narrow, with the majority resources being websites and lab material from the course. Maybe use more journal articles and reviews to expand the depth of the information presented. The structure and the lay out of the page is very clear with consistent headings and sub-headings, which makes the page very easy to read and follow.

Overall, the project page is looking good.There are just some minor parts to be completed and maybe a little bit more research needs to be done. :) hope this helps.
--Z3331330 18:35, 23 September 2012 (EST)

''Somatosensory''

The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?
The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

''Taste''

The introduction is very detailed but did not mention anything about the development of the taste. But I thought the mechanisms behind sweet and salty tastes are very interesting. Maybe do the same for the other 3 tastes? The image of the basic 5 tastes is a bit small, maybe upload a bigger version of the image. Also, the image is lacking some reference, copyright information and a student image template.

The type II receptor section is pretty good and descriptive but it does not really relate to the development of the taste. The taste map is a very eye-catchy image and it would be really useful if it had all the needed information such as the copyright notice. The timeline of the gustatory system is very well-presented and easy to read. I understand the project is not completed yet, therefore more images are still to be put in. Only 2 references have been used in the timeline section, maybe try to research more and use different resources. There are some citing error but it should be quite easy to fix.

Histories of discoveries section is very detailed and easy to read but the referencing needs to be fixed. The adult tongue and taste bud section is very clear and precise and contain a lot of useful information but it does not really relate to the research topic, should beware of going off-track. The hand-drawn diagram of the taste bud is impressive and easy to understand but again lacking in some referencing information such as who drew it. The abnormalities section is good and well-researched and it is interesting to know about which gene or receptors will effect the development of taste and sensation. Maybe the abnormalities section can be included into the current research section because abnormalities are repeated in the current research section below. There are detailed definitions of terms in the glossary which is good because it really helps the reader to understand more about the research topic.

Overall, the page is looking good. The main thing that needs to be fixed will be the images that are already on the page, they need the correct and essential information with them when uploaded on the page or else, they will get deleted and there will be no images on the page and the nice balance of images and text now will be gone. There seem to be a lot of anatomy and biology of the taste system but not a lot of information about their development. Although there is a timeline of development but i think more information is needed. Referencing is pretty good with only one or two minor citing error but it should be easy to fix. Structure of the page is clear and simple with headings and sub-headings being consistent, making the page easy to read and follow. Hope this helps :)

''Olfaction''

The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.
The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

''Hearing''

Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

==Lab 9 assessment==

(1)Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

'Stam2 expression pattern during embryo development.'

Signal transduction adaptor molecules 1 and 2 (STAM1 and STAM2). They are both involved in the endosomal sorting of the cargo proteins for trafficking towards the lysosome. STAM2 is activated by tyrosine phosphorylation and can also be stimulated by various cytokines and growth factors. It is involved in the regulation of endocytosis and also regulation of intracellular signal transduction for DNA synthesis through JAK2 and JAK3 tyrosine kinases.

In the paper, a mouse line have been created to enable the expression of STAM2 to be observed by X-gal histochemistry. At around embryonic day 16.5, it is evident that STAM2 is expressed in the heart, testes, olfactory bulbs, trigeminal and dorsal root ganglia, pituitary and medulla of the adrenal glands. Around embryonic day 18.5, the expression of STAM2 become much stronger, especially in areas of testes, ovaries, lungs, kidneys, urogenital sinus, pituitary and adrenal glands. Near the end of gestation, STAM2 expression is confined to regions such as nervous tissue, and endocrine organs like pituitary and adrenal glands and they are already highly secretory active at this stage of embryonic development. This paper demonstrates a very strong correlation between the development of the adrenal glands and the expression of STAM2. <ref><pubmed>22143071</pubmed></ref>

(2)Identify the embryonic layers and tissues that contribute to the developing teeth.

Teeth are formed from cells that derived from the ectoderm of the first branchial arch and the ectomesenchyme of the neural crest and also mesoderm.It is organized into 3 parts, the enamel organ, the dental papilla and the dental follicle. The enamel organ give rise to ameloblasts which produce enamel and the reduced enamel epithelium and ultimately determines the root shape of the tooth.The dental papilla contains cells that develop into odontoblasts which determines the crown shape of a tooth. Mesenchymal cells in the dental papilla are for the formation of tooth pulp. The dental follicle contribute to cementoblasts which form the cementum of the tooth, osteoblasts which give rise to the alveolar bone and fibroblasts give rise to periodontal ligamtns.

==Lab 11 assessment==

(1)Identify a recent research article (using the pubmed tags to cite) on iPS cells and summarise in a few paragraphs the main findings of the paper.

'Two-step differentiation of mast cells from induced pluripotent stem cells.'

Mast cells are responsible for the pathogenesis of many allergic diseases in the human body. There are mainly two types of mast cells and they are connective tissue type mast cells (CTMCs) and mucosal-type mast cells. This study aim to report on the generation and characterisation of connective tissue type mast cells that are derived from induced pluripotent stem cells (iPS cells) that originated from mouse. Mast cells are generated from mouse iPS cells and are characterised from several aspects including morphology, function and gene expression.

The study generated mast cells and differentiated them from mouse iPS cells from two major methods. The first one is by co-culturing the mouse iPS cells with OP9 stromal cells and the second one is the embryoid body formation method. With these two methods, they were able to produce mast cells that have characteristics similiar to CTMCs. When mouse iPS cells were generated with the OP9 stromal cells and also co-cultured with Swiss 3T3 fibroblasts, the result of the generation was that the mast cells exhibit even more of a functional phenotype. Therefore, the study provided a protocol with two step differentiation which allows the transformation of mouse iPS cells to mast cells. The two differentiation method was co-culture with OP9 stromal cells and co-culture with Swiss 3T3 fibroblasts.

The protocol provided by this study consist of mesoderm induction, mast cell specification, differentiation and maturation of mast cells from mouse iPS cells. The study also suggested a few cytokines and feeder cells that were essential for the development of iPS cells to mast cells. Interleukin-3 has been recgonised and considered to play a very important role in the differentiation of mast cells. OP9 cells may not be necessary for the specification of mast cells but it promotes the maturation of them. Swiss 3T3 fibroblasts have been proved to be essential for the maturation of the mast cells from mouse iPS cells. The successful protocol generated from the study has provided a novel method for more efficient generation of mast cells from mouse iPS cells, with the production of more mature mast cells. <ref><pubmed>23045993</pubmed></ref>

===References===
<references/>

User:Z3331330

2012-10-09T23:08:02Z

Z3331330: /* Lab Attendance */

==Lab Attendance==

Lab 1--[[User:Z3331330|Z3331330]] 11:49, 25 July 2012 (EST)
Lab 2--[[User:Z3331330|Z3331330]] 10:41, 1 August 2012 (EST)
Lab 3--[[User:Z3331330|Z3331330]] 13:00, 8 August 2012 (EST)
Lab 4--[[User:Z3331330|Z3331330]] 10:07, 15 August 2012 (EST)
Lab 5--[[User:Z3331330|Z3331330]] 10:08, 22 August 2012 (EST)
Lab 6--[[User:Z3331330|Z3331330]] 10:10, 29 August 2012 (EST)
Lab 7--[[User:Z3331330|Z3331330]] 10:05, 12 September 2012 (EST)
Lab 8--[[User:Z3331330|Z3331330]] 10:03, 19 September 2012 (EST)
Lab 9--[[User:Z3331330|Z3331330]] 10:08, 26 September 2012 (EST)
Lab 10--[[User:Z3331330|Z3331330]] 10:10, 3 October 2012 (EST)
Lab 11--[[User:Z3331330|Z3331330]] 10:07, 10 October 2012 (EST)

==Lab 1 Assessment==
(1)Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.

Many studies and experiments were conducted and they all contributed to the development of In Vitro Fertilization as it is today. Some early studies have used hamster gametes to prove the possibility of mammalian gametes being fertilized in vitro, done by Yanagimachi and Chang in1963. Chang, in 1959 has also done a study that demonstrated the normal development of a rabbit egg that was fertilized in vitro. Numerous experiments were done using different animals and species which proved the success of in vitro fertilization. Capacitation of the sperm in the uterus of the mother was a significant discovery to in vitro fertilisation. On July 25, 1978, the first successful 'test-tube' baby was born. Dr. Patrick Steptoe, a gynecologist and Dr. Robert Edwards, a physiologist, the team who pioneered the IVF were accredited for their contribution to IVF.

In 2010, Robert Edwards was awarded the 'Nobel prize in physiology or medicine' for his contribution in the development of "In Vitro Fertilization", see [http://www.nobelprize.org/]

(2)Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).

'Genes required for the common miracle of fertilization in Caenorhabditis Elegans' <ref><pubmed>18649278</pubmed></ref>

Fertilization is a result of various sperm-egg interactions and together these interactions lead to gamete fusions and egg activation.This paper describes the identity of genes that are responsible for the interactions between gametes during ferilization and the function of protein products that are produced by these specific genes. The paper focuses on the fertilization process in Caenorhabditis Elegans which is a type of worm. There are two main types of molecules that are essential in fertilization and they are sperm function molecules and egg function molecules. Spe-9 gene produces a single-pass transmembrane molecules with extracellular domain that contain 10 epidermal growth factor and it is responsible for adhesion or ligand receptor functions. Its critical presence on the surface of the sperm allow the sperm to bind to the oocytes during fertilization. Other genes such as Spe-38 is also identified with similar function.

Egg function genes such as egg-1 and egg-2 genes lead to the production of type II transmembrane molecules. Loss of these gene can lead to complete hermaphrodite fertility. Sperms will not be able to enter the oocytes.The main function of these genes is to act as oocyte surface receptor for sperms during fertilization. These discoveries and results in C.elegans provide a blueprint of the genetic control involved in the process of fertilization and encouraged discoveries of similar genes that are involved in fertilization in humans.

--[[User:Z8600021|Mark Hill]] 16:30, 11 September 2012 (EST) Question 1 is answered well and I like that you have discussed earlier research. Question 1 is also answered well, though a 2008 paper is not as recent as I was seeking as an answer. You will need to fix your referencing (ref 1 is blank because it is incorrectly formatted and should only contain the PMID (not PMC number) number without text)'''10/10'''

==lab 2 assessment==
===Degradation of ooctyes by sperm proteasomes===
--[[User:Z8600021|Mark Hill]] 16:49, 11 September 2012 (EST) This should be a sub-heading.

(1)[[File:Degradation_of_oocytes_by_sperm_proteasomes.png‎]]

(2) Rac-1 is a member of the Rho GTPases family of proteins. It was discovered that with the activation of the Rac-1 gene, its protein product can regulate the motility of the human endometrial stromal cells (HESCs) in reponse to the implantation of the embryo in the uterine wall. Rac-1 promotes the lamellipodial protrusion at front of the migrating cells. This protein also encourage the migration of HESCs away from the implantation site which then facilitate the invasion of trophoblast and lead to the inplantation of the embryo into the stromal compartment. <ref><pubmed>PMC2562412</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:32, 11 September 2012 (EST) Question 1 image is well named and contains all the requested information. Though the image is quite small 320 × 399 pixels and a larger version should have been sourced, also png files are quite large 125 KB, jpg are smaller). You have also misinterpreted my request as the file name should be a sub-heading on the file summary page, not here. Question 2 is also relevant to implantation. Rac proteins regulate the actin cytoskeleton and this is further explored in the 3rd year Cell Biology course. '''10/10'''

==Lab 3 assessment==

(1)Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

Answer: Gestational age is classified as the time elapsed from the first day of a women's last menstrual period, and the post-fertilization age is referred as the time since the fertilzation of the egg in the woman's uterus. The main difference is their starting date and gestational age is often two weeks earlier than the post-fertilization age. Clinically, gestational age is often used in describing human development because the start date of the gestational age can be clearly defined while the exact time of fertilization can be confusing. It is also essential for predicting consequences to the development of fetus from toxin exposure of infection during the gestational age.It is also important for evaluation of physical findings such as fetal growth and screening markers.

(2)Identify using histological descriptions at least 3 different types of tissues formed from somites.

3 types of tissues formed from somites:
- dermatome --> Skin are formed from dermatome. There are 3 layers to skin, epidermis which contain stratified squamous cells with epidermal ridges with thick layer of keratin. Dermis layer contain a lot of the vasculature such as blood vessels and glands, there are also dense collagen and irregular elastic fibres. Usually, this layer contains a lot of type I collagen fibre. The last layer is the hypodermis layer where its mainly adipose tissue.

- myotome--> skeletal muscle are developed from myotome. Skeletal muscle has a lot of myocytes and they are long and elongated with multiple nucleus. Their nucleus are often pushed to the periphery of the cells. They also contain myosin and actin which are called the thick and thin filament which cause striation appearance of the muscle cells.

- Sclerotome--> vertebrae and rib cartilages are developed from it, where different type of bone cells are present. The extracellular matrix of bone is formed through inorganic material such as phosphate along with some organic component being collagen fibres and ground substance.

--[[User:Z8600021|Mark Hill]] 16:41, 11 September 2012 (EST) Question 1 has been clearly and correctly answered. Question 2 the somite compartments and major tissues correctly identified. The one error is the answer for dermatome suggests that the epidermis is also a component of this compartment, while it is ectodermal in origin. '''9/10'''

==Lab 4 assessment==

(1)Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

The first invasive prenatal diagnostic techniques is called "chorionic villus sampling" and it involves a catheter passed via the vagina through the cervix and into the uterus to the placenta, under the guidance of ultrasound. There can be other approaches as well such as transvaginal and transabdominal. The catheter will then collect sample of the chorionic villus which is placental tissue. The sample will then be analyse for any chromosomal abnormalities or genetic disorders, and the karotype of the fetus will be determined.

The second technique is "Placental biopsy", it is similiar to the chorionic villus sampling, but it has a transabdominal approach to it. It can be performed at a later stage of the pregnancy. It is used to obtain a rapid result. The karyotype of the fetus can be determined and genetic disorders can be detected such as trisomy 21 and monosomy X.

(2)Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

"Transplantation of microencapsulated umbilical-cord-bloodderived hepatic-like cells for treatment of hepatic failure" [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3051145/?tool=pmcentrez]

The paper aim to investigate intraperitoneal transplantation of microencapsulated hepatic-like cells from human umbilical cord blood for treatment of hepatic failure in rats. There are a few candidates for this experiment but human umbilical cord blood (UCB) cells were thought to be the best as they have some advantages that other cells do not have. The frequencies of UCB hematopoietic stem or progenitor cells is much higher than those from bone marrow and peripheral blood. The paper also mentioned that there are three ways of inducing the UCB cells into hepatocytes-like cells and they are Co-culture with injured liver cell, growth factor-assisted and MNC transplantation.

In the experiment, CD34 cells are isolated from the UCB cells and through the combination of fibroblast growth factor and hepatocyte growth factor, the CD34 cells are induced to hepatocytes-like cells.
It was found that in the cultured cells, the level of human albumin, alpha-fetoprotein and GATA-4 mRNA and albumin positive cells have increased significantly suggesting the transformation of the CD34 cells into hepatic-like cells. The cultured system with growth factors have the ability to convert these UCB cells into hepatocytes phenotype and it is confirmed through PCR and immunohistochemcial staining. Then these hepatic-like cells are encapsulated and transplanted into the abdominal cavity of rats with acute hepatic failure. The transplantation occurs 48 hours after the onset of an acute hepatic failure.The microencapsulation of the cells provide a possibility to overcome the immuno-rejection from the AHF rats.

The result obtained from this experiment was that CD34 cells from the UCB cells can be converted into hepatic-like cells under suitable conditions with appropriate growth factors. The transplantation of these encapsulated hepatic-like cells have resulted in decreased mortality of the AHF rats. But these hepatic-like cells can only offer short term metabolic effect to these AHF rats and cannot interrupt or repair the damaged hepatocytes. Therefore the conclusion of this paper suggests the possibility of UCB cells used in conversion to hepatic-like cells that can temporarily alleviate the symptoms of Acute hepatic failure in rats bur not regenerating healthy hepatocytes. <ref><pubmed>PMC3051145</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:46, 11 September 2012 (EST) Question 1 You have clearly identified 2 invasive techniques diagnostic techniques. I would have liked specific disorders for the first technique, as you have for the second technique. Question 2 this is an excellent description of the paper and technique. You have used the UCB acronym correctly (citing in full the first time), though you still have problems in formatting your reference links, which only require the PMID number to link correctly. '''10/10'''

==Lab 7 assessment==
(1) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?

It is a mononuclear stem cell that are found in mature skeletal muscle fibres and promote their growth, repair and regeneration, they are usually situated between sarcolemma and basement membrane of muscle fibres.

Satellite cells are activated after muscle strains such as trauma, where myogenic regulatory factors will be expressed and they are similar to those produced by muscle precursor cells during muscle development. These cells proliferate and fuse with each other to form myotubes and slowly mature into myofibres. They can also fuse with damaged segments of muscle fibres. These cells can also give rise to new satellite cells. Heavy exercise can induce muscle hypertrophy which also encourage the growth and proliferation of these muscle satellite cells.

(2)In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?

In situations of long term motor nerve damage, since skeletal muscles are activated by these motor nerves, when they are damaged, the muscles will often lose their function and movement. There can be a complete loss of function or only a part of, depending on the severity of the damage to the nerve. When the muscle lose their initiation, they can present symptoms such as muscle twitching, cramping and muscle can become stiff due to the lack of movement. Muscles paralysed by spinal cord injury are usually atrophic, possesses lower tension generating capacity and is less fatigue resistant compared to normal muscles. Upper motor neuron paralysed muscles lose the normal type I (slow) and II (fast) fibre and become predominantly composed of type II (fast glycolytic) fibres. A transitional period can be seen ranging from 1 to 20 months after the injury where there is usually drop in the proportion of slow muscle fibres and a rise in the development of fast fibres.

==Lab 8 assessment==

''Vision''

I really liked the eye image at the top of the project page, it automatically drags my attention towards the page and it clearly shows what the project is going to be focused on. The introduction was good, its not too long but provide sufficient information about the project and as reader, we know what we can expect from the project page. The image used there is very good as well but maybe more labelling and explanation can be included.

Images from the textbook, Atlas of the development of men, both on the development of lens and the formation of optic vesicle, they are really good. I understand that the page is not complete yet, but just looking at these images, a lot of explanation and labelling need to be put in to ensure that readers know what is going on and actually learn from those images. The development of the optic nerve is good. Information provided is clear and precise. The whole process of the development was explained well and used simple terms so that it is very easy to follow and understand but maybe the images need to be labelled more? I saw that this section of the project, only 1-2 references is used? Maybe try to expand the research and include more information from different sources. I really liked the way that most of the images are hand-drawn, this really shows that you understand the process yourself and able to interpret all the knowledge you gathered from resources and produce something that is easy to understand and can actually teach readers about vision development.

There is a glossary at the end of the page which includes all the scientific terms, maybe expand this section a little bit more. Some scientific words are not included such as mesenchyme, as a science student, maybe we will understand these words but for the general public, they may not. That's why it is essential to have a glossary. I thought having an image gallery was a good idea, in that way, people can concentrate on only the image aspect of the project without all the text in between, allowing a different approach in looking at this project. Referencing of the project overall was good, except there is one citing error, no.13? But this should be quite easy to fix. In terms of variety of resources used, i thought was quite narrow, with the majority resources being websites and lab material from the course. Maybe use more journal articles and reviews to expand the depth of the information presented. The structure and the lay out of the page is very clear with consistent headings and sub-headings, which makes the page very easy to read and follow.

Overall, the project page is looking good.There are just some minor parts to be completed and maybe a little bit more research needs to be done. :) hope this helps.
--Z3331330 18:35, 23 September 2012 (EST)

''Somatosensory''

The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?
The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

''Taste''

The introduction is very detailed but did not mention anything about the development of the taste. But I thought the mechanisms behind sweet and salty tastes are very interesting. Maybe do the same for the other 3 tastes? The image of the basic 5 tastes is a bit small, maybe upload a bigger version of the image. Also, the image is lacking some reference, copyright information and a student image template.

The type II receptor section is pretty good and descriptive but it does not really relate to the development of the taste. The taste map is a very eye-catchy image and it would be really useful if it had all the needed information such as the copyright notice. The timeline of the gustatory system is very well-presented and easy to read. I understand the project is not completed yet, therefore more images are still to be put in. Only 2 references have been used in the timeline section, maybe try to research more and use different resources. There are some citing error but it should be quite easy to fix.

Histories of discoveries section is very detailed and easy to read but the referencing needs to be fixed. The adult tongue and taste bud section is very clear and precise and contain a lot of useful information but it does not really relate to the research topic, should beware of going off-track. The hand-drawn diagram of the taste bud is impressive and easy to understand but again lacking in some referencing information such as who drew it. The abnormalities section is good and well-researched and it is interesting to know about which gene or receptors will effect the development of taste and sensation. Maybe the abnormalities section can be included into the current research section because abnormalities are repeated in the current research section below. There are detailed definitions of terms in the glossary which is good because it really helps the reader to understand more about the research topic.

Overall, the page is looking good. The main thing that needs to be fixed will be the images that are already on the page, they need the correct and essential information with them when uploaded on the page or else, they will get deleted and there will be no images on the page and the nice balance of images and text now will be gone. There seem to be a lot of anatomy and biology of the taste system but not a lot of information about their development. Although there is a timeline of development but i think more information is needed. Referencing is pretty good with only one or two minor citing error but it should be easy to fix. Structure of the page is clear and simple with headings and sub-headings being consistent, making the page easy to read and follow. Hope this helps :)

''Olfaction''

The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.
The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

''Hearing''

Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

==Lab 9 assessment==

(1)Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

'Stam2 expression pattern during embryo development.'

Signal transduction adaptor molecules 1 and 2 (STAM1 and STAM2). They are both involved in the endosomal sorting of the cargo proteins for trafficking towards the lysosome. STAM2 is activated by tyrosine phosphorylation and can also be stimulated by various cytokines and growth factors. It is involved in the regulation of endocytosis and also regulation of intracellular signal transduction for DNA synthesis through JAK2 and JAK3 tyrosine kinases.

In the paper, a mouse line have been created to enable the expression of STAM2 to be observed by X-gal histochemistry. At around embryonic day 16.5, it is evident that STAM2 is expressed in the heart, testes, olfactory bulbs, trigeminal and dorsal root ganglia, pituitary and medulla of the adrenal glands. Around embryonic day 18.5, the expression of STAM2 become much stronger, especially in areas of testes, ovaries, lungs, kidneys, urogenital sinus, pituitary and adrenal glands. Near the end of gestation, STAM2 expression is confined to regions such as nervous tissue, and endocrine organs like pituitary and adrenal glands and they are already highly secretory active at this stage of embryonic development. This paper demonstrates a very strong correlation between the development of the adrenal glands and the expression of STAM2. <ref><pubmed>22143071</pubmed></ref>

(2)Identify the embryonic layers and tissues that contribute to the developing teeth.

Teeth are formed from cells that derived from the ectoderm of the first branchial arch and the ectomesenchyme of the neural crest and also mesoderm.It is organized into 3 parts, the enamel organ, the dental papilla and the dental follicle. The enamel organ give rise to ameloblasts which produce enamel and the reduced enamel epithelium and ultimately determines the root shape of the tooth.The dental papilla contains cells that develop into odontoblasts which determines the crown shape of a tooth. Mesenchymal cells in the dental papilla are for the formation of tooth pulp. The dental follicle contribute to cementoblasts which form the cementum of the tooth, osteoblasts which give rise to the alveolar bone and fibroblasts give rise to periodontal ligamtns.

===References===
<references/>

User:Z3331330

2012-10-09T23:07:45Z

Z3331330: /* Lab Attendance */

==Lab Attendance==

Lab 1--[[User:Z3331330|Z3331330]] 11:49, 25 July 2012 (EST)
Lab 2--[[User:Z3331330|Z3331330]] 10:41, 1 August 2012 (EST)
Lab 3--[[User:Z3331330|Z3331330]] 13:00, 8 August 2012 (EST)
Lab 4--[[User:Z3331330|Z3331330]] 10:07, 15 August 2012 (EST)
Lab 5--[[User:Z3331330|Z3331330]] 10:08, 22 August 2012 (EST)
Lab 6--[[User:Z3331330|Z3331330]] 10:10, 29 August 2012 (EST)
Lab 7--[[User:Z3331330|Z3331330]] 10:05, 12 September 2012 (EST)
Lab 8--[[User:Z3331330|Z3331330]] 10:03, 19 September 2012 (EST)
Lab 9--[[User:Z3331330|Z3331330]] 10:08, 26 September 2012 (EST)
Lab 10--[[User:Z3331330|Z3331330]] 10:10, 3 October 2012 (EST)
--[[User:Z3331330|Z3331330]] 10:07, 10 October 2012 (EST)

==Lab 1 Assessment==
(1)Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.

Many studies and experiments were conducted and they all contributed to the development of In Vitro Fertilization as it is today. Some early studies have used hamster gametes to prove the possibility of mammalian gametes being fertilized in vitro, done by Yanagimachi and Chang in1963. Chang, in 1959 has also done a study that demonstrated the normal development of a rabbit egg that was fertilized in vitro. Numerous experiments were done using different animals and species which proved the success of in vitro fertilization. Capacitation of the sperm in the uterus of the mother was a significant discovery to in vitro fertilisation. On July 25, 1978, the first successful 'test-tube' baby was born. Dr. Patrick Steptoe, a gynecologist and Dr. Robert Edwards, a physiologist, the team who pioneered the IVF were accredited for their contribution to IVF.

In 2010, Robert Edwards was awarded the 'Nobel prize in physiology or medicine' for his contribution in the development of "In Vitro Fertilization", see [http://www.nobelprize.org/]

(2)Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).

'Genes required for the common miracle of fertilization in Caenorhabditis Elegans' <ref><pubmed>18649278</pubmed></ref>

Fertilization is a result of various sperm-egg interactions and together these interactions lead to gamete fusions and egg activation.This paper describes the identity of genes that are responsible for the interactions between gametes during ferilization and the function of protein products that are produced by these specific genes. The paper focuses on the fertilization process in Caenorhabditis Elegans which is a type of worm. There are two main types of molecules that are essential in fertilization and they are sperm function molecules and egg function molecules. Spe-9 gene produces a single-pass transmembrane molecules with extracellular domain that contain 10 epidermal growth factor and it is responsible for adhesion or ligand receptor functions. Its critical presence on the surface of the sperm allow the sperm to bind to the oocytes during fertilization. Other genes such as Spe-38 is also identified with similar function.

Egg function genes such as egg-1 and egg-2 genes lead to the production of type II transmembrane molecules. Loss of these gene can lead to complete hermaphrodite fertility. Sperms will not be able to enter the oocytes.The main function of these genes is to act as oocyte surface receptor for sperms during fertilization. These discoveries and results in C.elegans provide a blueprint of the genetic control involved in the process of fertilization and encouraged discoveries of similar genes that are involved in fertilization in humans.

--[[User:Z8600021|Mark Hill]] 16:30, 11 September 2012 (EST) Question 1 is answered well and I like that you have discussed earlier research. Question 1 is also answered well, though a 2008 paper is not as recent as I was seeking as an answer. You will need to fix your referencing (ref 1 is blank because it is incorrectly formatted and should only contain the PMID (not PMC number) number without text)'''10/10'''

==lab 2 assessment==
===Degradation of ooctyes by sperm proteasomes===
--[[User:Z8600021|Mark Hill]] 16:49, 11 September 2012 (EST) This should be a sub-heading.

(1)[[File:Degradation_of_oocytes_by_sperm_proteasomes.png‎]]

(2) Rac-1 is a member of the Rho GTPases family of proteins. It was discovered that with the activation of the Rac-1 gene, its protein product can regulate the motility of the human endometrial stromal cells (HESCs) in reponse to the implantation of the embryo in the uterine wall. Rac-1 promotes the lamellipodial protrusion at front of the migrating cells. This protein also encourage the migration of HESCs away from the implantation site which then facilitate the invasion of trophoblast and lead to the inplantation of the embryo into the stromal compartment. <ref><pubmed>PMC2562412</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:32, 11 September 2012 (EST) Question 1 image is well named and contains all the requested information. Though the image is quite small 320 × 399 pixels and a larger version should have been sourced, also png files are quite large 125 KB, jpg are smaller). You have also misinterpreted my request as the file name should be a sub-heading on the file summary page, not here. Question 2 is also relevant to implantation. Rac proteins regulate the actin cytoskeleton and this is further explored in the 3rd year Cell Biology course. '''10/10'''

==Lab 3 assessment==

(1)Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

Answer: Gestational age is classified as the time elapsed from the first day of a women's last menstrual period, and the post-fertilization age is referred as the time since the fertilzation of the egg in the woman's uterus. The main difference is their starting date and gestational age is often two weeks earlier than the post-fertilization age. Clinically, gestational age is often used in describing human development because the start date of the gestational age can be clearly defined while the exact time of fertilization can be confusing. It is also essential for predicting consequences to the development of fetus from toxin exposure of infection during the gestational age.It is also important for evaluation of physical findings such as fetal growth and screening markers.

(2)Identify using histological descriptions at least 3 different types of tissues formed from somites.

3 types of tissues formed from somites:
- dermatome --> Skin are formed from dermatome. There are 3 layers to skin, epidermis which contain stratified squamous cells with epidermal ridges with thick layer of keratin. Dermis layer contain a lot of the vasculature such as blood vessels and glands, there are also dense collagen and irregular elastic fibres. Usually, this layer contains a lot of type I collagen fibre. The last layer is the hypodermis layer where its mainly adipose tissue.

- myotome--> skeletal muscle are developed from myotome. Skeletal muscle has a lot of myocytes and they are long and elongated with multiple nucleus. Their nucleus are often pushed to the periphery of the cells. They also contain myosin and actin which are called the thick and thin filament which cause striation appearance of the muscle cells.

- Sclerotome--> vertebrae and rib cartilages are developed from it, where different type of bone cells are present. The extracellular matrix of bone is formed through inorganic material such as phosphate along with some organic component being collagen fibres and ground substance.

--[[User:Z8600021|Mark Hill]] 16:41, 11 September 2012 (EST) Question 1 has been clearly and correctly answered. Question 2 the somite compartments and major tissues correctly identified. The one error is the answer for dermatome suggests that the epidermis is also a component of this compartment, while it is ectodermal in origin. '''9/10'''

==Lab 4 assessment==

(1)Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

The first invasive prenatal diagnostic techniques is called "chorionic villus sampling" and it involves a catheter passed via the vagina through the cervix and into the uterus to the placenta, under the guidance of ultrasound. There can be other approaches as well such as transvaginal and transabdominal. The catheter will then collect sample of the chorionic villus which is placental tissue. The sample will then be analyse for any chromosomal abnormalities or genetic disorders, and the karotype of the fetus will be determined.

The second technique is "Placental biopsy", it is similiar to the chorionic villus sampling, but it has a transabdominal approach to it. It can be performed at a later stage of the pregnancy. It is used to obtain a rapid result. The karyotype of the fetus can be determined and genetic disorders can be detected such as trisomy 21 and monosomy X.

(2)Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

"Transplantation of microencapsulated umbilical-cord-bloodderived hepatic-like cells for treatment of hepatic failure" [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3051145/?tool=pmcentrez]

The paper aim to investigate intraperitoneal transplantation of microencapsulated hepatic-like cells from human umbilical cord blood for treatment of hepatic failure in rats. There are a few candidates for this experiment but human umbilical cord blood (UCB) cells were thought to be the best as they have some advantages that other cells do not have. The frequencies of UCB hematopoietic stem or progenitor cells is much higher than those from bone marrow and peripheral blood. The paper also mentioned that there are three ways of inducing the UCB cells into hepatocytes-like cells and they are Co-culture with injured liver cell, growth factor-assisted and MNC transplantation.

In the experiment, CD34 cells are isolated from the UCB cells and through the combination of fibroblast growth factor and hepatocyte growth factor, the CD34 cells are induced to hepatocytes-like cells.
It was found that in the cultured cells, the level of human albumin, alpha-fetoprotein and GATA-4 mRNA and albumin positive cells have increased significantly suggesting the transformation of the CD34 cells into hepatic-like cells. The cultured system with growth factors have the ability to convert these UCB cells into hepatocytes phenotype and it is confirmed through PCR and immunohistochemcial staining. Then these hepatic-like cells are encapsulated and transplanted into the abdominal cavity of rats with acute hepatic failure. The transplantation occurs 48 hours after the onset of an acute hepatic failure.The microencapsulation of the cells provide a possibility to overcome the immuno-rejection from the AHF rats.

The result obtained from this experiment was that CD34 cells from the UCB cells can be converted into hepatic-like cells under suitable conditions with appropriate growth factors. The transplantation of these encapsulated hepatic-like cells have resulted in decreased mortality of the AHF rats. But these hepatic-like cells can only offer short term metabolic effect to these AHF rats and cannot interrupt or repair the damaged hepatocytes. Therefore the conclusion of this paper suggests the possibility of UCB cells used in conversion to hepatic-like cells that can temporarily alleviate the symptoms of Acute hepatic failure in rats bur not regenerating healthy hepatocytes. <ref><pubmed>PMC3051145</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:46, 11 September 2012 (EST) Question 1 You have clearly identified 2 invasive techniques diagnostic techniques. I would have liked specific disorders for the first technique, as you have for the second technique. Question 2 this is an excellent description of the paper and technique. You have used the UCB acronym correctly (citing in full the first time), though you still have problems in formatting your reference links, which only require the PMID number to link correctly. '''10/10'''

==Lab 7 assessment==
(1) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?

It is a mononuclear stem cell that are found in mature skeletal muscle fibres and promote their growth, repair and regeneration, they are usually situated between sarcolemma and basement membrane of muscle fibres.

Satellite cells are activated after muscle strains such as trauma, where myogenic regulatory factors will be expressed and they are similar to those produced by muscle precursor cells during muscle development. These cells proliferate and fuse with each other to form myotubes and slowly mature into myofibres. They can also fuse with damaged segments of muscle fibres. These cells can also give rise to new satellite cells. Heavy exercise can induce muscle hypertrophy which also encourage the growth and proliferation of these muscle satellite cells.

(2)In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?

In situations of long term motor nerve damage, since skeletal muscles are activated by these motor nerves, when they are damaged, the muscles will often lose their function and movement. There can be a complete loss of function or only a part of, depending on the severity of the damage to the nerve. When the muscle lose their initiation, they can present symptoms such as muscle twitching, cramping and muscle can become stiff due to the lack of movement. Muscles paralysed by spinal cord injury are usually atrophic, possesses lower tension generating capacity and is less fatigue resistant compared to normal muscles. Upper motor neuron paralysed muscles lose the normal type I (slow) and II (fast) fibre and become predominantly composed of type II (fast glycolytic) fibres. A transitional period can be seen ranging from 1 to 20 months after the injury where there is usually drop in the proportion of slow muscle fibres and a rise in the development of fast fibres.

==Lab 8 assessment==

''Vision''

I really liked the eye image at the top of the project page, it automatically drags my attention towards the page and it clearly shows what the project is going to be focused on. The introduction was good, its not too long but provide sufficient information about the project and as reader, we know what we can expect from the project page. The image used there is very good as well but maybe more labelling and explanation can be included.

Images from the textbook, Atlas of the development of men, both on the development of lens and the formation of optic vesicle, they are really good. I understand that the page is not complete yet, but just looking at these images, a lot of explanation and labelling need to be put in to ensure that readers know what is going on and actually learn from those images. The development of the optic nerve is good. Information provided is clear and precise. The whole process of the development was explained well and used simple terms so that it is very easy to follow and understand but maybe the images need to be labelled more? I saw that this section of the project, only 1-2 references is used? Maybe try to expand the research and include more information from different sources. I really liked the way that most of the images are hand-drawn, this really shows that you understand the process yourself and able to interpret all the knowledge you gathered from resources and produce something that is easy to understand and can actually teach readers about vision development.

There is a glossary at the end of the page which includes all the scientific terms, maybe expand this section a little bit more. Some scientific words are not included such as mesenchyme, as a science student, maybe we will understand these words but for the general public, they may not. That's why it is essential to have a glossary. I thought having an image gallery was a good idea, in that way, people can concentrate on only the image aspect of the project without all the text in between, allowing a different approach in looking at this project. Referencing of the project overall was good, except there is one citing error, no.13? But this should be quite easy to fix. In terms of variety of resources used, i thought was quite narrow, with the majority resources being websites and lab material from the course. Maybe use more journal articles and reviews to expand the depth of the information presented. The structure and the lay out of the page is very clear with consistent headings and sub-headings, which makes the page very easy to read and follow.

Overall, the project page is looking good.There are just some minor parts to be completed and maybe a little bit more research needs to be done. :) hope this helps.
--Z3331330 18:35, 23 September 2012 (EST)

''Somatosensory''

The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?
The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

''Taste''

The introduction is very detailed but did not mention anything about the development of the taste. But I thought the mechanisms behind sweet and salty tastes are very interesting. Maybe do the same for the other 3 tastes? The image of the basic 5 tastes is a bit small, maybe upload a bigger version of the image. Also, the image is lacking some reference, copyright information and a student image template.

The type II receptor section is pretty good and descriptive but it does not really relate to the development of the taste. The taste map is a very eye-catchy image and it would be really useful if it had all the needed information such as the copyright notice. The timeline of the gustatory system is very well-presented and easy to read. I understand the project is not completed yet, therefore more images are still to be put in. Only 2 references have been used in the timeline section, maybe try to research more and use different resources. There are some citing error but it should be quite easy to fix.

Histories of discoveries section is very detailed and easy to read but the referencing needs to be fixed. The adult tongue and taste bud section is very clear and precise and contain a lot of useful information but it does not really relate to the research topic, should beware of going off-track. The hand-drawn diagram of the taste bud is impressive and easy to understand but again lacking in some referencing information such as who drew it. The abnormalities section is good and well-researched and it is interesting to know about which gene or receptors will effect the development of taste and sensation. Maybe the abnormalities section can be included into the current research section because abnormalities are repeated in the current research section below. There are detailed definitions of terms in the glossary which is good because it really helps the reader to understand more about the research topic.

Overall, the page is looking good. The main thing that needs to be fixed will be the images that are already on the page, they need the correct and essential information with them when uploaded on the page or else, they will get deleted and there will be no images on the page and the nice balance of images and text now will be gone. There seem to be a lot of anatomy and biology of the taste system but not a lot of information about their development. Although there is a timeline of development but i think more information is needed. Referencing is pretty good with only one or two minor citing error but it should be easy to fix. Structure of the page is clear and simple with headings and sub-headings being consistent, making the page easy to read and follow. Hope this helps :)

''Olfaction''

The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.
The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

''Hearing''

Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

==Lab 9 assessment==

(1)Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

'Stam2 expression pattern during embryo development.'

Signal transduction adaptor molecules 1 and 2 (STAM1 and STAM2). They are both involved in the endosomal sorting of the cargo proteins for trafficking towards the lysosome. STAM2 is activated by tyrosine phosphorylation and can also be stimulated by various cytokines and growth factors. It is involved in the regulation of endocytosis and also regulation of intracellular signal transduction for DNA synthesis through JAK2 and JAK3 tyrosine kinases.

In the paper, a mouse line have been created to enable the expression of STAM2 to be observed by X-gal histochemistry. At around embryonic day 16.5, it is evident that STAM2 is expressed in the heart, testes, olfactory bulbs, trigeminal and dorsal root ganglia, pituitary and medulla of the adrenal glands. Around embryonic day 18.5, the expression of STAM2 become much stronger, especially in areas of testes, ovaries, lungs, kidneys, urogenital sinus, pituitary and adrenal glands. Near the end of gestation, STAM2 expression is confined to regions such as nervous tissue, and endocrine organs like pituitary and adrenal glands and they are already highly secretory active at this stage of embryonic development. This paper demonstrates a very strong correlation between the development of the adrenal glands and the expression of STAM2. <ref><pubmed>22143071</pubmed></ref>

(2)Identify the embryonic layers and tissues that contribute to the developing teeth.

Teeth are formed from cells that derived from the ectoderm of the first branchial arch and the ectomesenchyme of the neural crest and also mesoderm.It is organized into 3 parts, the enamel organ, the dental papilla and the dental follicle. The enamel organ give rise to ameloblasts which produce enamel and the reduced enamel epithelium and ultimately determines the root shape of the tooth.The dental papilla contains cells that develop into odontoblasts which determines the crown shape of a tooth. Mesenchymal cells in the dental papilla are for the formation of tooth pulp. The dental follicle contribute to cementoblasts which form the cementum of the tooth, osteoblasts which give rise to the alveolar bone and fibroblasts give rise to periodontal ligamtns.

===References===
<references/>

2012 Group Project 5

2012-10-04T12:52:42Z

Z3331330: /* Abnormal Development */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

[[Image:Optic_cup_at_carnegie_stage_17_.jpg‎|thumb|right|Optic Cup at Carnegie Stage 17]]

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
----
'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
----
'''Overview of Normal Retinal Development'''
[[Image:Retinal_Disc_to_form_Optic_Cup_at_Carnegie_stage_14.jpg|thumb|Right|Retinal Disc forming the Optic Cup]]
The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
----
Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
----
The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, [[#Glossary|coloboma]], optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of [[#Glossary|hemifacial asymmetry]]. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref> The aetiology of FAS can be both genetic and nutritional, a list of genes have been identified as potential targets for the [[#Glossary|teratogenic]] effects of alcohol on humans. Some animals studies have suggested nutritional issues are important risk factors that may contribute to FAS. It is evident that plasma zinc and copper concentration are lower in pregnant women that have high alcohol intake, compared to women who only drink lightly or not at all. Zinc can influence on the risk of FAS in humans. <ref name="PMID21425437"><pubmed>21425437</pubmed></ref>

Prenatal exposure to alcohol can cause profound effects and impacts on fetal development. These include alterations to somatic growth and specific minor malformation of facial structures.The most significant and important effect that fetal alcohol syndrome have on fetal development is on brain which may leads to substantial problems with neurobehavioral development. And defect in brain development an cause decreased IQ, hyperactivity, behavioural and adaptive difficulties. Also, there can be deficits in motor function, attention, verbal language and visuo-spatial skills.<ref name="PMID21425437"/>

FAS can also cause alterations to facial structure such as [[#Glossary|coloboma]], hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* ''' Choroid fissure''' - Middle, vascular coat of the eye which resides between the sclera and the retina.

* ''' Coloboma''' - Failure of closure of choroid fissure that should be closed during the 7th week of development

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* ''' Hemifacial asymmetry''' - also known as hemifacial microsomia, there are marked three dimensional asymmetry of various facial structure: the mandible, the ear, the maxilla, the zygoma and the orbit.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Teratrogenic''' - Substances or agents that can interfere with normal embryonic development

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

[http://www.albinism.org/ Albanism and Hypopigmentation Organisation]

[http://www.geneticalliance.org/ Genetic Alliance - advocacy, education & empowerment]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-04T12:52:03Z

Z3331330: /* Abnormal Development */

2012 Group Project 5

2012-10-04T05:56:38Z

Z3331330: /* Anophthalmia and Microphthalmia */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, [[#Glossary|coloboma]], optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of [[#Glossary|hemifacial asymmetry]]. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref> The aetiology of FAS can be both genetic and nutritional, a list of genes have been identified as potential targets for the [[#Glossary|teratogenic]] effects of alcohol on humans. Some animals studies have suggested nutritional issues are important risk factors that may contribute to FAS. It is evident that plasma zinc and copper concentration are lower in pregnant women that have high alcohol intake, compared to women who only drink lightly or not at all. Zinc can influence on the risk of FAS in humans. <ref name="PMID21425437"><pubmed>21425437</pubmed></ref>

Prenatal exposure to alcohol can cause profound effects and impacts on fetal development. These include alterations to somatic growth and specific minor malformation of facial structures.The most significant and important effect that fetal alcohol syndrome have on fetal development is on brain which may leads to substantial problems with neurobehavioral development. And defect in brain development an cause decreased IQ, hyperactivity, behavioural and adaptive difficulties. Also, there can be deficits in motor function, attention, verbal language and visuo-spatial skills.<ref name="PMID21425437"/>

FAS can also cause alterations to facial structure such as [[#Glossary|coloboma]], hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* ''' Choroid fissure''' - Middle, vascular coat of the eye which resides between the sclera and the retina.

* ''' Coloboma''' - Failure of closure of choroid fissure that should be closed during the 7th week of development

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* ''' Hemifacial asymmetry''' - also known as hemifacial microsomia, there are marked three dimensional asymmetry of various facial structure: the mandible, the ear, the maxilla, the zygoma and the orbit.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Teratrogenic''' - Substances or agents that can interfere with normal embryonic development

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 5

2012-10-04T05:51:13Z

Z3331330: /* Glossary */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
----
'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, [[#Glossary|coloboma]], optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref> The aetiology of FAS can be both genetic and nutritional, a list of genes have been identified as potential targets for the [[#Glossary|teratogenic]] effects of alcohol on humans. Some animals studies have suggested nutritional issues are important risk factors that may contribute to FAS. It is evident that plasma zinc and copper concentration are lower in pregnant women that have high alcohol intake, compared to women who only drink lightly or not at all. Zinc can influence on the risk of FAS in humans. <ref name="PMID21425437"><pubmed>21425437</pubmed></ref>

Prenatal exposure to alcohol can cause profound effects and impacts on fetal development. These include alterations to somatic growth and specific minor malformation of facial structures.The most significant and important effect that fetal alcohol syndrome have on fetal development is on brain which may leads to substantial problems with neurobehavioral development. And defect in brain development an cause decreased IQ, hyperactivity, behavioural and adaptive difficulties. Also, there can be deficits in motor function, attention, verbal language and visuo-spatial skills.<ref name="PMID21425437"/>

FAS can also cause alterations to facial structure such as [[#Glossary|coloboma]], hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* ''' Choroid fissure''' - Middle, vascular coat of the eye which resides between the sclera and the retina.

* ''' Coloboma''' - Failure of closure of choroid fissure that should be closed during the 7th week of development

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* ''' Hemifacial asymmetry''' - also known as hemifacial microsomia, there are marked three dimensional asymmetry of various facial structure: the mandible, the ear, the maxilla, the zygoma and the orbit.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Teratrogenic''' - Substances or agents that can interfere with normal embryonic development

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-03T11:04:13Z

Z3331330: /* Anophthalmia and Microphthalmia */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, [[#Glossary|coloboma]], optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref> The aetiology of FAS can be both genetic and nutritional, a list of genes have been identified as potential targets for the [[#Glossary|teratogenic]] effects of alcohol on humans. Some animals studies have suggested nutritional issues are important risk factors that may contribute to FAS. It is evident that plasma zinc and copper concentration are lower in pregnant women that have high alcohol intake, compared to women who only drink lightly or not at all. Zinc can influence on the risk of FAS in humans. <ref name="PMID21425437"><pubmed>21425437</pubmed></ref>

Prenatal exposure to alcohol can cause profound effects and impacts on fetal development. These include alterations to somatic growth and specific minor malformation of facial structures.The most significant and important effect that fetal alcohol syndrome have on fetal development is on brain which may leads to substantial problems with neurobehavioral development. And defect in brain development an cause decreased IQ, hyperactivity, behavioural and adaptive difficulties. Also, there can be deficits in motor function, attention, verbal language and visuo-spatial skills.<ref name="PMID21425437"/>

FAS can also cause alterations to facial structure such as [[#Glossary|coloboma]], hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* ''' Choroid fissure''' - Middle, vascular coat of the eye which resides between the sclera and the retina.

* ''' Coloboma''' - Failure of closure of choroid fissure that should be closed during the 7th week of development

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Teratrogenic''' - Substances or agents that can interfere with normal embryonic development

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-03T11:01:01Z

Z3331330: /* Glossary */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref> The aetiology of FAS can be both genetic and nutritional, a list of genes have been identified as potential targets for the [[#Glossary|teratogenic]] effects of alcohol on humans. Some animals studies have suggested nutritional issues are important risk factors that may contribute to FAS. It is evident that plasma zinc and copper concentration are lower in pregnant women that have high alcohol intake, compared to women who only drink lightly or not at all. Zinc can influence on the risk of FAS in humans. <ref name="PMID21425437"><pubmed>21425437</pubmed></ref>

Prenatal exposure to alcohol can cause profound effects and impacts on fetal development. These include alterations to somatic growth and specific minor malformation of facial structures.The most significant and important effect that fetal alcohol syndrome have on fetal development is on brain which may leads to substantial problems with neurobehavioral development. And defect in brain development an cause decreased IQ, hyperactivity, behavioural and adaptive difficulties. Also, there can be deficits in motor function, attention, verbal language and visuo-spatial skills.<ref name="PMID21425437"/>

FAS can also cause alterations to facial structure such as [[#Glossary|coloboma]], hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* ''' Choroid fissure''' - Middle, vascular coat of the eye which resides between the sclera and the retina.

* ''' Coloboma''' - Failure of closure of choroid fissure that should be closed during the 7th week of development

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Teratrogenic''' - Substances or agents that can interfere with normal embryonic development

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-03T11:00:04Z

Z3331330: /* Glossary */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref> The aetiology of FAS can be both genetic and nutritional, a list of genes have been identified as potential targets for the [[#Glossary|teratogenic]] effects of alcohol on humans. Some animals studies have suggested nutritional issues are important risk factors that may contribute to FAS. It is evident that plasma zinc and copper concentration are lower in pregnant women that have high alcohol intake, compared to women who only drink lightly or not at all. Zinc can influence on the risk of FAS in humans. <ref name="PMID21425437"><pubmed>21425437</pubmed></ref>

Prenatal exposure to alcohol can cause profound effects and impacts on fetal development. These include alterations to somatic growth and specific minor malformation of facial structures.The most significant and important effect that fetal alcohol syndrome have on fetal development is on brain which may leads to substantial problems with neurobehavioral development. And defect in brain development an cause decreased IQ, hyperactivity, behavioural and adaptive difficulties. Also, there can be deficits in motor function, attention, verbal language and visuo-spatial skills.<ref name="PMID21425437"/>

FAS can also cause alterations to facial structure such as [[#Glossary|coloboma]], hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* ''' Coloboma''' - Failure of closure of choroid fissure that should be closed during the 7th week of development

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Teratrogenic''' - Substances or agents that can interfere with normal embryonic development

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-03T10:58:38Z

Z3331330: /* Fetal alcohol syndrome */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref> The aetiology of FAS can be both genetic and nutritional, a list of genes have been identified as potential targets for the [[#Glossary|teratogenic]] effects of alcohol on humans. Some animals studies have suggested nutritional issues are important risk factors that may contribute to FAS. It is evident that plasma zinc and copper concentration are lower in pregnant women that have high alcohol intake, compared to women who only drink lightly or not at all. Zinc can influence on the risk of FAS in humans. <ref name="PMID21425437"><pubmed>21425437</pubmed></ref>

Prenatal exposure to alcohol can cause profound effects and impacts on fetal development. These include alterations to somatic growth and specific minor malformation of facial structures.The most significant and important effect that fetal alcohol syndrome have on fetal development is on brain which may leads to substantial problems with neurobehavioral development. And defect in brain development an cause decreased IQ, hyperactivity, behavioural and adaptive difficulties. Also, there can be deficits in motor function, attention, verbal language and visuo-spatial skills.<ref name="PMID21425437"/>

FAS can also cause alterations to facial structure such as [[#Glossary|coloboma]], hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Teratrogenic''' - Substances or agents that can interfere with normal embryonic development

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-03T10:56:57Z

Z3331330: /* Fetal alcohol syndrome */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref> The aetiology of FAS can be both genetic and nutritional, a list of genes have been identified as potential targets for the [[#Glossary|teratogenic]] effects of alcohol on humans. Some animals studies have suggested nutritional issues are important risk factors that may contribute to FAS. It is evident that plasma zinc and copper concentration are lower in pregnant women that have high alcohol intake, compared to women who only drink lightly or not at all. Zinc can influence on the risk of FAS in humans. <ref name="PMID21425437"><pubmed>21425437</pubmed></ref>

Prenatal exposure to alcohol can cause profound effects and impacts on fetal development. These include alterations to somatic growth and specific minor malformation of facial structures.The most significant and important effect that fetal alcohol syndrome have on fetal development is on brain which may leads to substantial problems with neurobehavioral development. And defect in brain development an cause decreased IQ, hyperactivity, behavioural and adaptive difficulties. Also, there can be deficits in motor function, attention, verbal language and visuo-spatial skills.<ref name="PMID21425437"/>

FAS can also cause alterations to facial structure such as coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Teratrogenic''' - Substances or agents that can interfere with normal embryonic development

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-03T10:55:20Z

Z3331330: /* Glossary */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref> The aetiology of FAS can be both genetic and nutritional, a list of genes have been identified as potential targets for the teratogenic effects of alcohol on humans. Some animals studies have suggested nutritional issues are important risk factors that may contribute to FAS. It is evident that plasma zinc and copper concentration are lower in pregnant women that have high alcohol intake, compared to women who only drink lightly or not at all. Zinc can influence on the risk of FAS in humans. <ref name="PMID21425437"><pubmed>21425437</pubmed></ref>

Prenatal exposure to alcohol can cause profound effects and impacts on fetal development. These include alterations to somatic growth and specific minor malformation of facial structures.The most significant and important effect that fetal alcohol syndrome have on fetal development is on brain which may leads to substantial problems with neurobehavioral development. And defect in brain development an cause decreased IQ, hyperactivity, behavioural and adaptive difficulties. Also, there can be deficits in motor function, attention, verbal language and visuo-spatial skills.<ref name="PMID21425437"/>

FAS can also cause alterations to facial structure such as coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Teratrogenic''' - Substances or agents that can interfere with normal embryonic development

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-03T10:51:01Z

Z3331330: /* Fetal alcohol syndrome */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref> The aetiology of FAS can be both genetic and nutritional, a list of genes have been identified as potential targets for the teratogenic effects of alcohol on humans. Some animals studies have suggested nutritional issues are important risk factors that may contribute to FAS. It is evident that plasma zinc and copper concentration are lower in pregnant women that have high alcohol intake, compared to women who only drink lightly or not at all. Zinc can influence on the risk of FAS in humans. <ref name="PMID21425437"><pubmed>21425437</pubmed></ref>

Prenatal exposure to alcohol can cause profound effects and impacts on fetal development. These include alterations to somatic growth and specific minor malformation of facial structures.The most significant and important effect that fetal alcohol syndrome have on fetal development is on brain which may leads to substantial problems with neurobehavioral development. And defect in brain development an cause decreased IQ, hyperactivity, behavioural and adaptive difficulties. Also, there can be deficits in motor function, attention, verbal language and visuo-spatial skills.<ref name="PMID21425437"/>

FAS can also cause alterations to facial structure such as coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 5

2012-10-03T10:00:35Z

Z3331330: /* Anophthalmia and Microphthalmia */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-03T09:59:31Z

Z3331330: /* Anophthalmia and Microphthalmia */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
----
The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-03T09:57:49Z

Z3331330: /* Abnormal Development */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

2012 Group Project 5

2012-10-03T08:49:48Z

Z3331330: /* Abnormal Development */

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|right]]
=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congenital Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of Microphthalmia (development of abnormally small eye) and Anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|thumb|left|Optic placode visible at stage 14 embryo]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left|Photograph of patient IV:3 showing bilateral cataracts (radial spoke-shaped) and keratoconus.]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right|A: Ectatic white cornea. B: Fundus photograph of the same patient at six months. Note the normal fundus features.]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png|thumb|right|Comparison of phenotypes between normal and PAX6 mutant across different animals]]
The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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[[File:FASface.jpg|thumb|left|Facial Appearance of Fetal Alcohol Syndrome]]

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-10-03T00:28:26Z

Z3331330: /* Abnormal Corneal Development */

=Abnormal Vision=

==Introduction==
This page will be discussing Abnormal development of vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye.

Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as Leber Congential Amaurosis and others discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision.

==Normal Eye Development==
[[File:Stage14 sem2cl.jpg|left]]
In order to fully comprehend abnormal development, an understanding of the normal early development of the eye is important. It begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

For more information on normal development please [[Sensory_-_Vision_Development|click here]]

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|left|Comparison between fundus in Albinism and Normal eye]]

Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>
[[File:LCA patient.jpg|thumb|left]]

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.
[[File:LCA fundus and cataracts.jpg|thumb|right]]
'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. the following papers go into depth, the research taking place to restore retinal function.

''Gene therapy restores vision in a canine model of childhood blindness.''

This proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284/>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>.

''Treatment of Leber Congenital Amaurosis Due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results of a Phase I Trial''

This Paper had three adult patients with LCA from RPE65 mutation. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model.<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The eye with the worst function was used in this study with the other left for comparison. During this procedure a core and peripheral vitrectomy was performed.<ref name=PMIDPMC2940541/>
All patients in this study noticed light sensitivity in the eye but to differing degrees. This paper calls for a greater understanding of positive and negative effects of subretinal injection. It also states that the dismal results are due to the advance stage of the disease and suggests that these trials should be conducted on children.<ref name=PMIDPMC2940541/>

''Effect of gene therapy on visual function in Leber's congenital amaurosis''

This article was a study on clinical administration of gene therapy on patients with early onset severe retinal dystrophy aged between 17-23 years, undertaken in 2008.<ref name=PMID18441371/>
The procedure in this paper was subretinal injection of AAV RPE65 vector and the results showed an improvement in visual function. This study reported that AAV produced no adverse effects on patients. It also stated that while the results were not perfect it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

''Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis''

This article was investigating whether the remaining cones in late LCA can be rescued using AAV. In the test subject (mouse with natural LCA) there was early cone degeneration by RPE65 mutation with some peripheral M cones remaining.<ref name=PMIDPMC3053305><pubmed>PMC3053305</pubmed></ref>
The outcome of this trial strengthened the results of previous experiments that AAV gene therapy can help to restore S and M cone function and morphology. It also explained that if treatment is delayed AAV can also help to restore M cone function in late LCA patients.<ref name=PMIDPMC3053305/>

====Anophthalmia and Microphthalmia====
----
The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical Manifestation'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Treatment'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
----

====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
----

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

[http://www.visionaustralia.org.au Vision Australia]

[http://www.blindness.org Foundation Fighting Blindness]

[http://www.guidedogsaustralia.com/ Guide Dogs Australia]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

User:Z3331330

2012-10-03T00:10:24Z

Z3331330: /* Lab Attendance */

==Lab Attendance==

Lab 1--[[User:Z3331330|Z3331330]] 11:49, 25 July 2012 (EST)
Lab 2--[[User:Z3331330|Z3331330]] 10:41, 1 August 2012 (EST)
Lab 3--[[User:Z3331330|Z3331330]] 13:00, 8 August 2012 (EST)
Lab 4--[[User:Z3331330|Z3331330]] 10:07, 15 August 2012 (EST)
Lab 5--[[User:Z3331330|Z3331330]] 10:08, 22 August 2012 (EST)
Lab 6--[[User:Z3331330|Z3331330]] 10:10, 29 August 2012 (EST)
Lab 7--[[User:Z3331330|Z3331330]] 10:05, 12 September 2012 (EST)
Lab 8--[[User:Z3331330|Z3331330]] 10:03, 19 September 2012 (EST)
Lab 9--[[User:Z3331330|Z3331330]] 10:08, 26 September 2012 (EST)
Lab 10--[[User:Z3331330|Z3331330]] 10:10, 3 October 2012 (EST)

==Lab 1 Assessment==
(1)Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.

Many studies and experiments were conducted and they all contributed to the development of In Vitro Fertilization as it is today. Some early studies have used hamster gametes to prove the possibility of mammalian gametes being fertilized in vitro, done by Yanagimachi and Chang in1963. Chang, in 1959 has also done a study that demonstrated the normal development of a rabbit egg that was fertilized in vitro. Numerous experiments were done using different animals and species which proved the success of in vitro fertilization. Capacitation of the sperm in the uterus of the mother was a significant discovery to in vitro fertilisation. On July 25, 1978, the first successful 'test-tube' baby was born. Dr. Patrick Steptoe, a gynecologist and Dr. Robert Edwards, a physiologist, the team who pioneered the IVF were accredited for their contribution to IVF.

In 2010, Robert Edwards was awarded the 'Nobel prize in physiology or medicine' for his contribution in the development of "In Vitro Fertilization", see [http://www.nobelprize.org/]

(2)Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).

'Genes required for the common miracle of fertilization in Caenorhabditis Elegans' <ref><pubmed>18649278</pubmed></ref>

Fertilization is a result of various sperm-egg interactions and together these interactions lead to gamete fusions and egg activation.This paper describes the identity of genes that are responsible for the interactions between gametes during ferilization and the function of protein products that are produced by these specific genes. The paper focuses on the fertilization process in Caenorhabditis Elegans which is a type of worm. There are two main types of molecules that are essential in fertilization and they are sperm function molecules and egg function molecules. Spe-9 gene produces a single-pass transmembrane molecules with extracellular domain that contain 10 epidermal growth factor and it is responsible for adhesion or ligand receptor functions. Its critical presence on the surface of the sperm allow the sperm to bind to the oocytes during fertilization. Other genes such as Spe-38 is also identified with similar function.

Egg function genes such as egg-1 and egg-2 genes lead to the production of type II transmembrane molecules. Loss of these gene can lead to complete hermaphrodite fertility. Sperms will not be able to enter the oocytes.The main function of these genes is to act as oocyte surface receptor for sperms during fertilization. These discoveries and results in C.elegans provide a blueprint of the genetic control involved in the process of fertilization and encouraged discoveries of similar genes that are involved in fertilization in humans.

--[[User:Z8600021|Mark Hill]] 16:30, 11 September 2012 (EST) Question 1 is answered well and I like that you have discussed earlier research. Question 1 is also answered well, though a 2008 paper is not as recent as I was seeking as an answer. You will need to fix your referencing (ref 1 is blank because it is incorrectly formatted and should only contain the PMID (not PMC number) number without text)'''10/10'''

==lab 2 assessment==
===Degradation of ooctyes by sperm proteasomes===
--[[User:Z8600021|Mark Hill]] 16:49, 11 September 2012 (EST) This should be a sub-heading.

(1)[[File:Degradation_of_oocytes_by_sperm_proteasomes.png‎]]

(2) Rac-1 is a member of the Rho GTPases family of proteins. It was discovered that with the activation of the Rac-1 gene, its protein product can regulate the motility of the human endometrial stromal cells (HESCs) in reponse to the implantation of the embryo in the uterine wall. Rac-1 promotes the lamellipodial protrusion at front of the migrating cells. This protein also encourage the migration of HESCs away from the implantation site which then facilitate the invasion of trophoblast and lead to the inplantation of the embryo into the stromal compartment. <ref><pubmed>PMC2562412</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:32, 11 September 2012 (EST) Question 1 image is well named and contains all the requested information. Though the image is quite small 320 × 399 pixels and a larger version should have been sourced, also png files are quite large 125 KB, jpg are smaller). You have also misinterpreted my request as the file name should be a sub-heading on the file summary page, not here. Question 2 is also relevant to implantation. Rac proteins regulate the actin cytoskeleton and this is further explored in the 3rd year Cell Biology course. '''10/10'''

==Lab 3 assessment==

(1)Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

Answer: Gestational age is classified as the time elapsed from the first day of a women's last menstrual period, and the post-fertilization age is referred as the time since the fertilzation of the egg in the woman's uterus. The main difference is their starting date and gestational age is often two weeks earlier than the post-fertilization age. Clinically, gestational age is often used in describing human development because the start date of the gestational age can be clearly defined while the exact time of fertilization can be confusing. It is also essential for predicting consequences to the development of fetus from toxin exposure of infection during the gestational age.It is also important for evaluation of physical findings such as fetal growth and screening markers.

(2)Identify using histological descriptions at least 3 different types of tissues formed from somites.

3 types of tissues formed from somites:
- dermatome --> Skin are formed from dermatome. There are 3 layers to skin, epidermis which contain stratified squamous cells with epidermal ridges with thick layer of keratin. Dermis layer contain a lot of the vasculature such as blood vessels and glands, there are also dense collagen and irregular elastic fibres. Usually, this layer contains a lot of type I collagen fibre. The last layer is the hypodermis layer where its mainly adipose tissue.

- myotome--> skeletal muscle are developed from myotome. Skeletal muscle has a lot of myocytes and they are long and elongated with multiple nucleus. Their nucleus are often pushed to the periphery of the cells. They also contain myosin and actin which are called the thick and thin filament which cause striation appearance of the muscle cells.

- Sclerotome--> vertebrae and rib cartilages are developed from it, where different type of bone cells are present. The extracellular matrix of bone is formed through inorganic material such as phosphate along with some organic component being collagen fibres and ground substance.

--[[User:Z8600021|Mark Hill]] 16:41, 11 September 2012 (EST) Question 1 has been clearly and correctly answered. Question 2 the somite compartments and major tissues correctly identified. The one error is the answer for dermatome suggests that the epidermis is also a component of this compartment, while it is ectodermal in origin. '''9/10'''

==Lab 4 assessment==

(1)Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

The first invasive prenatal diagnostic techniques is called "chorionic villus sampling" and it involves a catheter passed via the vagina through the cervix and into the uterus to the placenta, under the guidance of ultrasound. There can be other approaches as well such as transvaginal and transabdominal. The catheter will then collect sample of the chorionic villus which is placental tissue. The sample will then be analyse for any chromosomal abnormalities or genetic disorders, and the karotype of the fetus will be determined.

The second technique is "Placental biopsy", it is similiar to the chorionic villus sampling, but it has a transabdominal approach to it. It can be performed at a later stage of the pregnancy. It is used to obtain a rapid result. The karyotype of the fetus can be determined and genetic disorders can be detected such as trisomy 21 and monosomy X.

(2)Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

"Transplantation of microencapsulated umbilical-cord-bloodderived hepatic-like cells for treatment of hepatic failure" [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3051145/?tool=pmcentrez]

The paper aim to investigate intraperitoneal transplantation of microencapsulated hepatic-like cells from human umbilical cord blood for treatment of hepatic failure in rats. There are a few candidates for this experiment but human umbilical cord blood (UCB) cells were thought to be the best as they have some advantages that other cells do not have. The frequencies of UCB hematopoietic stem or progenitor cells is much higher than those from bone marrow and peripheral blood. The paper also mentioned that there are three ways of inducing the UCB cells into hepatocytes-like cells and they are Co-culture with injured liver cell, growth factor-assisted and MNC transplantation.

In the experiment, CD34 cells are isolated from the UCB cells and through the combination of fibroblast growth factor and hepatocyte growth factor, the CD34 cells are induced to hepatocytes-like cells.
It was found that in the cultured cells, the level of human albumin, alpha-fetoprotein and GATA-4 mRNA and albumin positive cells have increased significantly suggesting the transformation of the CD34 cells into hepatic-like cells. The cultured system with growth factors have the ability to convert these UCB cells into hepatocytes phenotype and it is confirmed through PCR and immunohistochemcial staining. Then these hepatic-like cells are encapsulated and transplanted into the abdominal cavity of rats with acute hepatic failure. The transplantation occurs 48 hours after the onset of an acute hepatic failure.The microencapsulation of the cells provide a possibility to overcome the immuno-rejection from the AHF rats.

The result obtained from this experiment was that CD34 cells from the UCB cells can be converted into hepatic-like cells under suitable conditions with appropriate growth factors. The transplantation of these encapsulated hepatic-like cells have resulted in decreased mortality of the AHF rats. But these hepatic-like cells can only offer short term metabolic effect to these AHF rats and cannot interrupt or repair the damaged hepatocytes. Therefore the conclusion of this paper suggests the possibility of UCB cells used in conversion to hepatic-like cells that can temporarily alleviate the symptoms of Acute hepatic failure in rats bur not regenerating healthy hepatocytes. <ref><pubmed>PMC3051145</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:46, 11 September 2012 (EST) Question 1 You have clearly identified 2 invasive techniques diagnostic techniques. I would have liked specific disorders for the first technique, as you have for the second technique. Question 2 this is an excellent description of the paper and technique. You have used the UCB acronym correctly (citing in full the first time), though you still have problems in formatting your reference links, which only require the PMID number to link correctly. '''10/10'''

==Lab 7 assessment==
(1) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?

It is a mononuclear stem cell that are found in mature skeletal muscle fibres and promote their growth, repair and regeneration, they are usually situated between sarcolemma and basement membrane of muscle fibres.

Satellite cells are activated after muscle strains such as trauma, where myogenic regulatory factors will be expressed and they are similar to those produced by muscle precursor cells during muscle development. These cells proliferate and fuse with each other to form myotubes and slowly mature into myofibres. They can also fuse with damaged segments of muscle fibres. These cells can also give rise to new satellite cells. Heavy exercise can induce muscle hypertrophy which also encourage the growth and proliferation of these muscle satellite cells.

(2)In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?

In situations of long term motor nerve damage, since skeletal muscles are activated by these motor nerves, when they are damaged, the muscles will often lose their function and movement. There can be a complete loss of function or only a part of, depending on the severity of the damage to the nerve. When the muscle lose their initiation, they can present symptoms such as muscle twitching, cramping and muscle can become stiff due to the lack of movement. Muscles paralysed by spinal cord injury are usually atrophic, possesses lower tension generating capacity and is less fatigue resistant compared to normal muscles. Upper motor neuron paralysed muscles lose the normal type I (slow) and II (fast) fibre and become predominantly composed of type II (fast glycolytic) fibres. A transitional period can be seen ranging from 1 to 20 months after the injury where there is usually drop in the proportion of slow muscle fibres and a rise in the development of fast fibres.

==Lab 8 assessment==

''Vision''

I really liked the eye image at the top of the project page, it automatically drags my attention towards the page and it clearly shows what the project is going to be focused on. The introduction was good, its not too long but provide sufficient information about the project and as reader, we know what we can expect from the project page. The image used there is very good as well but maybe more labelling and explanation can be included.

Images from the textbook, Atlas of the development of men, both on the development of lens and the formation of optic vesicle, they are really good. I understand that the page is not complete yet, but just looking at these images, a lot of explanation and labelling need to be put in to ensure that readers know what is going on and actually learn from those images. The development of the optic nerve is good. Information provided is clear and precise. The whole process of the development was explained well and used simple terms so that it is very easy to follow and understand but maybe the images need to be labelled more? I saw that this section of the project, only 1-2 references is used? Maybe try to expand the research and include more information from different sources. I really liked the way that most of the images are hand-drawn, this really shows that you understand the process yourself and able to interpret all the knowledge you gathered from resources and produce something that is easy to understand and can actually teach readers about vision development.

There is a glossary at the end of the page which includes all the scientific terms, maybe expand this section a little bit more. Some scientific words are not included such as mesenchyme, as a science student, maybe we will understand these words but for the general public, they may not. That's why it is essential to have a glossary. I thought having an image gallery was a good idea, in that way, people can concentrate on only the image aspect of the project without all the text in between, allowing a different approach in looking at this project. Referencing of the project overall was good, except there is one citing error, no.13? But this should be quite easy to fix. In terms of variety of resources used, i thought was quite narrow, with the majority resources being websites and lab material from the course. Maybe use more journal articles and reviews to expand the depth of the information presented. The structure and the lay out of the page is very clear with consistent headings and sub-headings, which makes the page very easy to read and follow.

Overall, the project page is looking good.There are just some minor parts to be completed and maybe a little bit more research needs to be done. :) hope this helps.
--Z3331330 18:35, 23 September 2012 (EST)

''Somatosensory''

The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?
The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

''Taste''

The introduction is very detailed but did not mention anything about the development of the taste. But I thought the mechanisms behind sweet and salty tastes are very interesting. Maybe do the same for the other 3 tastes? The image of the basic 5 tastes is a bit small, maybe upload a bigger version of the image. Also, the image is lacking some reference, copyright information and a student image template.

The type II receptor section is pretty good and descriptive but it does not really relate to the development of the taste. The taste map is a very eye-catchy image and it would be really useful if it had all the needed information such as the copyright notice. The timeline of the gustatory system is very well-presented and easy to read. I understand the project is not completed yet, therefore more images are still to be put in. Only 2 references have been used in the timeline section, maybe try to research more and use different resources. There are some citing error but it should be quite easy to fix.

Histories of discoveries section is very detailed and easy to read but the referencing needs to be fixed. The adult tongue and taste bud section is very clear and precise and contain a lot of useful information but it does not really relate to the research topic, should beware of going off-track. The hand-drawn diagram of the taste bud is impressive and easy to understand but again lacking in some referencing information such as who drew it. The abnormalities section is good and well-researched and it is interesting to know about which gene or receptors will effect the development of taste and sensation. Maybe the abnormalities section can be included into the current research section because abnormalities are repeated in the current research section below. There are detailed definitions of terms in the glossary which is good because it really helps the reader to understand more about the research topic.

Overall, the page is looking good. The main thing that needs to be fixed will be the images that are already on the page, they need the correct and essential information with them when uploaded on the page or else, they will get deleted and there will be no images on the page and the nice balance of images and text now will be gone. There seem to be a lot of anatomy and biology of the taste system but not a lot of information about their development. Although there is a timeline of development but i think more information is needed. Referencing is pretty good with only one or two minor citing error but it should be easy to fix. Structure of the page is clear and simple with headings and sub-headings being consistent, making the page easy to read and follow. Hope this helps :)

''Olfaction''

The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.
The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

''Hearing''

Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

==Lab 9 assessment==

(1)Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

'Stam2 expression pattern during embryo development.'

Signal transduction adaptor molecules 1 and 2 (STAM1 and STAM2). They are both involved in the endosomal sorting of the cargo proteins for trafficking towards the lysosome. STAM2 is activated by tyrosine phosphorylation and can also be stimulated by various cytokines and growth factors. It is involved in the regulation of endocytosis and also regulation of intracellular signal transduction for DNA synthesis through JAK2 and JAK3 tyrosine kinases.

In the paper, a mouse line have been created to enable the expression of STAM2 to be observed by X-gal histochemistry. At around embryonic day 16.5, it is evident that STAM2 is expressed in the heart, testes, olfactory bulbs, trigeminal and dorsal root ganglia, pituitary and medulla of the adrenal glands. Around embryonic day 18.5, the expression of STAM2 become much stronger, especially in areas of testes, ovaries, lungs, kidneys, urogenital sinus, pituitary and adrenal glands. Near the end of gestation, STAM2 expression is confined to regions such as nervous tissue, and endocrine organs like pituitary and adrenal glands and they are already highly secretory active at this stage of embryonic development. This paper demonstrates a very strong correlation between the development of the adrenal glands and the expression of STAM2. <ref><pubmed>22143071</pubmed></ref>

(2)Identify the embryonic layers and tissues that contribute to the developing teeth.

Teeth are formed from cells that derived from the ectoderm of the first branchial arch and the ectomesenchyme of the neural crest and also mesoderm.It is organized into 3 parts, the enamel organ, the dental papilla and the dental follicle. The enamel organ give rise to ameloblasts which produce enamel and the reduced enamel epithelium and ultimately determines the root shape of the tooth.The dental papilla contains cells that develop into odontoblasts which determines the crown shape of a tooth. Mesenchymal cells in the dental papilla are for the formation of tooth pulp. The dental follicle contribute to cementoblasts which form the cementum of the tooth, osteoblasts which give rise to the alveolar bone and fibroblasts give rise to periodontal ligamtns.

===References===
<references/>

User:Z3331330

2012-10-03T00:10:03Z

Z3331330: /* Lab Attendance */

==Lab Attendance==

Lab 1--[[User:Z3331330|Z3331330]] 11:49, 25 July 2012 (EST)
Lab 2--[[User:Z3331330|Z3331330]] 10:41, 1 August 2012 (EST)
Lab 3--[[User:Z3331330|Z3331330]] 13:00, 8 August 2012 (EST)
Lab 4--[[User:Z3331330|Z3331330]] 10:07, 15 August 2012 (EST)
Lab 5--[[User:Z3331330|Z3331330]] 10:08, 22 August 2012 (EST)
Lab 6--[[User:Z3331330|Z3331330]] 10:10, 29 August 2012 (EST)
Lab 7--[[User:Z3331330|Z3331330]] 10:05, 12 September 2012 (EST)
Lab 8--[[User:Z3331330|Z3331330]] 10:03, 19 September 2012 (EST)
Lab 9--[[User:Z3331330|Z3331330]] 10:08, 26 September 2012 (EST)
--[[User:Z3331330|Z3331330]] 10:10, 3 October 2012 (EST)

==Lab 1 Assessment==
(1)Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.

Many studies and experiments were conducted and they all contributed to the development of In Vitro Fertilization as it is today. Some early studies have used hamster gametes to prove the possibility of mammalian gametes being fertilized in vitro, done by Yanagimachi and Chang in1963. Chang, in 1959 has also done a study that demonstrated the normal development of a rabbit egg that was fertilized in vitro. Numerous experiments were done using different animals and species which proved the success of in vitro fertilization. Capacitation of the sperm in the uterus of the mother was a significant discovery to in vitro fertilisation. On July 25, 1978, the first successful 'test-tube' baby was born. Dr. Patrick Steptoe, a gynecologist and Dr. Robert Edwards, a physiologist, the team who pioneered the IVF were accredited for their contribution to IVF.

In 2010, Robert Edwards was awarded the 'Nobel prize in physiology or medicine' for his contribution in the development of "In Vitro Fertilization", see [http://www.nobelprize.org/]

(2)Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).

'Genes required for the common miracle of fertilization in Caenorhabditis Elegans' <ref><pubmed>18649278</pubmed></ref>

Fertilization is a result of various sperm-egg interactions and together these interactions lead to gamete fusions and egg activation.This paper describes the identity of genes that are responsible for the interactions between gametes during ferilization and the function of protein products that are produced by these specific genes. The paper focuses on the fertilization process in Caenorhabditis Elegans which is a type of worm. There are two main types of molecules that are essential in fertilization and they are sperm function molecules and egg function molecules. Spe-9 gene produces a single-pass transmembrane molecules with extracellular domain that contain 10 epidermal growth factor and it is responsible for adhesion or ligand receptor functions. Its critical presence on the surface of the sperm allow the sperm to bind to the oocytes during fertilization. Other genes such as Spe-38 is also identified with similar function.

Egg function genes such as egg-1 and egg-2 genes lead to the production of type II transmembrane molecules. Loss of these gene can lead to complete hermaphrodite fertility. Sperms will not be able to enter the oocytes.The main function of these genes is to act as oocyte surface receptor for sperms during fertilization. These discoveries and results in C.elegans provide a blueprint of the genetic control involved in the process of fertilization and encouraged discoveries of similar genes that are involved in fertilization in humans.

--[[User:Z8600021|Mark Hill]] 16:30, 11 September 2012 (EST) Question 1 is answered well and I like that you have discussed earlier research. Question 1 is also answered well, though a 2008 paper is not as recent as I was seeking as an answer. You will need to fix your referencing (ref 1 is blank because it is incorrectly formatted and should only contain the PMID (not PMC number) number without text)'''10/10'''

==lab 2 assessment==
===Degradation of ooctyes by sperm proteasomes===
--[[User:Z8600021|Mark Hill]] 16:49, 11 September 2012 (EST) This should be a sub-heading.

(1)[[File:Degradation_of_oocytes_by_sperm_proteasomes.png‎]]

(2) Rac-1 is a member of the Rho GTPases family of proteins. It was discovered that with the activation of the Rac-1 gene, its protein product can regulate the motility of the human endometrial stromal cells (HESCs) in reponse to the implantation of the embryo in the uterine wall. Rac-1 promotes the lamellipodial protrusion at front of the migrating cells. This protein also encourage the migration of HESCs away from the implantation site which then facilitate the invasion of trophoblast and lead to the inplantation of the embryo into the stromal compartment. <ref><pubmed>PMC2562412</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:32, 11 September 2012 (EST) Question 1 image is well named and contains all the requested information. Though the image is quite small 320 × 399 pixels and a larger version should have been sourced, also png files are quite large 125 KB, jpg are smaller). You have also misinterpreted my request as the file name should be a sub-heading on the file summary page, not here. Question 2 is also relevant to implantation. Rac proteins regulate the actin cytoskeleton and this is further explored in the 3rd year Cell Biology course. '''10/10'''

==Lab 3 assessment==

(1)Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

Answer: Gestational age is classified as the time elapsed from the first day of a women's last menstrual period, and the post-fertilization age is referred as the time since the fertilzation of the egg in the woman's uterus. The main difference is their starting date and gestational age is often two weeks earlier than the post-fertilization age. Clinically, gestational age is often used in describing human development because the start date of the gestational age can be clearly defined while the exact time of fertilization can be confusing. It is also essential for predicting consequences to the development of fetus from toxin exposure of infection during the gestational age.It is also important for evaluation of physical findings such as fetal growth and screening markers.

(2)Identify using histological descriptions at least 3 different types of tissues formed from somites.

3 types of tissues formed from somites:
- dermatome --> Skin are formed from dermatome. There are 3 layers to skin, epidermis which contain stratified squamous cells with epidermal ridges with thick layer of keratin. Dermis layer contain a lot of the vasculature such as blood vessels and glands, there are also dense collagen and irregular elastic fibres. Usually, this layer contains a lot of type I collagen fibre. The last layer is the hypodermis layer where its mainly adipose tissue.

- myotome--> skeletal muscle are developed from myotome. Skeletal muscle has a lot of myocytes and they are long and elongated with multiple nucleus. Their nucleus are often pushed to the periphery of the cells. They also contain myosin and actin which are called the thick and thin filament which cause striation appearance of the muscle cells.

- Sclerotome--> vertebrae and rib cartilages are developed from it, where different type of bone cells are present. The extracellular matrix of bone is formed through inorganic material such as phosphate along with some organic component being collagen fibres and ground substance.

--[[User:Z8600021|Mark Hill]] 16:41, 11 September 2012 (EST) Question 1 has been clearly and correctly answered. Question 2 the somite compartments and major tissues correctly identified. The one error is the answer for dermatome suggests that the epidermis is also a component of this compartment, while it is ectodermal in origin. '''9/10'''

==Lab 4 assessment==

(1)Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

The first invasive prenatal diagnostic techniques is called "chorionic villus sampling" and it involves a catheter passed via the vagina through the cervix and into the uterus to the placenta, under the guidance of ultrasound. There can be other approaches as well such as transvaginal and transabdominal. The catheter will then collect sample of the chorionic villus which is placental tissue. The sample will then be analyse for any chromosomal abnormalities or genetic disorders, and the karotype of the fetus will be determined.

The second technique is "Placental biopsy", it is similiar to the chorionic villus sampling, but it has a transabdominal approach to it. It can be performed at a later stage of the pregnancy. It is used to obtain a rapid result. The karyotype of the fetus can be determined and genetic disorders can be detected such as trisomy 21 and monosomy X.

(2)Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

"Transplantation of microencapsulated umbilical-cord-bloodderived hepatic-like cells for treatment of hepatic failure" [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3051145/?tool=pmcentrez]

The paper aim to investigate intraperitoneal transplantation of microencapsulated hepatic-like cells from human umbilical cord blood for treatment of hepatic failure in rats. There are a few candidates for this experiment but human umbilical cord blood (UCB) cells were thought to be the best as they have some advantages that other cells do not have. The frequencies of UCB hematopoietic stem or progenitor cells is much higher than those from bone marrow and peripheral blood. The paper also mentioned that there are three ways of inducing the UCB cells into hepatocytes-like cells and they are Co-culture with injured liver cell, growth factor-assisted and MNC transplantation.

In the experiment, CD34 cells are isolated from the UCB cells and through the combination of fibroblast growth factor and hepatocyte growth factor, the CD34 cells are induced to hepatocytes-like cells.
It was found that in the cultured cells, the level of human albumin, alpha-fetoprotein and GATA-4 mRNA and albumin positive cells have increased significantly suggesting the transformation of the CD34 cells into hepatic-like cells. The cultured system with growth factors have the ability to convert these UCB cells into hepatocytes phenotype and it is confirmed through PCR and immunohistochemcial staining. Then these hepatic-like cells are encapsulated and transplanted into the abdominal cavity of rats with acute hepatic failure. The transplantation occurs 48 hours after the onset of an acute hepatic failure.The microencapsulation of the cells provide a possibility to overcome the immuno-rejection from the AHF rats.

The result obtained from this experiment was that CD34 cells from the UCB cells can be converted into hepatic-like cells under suitable conditions with appropriate growth factors. The transplantation of these encapsulated hepatic-like cells have resulted in decreased mortality of the AHF rats. But these hepatic-like cells can only offer short term metabolic effect to these AHF rats and cannot interrupt or repair the damaged hepatocytes. Therefore the conclusion of this paper suggests the possibility of UCB cells used in conversion to hepatic-like cells that can temporarily alleviate the symptoms of Acute hepatic failure in rats bur not regenerating healthy hepatocytes. <ref><pubmed>PMC3051145</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:46, 11 September 2012 (EST) Question 1 You have clearly identified 2 invasive techniques diagnostic techniques. I would have liked specific disorders for the first technique, as you have for the second technique. Question 2 this is an excellent description of the paper and technique. You have used the UCB acronym correctly (citing in full the first time), though you still have problems in formatting your reference links, which only require the PMID number to link correctly. '''10/10'''

==Lab 7 assessment==
(1) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?

It is a mononuclear stem cell that are found in mature skeletal muscle fibres and promote their growth, repair and regeneration, they are usually situated between sarcolemma and basement membrane of muscle fibres.

Satellite cells are activated after muscle strains such as trauma, where myogenic regulatory factors will be expressed and they are similar to those produced by muscle precursor cells during muscle development. These cells proliferate and fuse with each other to form myotubes and slowly mature into myofibres. They can also fuse with damaged segments of muscle fibres. These cells can also give rise to new satellite cells. Heavy exercise can induce muscle hypertrophy which also encourage the growth and proliferation of these muscle satellite cells.

(2)In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?

In situations of long term motor nerve damage, since skeletal muscles are activated by these motor nerves, when they are damaged, the muscles will often lose their function and movement. There can be a complete loss of function or only a part of, depending on the severity of the damage to the nerve. When the muscle lose their initiation, they can present symptoms such as muscle twitching, cramping and muscle can become stiff due to the lack of movement. Muscles paralysed by spinal cord injury are usually atrophic, possesses lower tension generating capacity and is less fatigue resistant compared to normal muscles. Upper motor neuron paralysed muscles lose the normal type I (slow) and II (fast) fibre and become predominantly composed of type II (fast glycolytic) fibres. A transitional period can be seen ranging from 1 to 20 months after the injury where there is usually drop in the proportion of slow muscle fibres and a rise in the development of fast fibres.

==Lab 8 assessment==

''Vision''

I really liked the eye image at the top of the project page, it automatically drags my attention towards the page and it clearly shows what the project is going to be focused on. The introduction was good, its not too long but provide sufficient information about the project and as reader, we know what we can expect from the project page. The image used there is very good as well but maybe more labelling and explanation can be included.

Images from the textbook, Atlas of the development of men, both on the development of lens and the formation of optic vesicle, they are really good. I understand that the page is not complete yet, but just looking at these images, a lot of explanation and labelling need to be put in to ensure that readers know what is going on and actually learn from those images. The development of the optic nerve is good. Information provided is clear and precise. The whole process of the development was explained well and used simple terms so that it is very easy to follow and understand but maybe the images need to be labelled more? I saw that this section of the project, only 1-2 references is used? Maybe try to expand the research and include more information from different sources. I really liked the way that most of the images are hand-drawn, this really shows that you understand the process yourself and able to interpret all the knowledge you gathered from resources and produce something that is easy to understand and can actually teach readers about vision development.

There is a glossary at the end of the page which includes all the scientific terms, maybe expand this section a little bit more. Some scientific words are not included such as mesenchyme, as a science student, maybe we will understand these words but for the general public, they may not. That's why it is essential to have a glossary. I thought having an image gallery was a good idea, in that way, people can concentrate on only the image aspect of the project without all the text in between, allowing a different approach in looking at this project. Referencing of the project overall was good, except there is one citing error, no.13? But this should be quite easy to fix. In terms of variety of resources used, i thought was quite narrow, with the majority resources being websites and lab material from the course. Maybe use more journal articles and reviews to expand the depth of the information presented. The structure and the lay out of the page is very clear with consistent headings and sub-headings, which makes the page very easy to read and follow.

Overall, the project page is looking good.There are just some minor parts to be completed and maybe a little bit more research needs to be done. :) hope this helps.
--Z3331330 18:35, 23 September 2012 (EST)

''Somatosensory''

The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?
The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

''Taste''

The introduction is very detailed but did not mention anything about the development of the taste. But I thought the mechanisms behind sweet and salty tastes are very interesting. Maybe do the same for the other 3 tastes? The image of the basic 5 tastes is a bit small, maybe upload a bigger version of the image. Also, the image is lacking some reference, copyright information and a student image template.

The type II receptor section is pretty good and descriptive but it does not really relate to the development of the taste. The taste map is a very eye-catchy image and it would be really useful if it had all the needed information such as the copyright notice. The timeline of the gustatory system is very well-presented and easy to read. I understand the project is not completed yet, therefore more images are still to be put in. Only 2 references have been used in the timeline section, maybe try to research more and use different resources. There are some citing error but it should be quite easy to fix.

Histories of discoveries section is very detailed and easy to read but the referencing needs to be fixed. The adult tongue and taste bud section is very clear and precise and contain a lot of useful information but it does not really relate to the research topic, should beware of going off-track. The hand-drawn diagram of the taste bud is impressive and easy to understand but again lacking in some referencing information such as who drew it. The abnormalities section is good and well-researched and it is interesting to know about which gene or receptors will effect the development of taste and sensation. Maybe the abnormalities section can be included into the current research section because abnormalities are repeated in the current research section below. There are detailed definitions of terms in the glossary which is good because it really helps the reader to understand more about the research topic.

Overall, the page is looking good. The main thing that needs to be fixed will be the images that are already on the page, they need the correct and essential information with them when uploaded on the page or else, they will get deleted and there will be no images on the page and the nice balance of images and text now will be gone. There seem to be a lot of anatomy and biology of the taste system but not a lot of information about their development. Although there is a timeline of development but i think more information is needed. Referencing is pretty good with only one or two minor citing error but it should be easy to fix. Structure of the page is clear and simple with headings and sub-headings being consistent, making the page easy to read and follow. Hope this helps :)

''Olfaction''

The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.
The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

''Hearing''

Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

==Lab 9 assessment==

(1)Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

'Stam2 expression pattern during embryo development.'

Signal transduction adaptor molecules 1 and 2 (STAM1 and STAM2). They are both involved in the endosomal sorting of the cargo proteins for trafficking towards the lysosome. STAM2 is activated by tyrosine phosphorylation and can also be stimulated by various cytokines and growth factors. It is involved in the regulation of endocytosis and also regulation of intracellular signal transduction for DNA synthesis through JAK2 and JAK3 tyrosine kinases.

In the paper, a mouse line have been created to enable the expression of STAM2 to be observed by X-gal histochemistry. At around embryonic day 16.5, it is evident that STAM2 is expressed in the heart, testes, olfactory bulbs, trigeminal and dorsal root ganglia, pituitary and medulla of the adrenal glands. Around embryonic day 18.5, the expression of STAM2 become much stronger, especially in areas of testes, ovaries, lungs, kidneys, urogenital sinus, pituitary and adrenal glands. Near the end of gestation, STAM2 expression is confined to regions such as nervous tissue, and endocrine organs like pituitary and adrenal glands and they are already highly secretory active at this stage of embryonic development. This paper demonstrates a very strong correlation between the development of the adrenal glands and the expression of STAM2. <ref><pubmed>22143071</pubmed></ref>

(2)Identify the embryonic layers and tissues that contribute to the developing teeth.

Teeth are formed from cells that derived from the ectoderm of the first branchial arch and the ectomesenchyme of the neural crest and also mesoderm.It is organized into 3 parts, the enamel organ, the dental papilla and the dental follicle. The enamel organ give rise to ameloblasts which produce enamel and the reduced enamel epithelium and ultimately determines the root shape of the tooth.The dental papilla contains cells that develop into odontoblasts which determines the crown shape of a tooth. Mesenchymal cells in the dental papilla are for the formation of tooth pulp. The dental follicle contribute to cementoblasts which form the cementum of the tooth, osteoblasts which give rise to the alveolar bone and fibroblasts give rise to periodontal ligamtns.

===References===
<references/>

User:Z3331330

2012-10-01T09:38:52Z

Z3331330: /* Lab 9 assessment */

==Lab Attendance==

Lab 1--[[User:Z3331330|Z3331330]] 11:49, 25 July 2012 (EST)
Lab 2--[[User:Z3331330|Z3331330]] 10:41, 1 August 2012 (EST)
Lab 3--[[User:Z3331330|Z3331330]] 13:00, 8 August 2012 (EST)
Lab 4--[[User:Z3331330|Z3331330]] 10:07, 15 August 2012 (EST)
Lab 5--[[User:Z3331330|Z3331330]] 10:08, 22 August 2012 (EST)
Lab 6--[[User:Z3331330|Z3331330]] 10:10, 29 August 2012 (EST)
Lab 7--[[User:Z3331330|Z3331330]] 10:05, 12 September 2012 (EST)
Lab 8--[[User:Z3331330|Z3331330]] 10:03, 19 September 2012 (EST)
Lab 9--[[User:Z3331330|Z3331330]] 10:08, 26 September 2012 (EST)

==Lab 1 Assessment==
(1)Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.

Many studies and experiments were conducted and they all contributed to the development of In Vitro Fertilization as it is today. Some early studies have used hamster gametes to prove the possibility of mammalian gametes being fertilized in vitro, done by Yanagimachi and Chang in1963. Chang, in 1959 has also done a study that demonstrated the normal development of a rabbit egg that was fertilized in vitro. Numerous experiments were done using different animals and species which proved the success of in vitro fertilization. Capacitation of the sperm in the uterus of the mother was a significant discovery to in vitro fertilisation. On July 25, 1978, the first successful 'test-tube' baby was born. Dr. Patrick Steptoe, a gynecologist and Dr. Robert Edwards, a physiologist, the team who pioneered the IVF were accredited for their contribution to IVF.

In 2010, Robert Edwards was awarded the 'Nobel prize in physiology or medicine' for his contribution in the development of "In Vitro Fertilization", see [http://www.nobelprize.org/]

(2)Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).

'Genes required for the common miracle of fertilization in Caenorhabditis Elegans' <ref><pubmed>18649278</pubmed></ref>

Fertilization is a result of various sperm-egg interactions and together these interactions lead to gamete fusions and egg activation.This paper describes the identity of genes that are responsible for the interactions between gametes during ferilization and the function of protein products that are produced by these specific genes. The paper focuses on the fertilization process in Caenorhabditis Elegans which is a type of worm. There are two main types of molecules that are essential in fertilization and they are sperm function molecules and egg function molecules. Spe-9 gene produces a single-pass transmembrane molecules with extracellular domain that contain 10 epidermal growth factor and it is responsible for adhesion or ligand receptor functions. Its critical presence on the surface of the sperm allow the sperm to bind to the oocytes during fertilization. Other genes such as Spe-38 is also identified with similar function.

Egg function genes such as egg-1 and egg-2 genes lead to the production of type II transmembrane molecules. Loss of these gene can lead to complete hermaphrodite fertility. Sperms will not be able to enter the oocytes.The main function of these genes is to act as oocyte surface receptor for sperms during fertilization. These discoveries and results in C.elegans provide a blueprint of the genetic control involved in the process of fertilization and encouraged discoveries of similar genes that are involved in fertilization in humans.

--[[User:Z8600021|Mark Hill]] 16:30, 11 September 2012 (EST) Question 1 is answered well and I like that you have discussed earlier research. Question 1 is also answered well, though a 2008 paper is not as recent as I was seeking as an answer. You will need to fix your referencing (ref 1 is blank because it is incorrectly formatted and should only contain the PMID (not PMC number) number without text)'''10/10'''

==lab 2 assessment==
===Degradation of ooctyes by sperm proteasomes===
--[[User:Z8600021|Mark Hill]] 16:49, 11 September 2012 (EST) This should be a sub-heading.

(1)[[File:Degradation_of_oocytes_by_sperm_proteasomes.png‎]]

(2) Rac-1 is a member of the Rho GTPases family of proteins. It was discovered that with the activation of the Rac-1 gene, its protein product can regulate the motility of the human endometrial stromal cells (HESCs) in reponse to the implantation of the embryo in the uterine wall. Rac-1 promotes the lamellipodial protrusion at front of the migrating cells. This protein also encourage the migration of HESCs away from the implantation site which then facilitate the invasion of trophoblast and lead to the inplantation of the embryo into the stromal compartment. <ref><pubmed>PMC2562412</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:32, 11 September 2012 (EST) Question 1 image is well named and contains all the requested information. Though the image is quite small 320 × 399 pixels and a larger version should have been sourced, also png files are quite large 125 KB, jpg are smaller). You have also misinterpreted my request as the file name should be a sub-heading on the file summary page, not here. Question 2 is also relevant to implantation. Rac proteins regulate the actin cytoskeleton and this is further explored in the 3rd year Cell Biology course. '''10/10'''

==Lab 3 assessment==

(1)Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

Answer: Gestational age is classified as the time elapsed from the first day of a women's last menstrual period, and the post-fertilization age is referred as the time since the fertilzation of the egg in the woman's uterus. The main difference is their starting date and gestational age is often two weeks earlier than the post-fertilization age. Clinically, gestational age is often used in describing human development because the start date of the gestational age can be clearly defined while the exact time of fertilization can be confusing. It is also essential for predicting consequences to the development of fetus from toxin exposure of infection during the gestational age.It is also important for evaluation of physical findings such as fetal growth and screening markers.

(2)Identify using histological descriptions at least 3 different types of tissues formed from somites.

3 types of tissues formed from somites:
- dermatome --> Skin are formed from dermatome. There are 3 layers to skin, epidermis which contain stratified squamous cells with epidermal ridges with thick layer of keratin. Dermis layer contain a lot of the vasculature such as blood vessels and glands, there are also dense collagen and irregular elastic fibres. Usually, this layer contains a lot of type I collagen fibre. The last layer is the hypodermis layer where its mainly adipose tissue.

- myotome--> skeletal muscle are developed from myotome. Skeletal muscle has a lot of myocytes and they are long and elongated with multiple nucleus. Their nucleus are often pushed to the periphery of the cells. They also contain myosin and actin which are called the thick and thin filament which cause striation appearance of the muscle cells.

- Sclerotome--> vertebrae and rib cartilages are developed from it, where different type of bone cells are present. The extracellular matrix of bone is formed through inorganic material such as phosphate along with some organic component being collagen fibres and ground substance.

--[[User:Z8600021|Mark Hill]] 16:41, 11 September 2012 (EST) Question 1 has been clearly and correctly answered. Question 2 the somite compartments and major tissues correctly identified. The one error is the answer for dermatome suggests that the epidermis is also a component of this compartment, while it is ectodermal in origin. '''9/10'''

==Lab 4 assessment==

(1)Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

The first invasive prenatal diagnostic techniques is called "chorionic villus sampling" and it involves a catheter passed via the vagina through the cervix and into the uterus to the placenta, under the guidance of ultrasound. There can be other approaches as well such as transvaginal and transabdominal. The catheter will then collect sample of the chorionic villus which is placental tissue. The sample will then be analyse for any chromosomal abnormalities or genetic disorders, and the karotype of the fetus will be determined.

The second technique is "Placental biopsy", it is similiar to the chorionic villus sampling, but it has a transabdominal approach to it. It can be performed at a later stage of the pregnancy. It is used to obtain a rapid result. The karyotype of the fetus can be determined and genetic disorders can be detected such as trisomy 21 and monosomy X.

(2)Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

"Transplantation of microencapsulated umbilical-cord-bloodderived hepatic-like cells for treatment of hepatic failure" [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3051145/?tool=pmcentrez]

The paper aim to investigate intraperitoneal transplantation of microencapsulated hepatic-like cells from human umbilical cord blood for treatment of hepatic failure in rats. There are a few candidates for this experiment but human umbilical cord blood (UCB) cells were thought to be the best as they have some advantages that other cells do not have. The frequencies of UCB hematopoietic stem or progenitor cells is much higher than those from bone marrow and peripheral blood. The paper also mentioned that there are three ways of inducing the UCB cells into hepatocytes-like cells and they are Co-culture with injured liver cell, growth factor-assisted and MNC transplantation.

In the experiment, CD34 cells are isolated from the UCB cells and through the combination of fibroblast growth factor and hepatocyte growth factor, the CD34 cells are induced to hepatocytes-like cells.
It was found that in the cultured cells, the level of human albumin, alpha-fetoprotein and GATA-4 mRNA and albumin positive cells have increased significantly suggesting the transformation of the CD34 cells into hepatic-like cells. The cultured system with growth factors have the ability to convert these UCB cells into hepatocytes phenotype and it is confirmed through PCR and immunohistochemcial staining. Then these hepatic-like cells are encapsulated and transplanted into the abdominal cavity of rats with acute hepatic failure. The transplantation occurs 48 hours after the onset of an acute hepatic failure.The microencapsulation of the cells provide a possibility to overcome the immuno-rejection from the AHF rats.

The result obtained from this experiment was that CD34 cells from the UCB cells can be converted into hepatic-like cells under suitable conditions with appropriate growth factors. The transplantation of these encapsulated hepatic-like cells have resulted in decreased mortality of the AHF rats. But these hepatic-like cells can only offer short term metabolic effect to these AHF rats and cannot interrupt or repair the damaged hepatocytes. Therefore the conclusion of this paper suggests the possibility of UCB cells used in conversion to hepatic-like cells that can temporarily alleviate the symptoms of Acute hepatic failure in rats bur not regenerating healthy hepatocytes. <ref><pubmed>PMC3051145</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:46, 11 September 2012 (EST) Question 1 You have clearly identified 2 invasive techniques diagnostic techniques. I would have liked specific disorders for the first technique, as you have for the second technique. Question 2 this is an excellent description of the paper and technique. You have used the UCB acronym correctly (citing in full the first time), though you still have problems in formatting your reference links, which only require the PMID number to link correctly. '''10/10'''

==Lab 7 assessment==
(1) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?

It is a mononuclear stem cell that are found in mature skeletal muscle fibres and promote their growth, repair and regeneration, they are usually situated between sarcolemma and basement membrane of muscle fibres.

Satellite cells are activated after muscle strains such as trauma, where myogenic regulatory factors will be expressed and they are similar to those produced by muscle precursor cells during muscle development. These cells proliferate and fuse with each other to form myotubes and slowly mature into myofibres. They can also fuse with damaged segments of muscle fibres. These cells can also give rise to new satellite cells. Heavy exercise can induce muscle hypertrophy which also encourage the growth and proliferation of these muscle satellite cells.

(2)In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?

In situations of long term motor nerve damage, since skeletal muscles are activated by these motor nerves, when they are damaged, the muscles will often lose their function and movement. There can be a complete loss of function or only a part of, depending on the severity of the damage to the nerve. When the muscle lose their initiation, they can present symptoms such as muscle twitching, cramping and muscle can become stiff due to the lack of movement. Muscles paralysed by spinal cord injury are usually atrophic, possesses lower tension generating capacity and is less fatigue resistant compared to normal muscles. Upper motor neuron paralysed muscles lose the normal type I (slow) and II (fast) fibre and become predominantly composed of type II (fast glycolytic) fibres. A transitional period can be seen ranging from 1 to 20 months after the injury where there is usually drop in the proportion of slow muscle fibres and a rise in the development of fast fibres.

==Lab 8 assessment==

''Vision''

I really liked the eye image at the top of the project page, it automatically drags my attention towards the page and it clearly shows what the project is going to be focused on. The introduction was good, its not too long but provide sufficient information about the project and as reader, we know what we can expect from the project page. The image used there is very good as well but maybe more labelling and explanation can be included.

Images from the textbook, Atlas of the development of men, both on the development of lens and the formation of optic vesicle, they are really good. I understand that the page is not complete yet, but just looking at these images, a lot of explanation and labelling need to be put in to ensure that readers know what is going on and actually learn from those images. The development of the optic nerve is good. Information provided is clear and precise. The whole process of the development was explained well and used simple terms so that it is very easy to follow and understand but maybe the images need to be labelled more? I saw that this section of the project, only 1-2 references is used? Maybe try to expand the research and include more information from different sources. I really liked the way that most of the images are hand-drawn, this really shows that you understand the process yourself and able to interpret all the knowledge you gathered from resources and produce something that is easy to understand and can actually teach readers about vision development.

There is a glossary at the end of the page which includes all the scientific terms, maybe expand this section a little bit more. Some scientific words are not included such as mesenchyme, as a science student, maybe we will understand these words but for the general public, they may not. That's why it is essential to have a glossary. I thought having an image gallery was a good idea, in that way, people can concentrate on only the image aspect of the project without all the text in between, allowing a different approach in looking at this project. Referencing of the project overall was good, except there is one citing error, no.13? But this should be quite easy to fix. In terms of variety of resources used, i thought was quite narrow, with the majority resources being websites and lab material from the course. Maybe use more journal articles and reviews to expand the depth of the information presented. The structure and the lay out of the page is very clear with consistent headings and sub-headings, which makes the page very easy to read and follow.

Overall, the project page is looking good.There are just some minor parts to be completed and maybe a little bit more research needs to be done. :) hope this helps.
--Z3331330 18:35, 23 September 2012 (EST)

''Somatosensory''

The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?
The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

''Taste''

The introduction is very detailed but did not mention anything about the development of the taste. But I thought the mechanisms behind sweet and salty tastes are very interesting. Maybe do the same for the other 3 tastes? The image of the basic 5 tastes is a bit small, maybe upload a bigger version of the image. Also, the image is lacking some reference, copyright information and a student image template.

The type II receptor section is pretty good and descriptive but it does not really relate to the development of the taste. The taste map is a very eye-catchy image and it would be really useful if it had all the needed information such as the copyright notice. The timeline of the gustatory system is very well-presented and easy to read. I understand the project is not completed yet, therefore more images are still to be put in. Only 2 references have been used in the timeline section, maybe try to research more and use different resources. There are some citing error but it should be quite easy to fix.

Histories of discoveries section is very detailed and easy to read but the referencing needs to be fixed. The adult tongue and taste bud section is very clear and precise and contain a lot of useful information but it does not really relate to the research topic, should beware of going off-track. The hand-drawn diagram of the taste bud is impressive and easy to understand but again lacking in some referencing information such as who drew it. The abnormalities section is good and well-researched and it is interesting to know about which gene or receptors will effect the development of taste and sensation. Maybe the abnormalities section can be included into the current research section because abnormalities are repeated in the current research section below. There are detailed definitions of terms in the glossary which is good because it really helps the reader to understand more about the research topic.

Overall, the page is looking good. The main thing that needs to be fixed will be the images that are already on the page, they need the correct and essential information with them when uploaded on the page or else, they will get deleted and there will be no images on the page and the nice balance of images and text now will be gone. There seem to be a lot of anatomy and biology of the taste system but not a lot of information about their development. Although there is a timeline of development but i think more information is needed. Referencing is pretty good with only one or two minor citing error but it should be easy to fix. Structure of the page is clear and simple with headings and sub-headings being consistent, making the page easy to read and follow. Hope this helps :)

''Olfaction''

The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.
The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

''Hearing''

Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

==Lab 9 assessment==

(1)Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

'Stam2 expression pattern during embryo development.'

Signal transduction adaptor molecules 1 and 2 (STAM1 and STAM2). They are both involved in the endosomal sorting of the cargo proteins for trafficking towards the lysosome. STAM2 is activated by tyrosine phosphorylation and can also be stimulated by various cytokines and growth factors. It is involved in the regulation of endocytosis and also regulation of intracellular signal transduction for DNA synthesis through JAK2 and JAK3 tyrosine kinases.

In the paper, a mouse line have been created to enable the expression of STAM2 to be observed by X-gal histochemistry. At around embryonic day 16.5, it is evident that STAM2 is expressed in the heart, testes, olfactory bulbs, trigeminal and dorsal root ganglia, pituitary and medulla of the adrenal glands. Around embryonic day 18.5, the expression of STAM2 become much stronger, especially in areas of testes, ovaries, lungs, kidneys, urogenital sinus, pituitary and adrenal glands. Near the end of gestation, STAM2 expression is confined to regions such as nervous tissue, and endocrine organs like pituitary and adrenal glands and they are already highly secretory active at this stage of embryonic development. This paper demonstrates a very strong correlation between the development of the adrenal glands and the expression of STAM2. <ref><pubmed>22143071</pubmed></ref>

(2)Identify the embryonic layers and tissues that contribute to the developing teeth.

Teeth are formed from cells that derived from the ectoderm of the first branchial arch and the ectomesenchyme of the neural crest and also mesoderm.It is organized into 3 parts, the enamel organ, the dental papilla and the dental follicle. The enamel organ give rise to ameloblasts which produce enamel and the reduced enamel epithelium and ultimately determines the root shape of the tooth.The dental papilla contains cells that develop into odontoblasts which determines the crown shape of a tooth. Mesenchymal cells in the dental papilla are for the formation of tooth pulp. The dental follicle contribute to cementoblasts which form the cementum of the tooth, osteoblasts which give rise to the alveolar bone and fibroblasts give rise to periodontal ligamtns.

===References===
<references/>

User:Z3331330

2012-10-01T09:38:03Z

Z3331330: /* Lab 8 assessment */

==Lab Attendance==

Lab 1--[[User:Z3331330|Z3331330]] 11:49, 25 July 2012 (EST)
Lab 2--[[User:Z3331330|Z3331330]] 10:41, 1 August 2012 (EST)
Lab 3--[[User:Z3331330|Z3331330]] 13:00, 8 August 2012 (EST)
Lab 4--[[User:Z3331330|Z3331330]] 10:07, 15 August 2012 (EST)
Lab 5--[[User:Z3331330|Z3331330]] 10:08, 22 August 2012 (EST)
Lab 6--[[User:Z3331330|Z3331330]] 10:10, 29 August 2012 (EST)
Lab 7--[[User:Z3331330|Z3331330]] 10:05, 12 September 2012 (EST)
Lab 8--[[User:Z3331330|Z3331330]] 10:03, 19 September 2012 (EST)
Lab 9--[[User:Z3331330|Z3331330]] 10:08, 26 September 2012 (EST)

==Lab 1 Assessment==
(1)Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.

Many studies and experiments were conducted and they all contributed to the development of In Vitro Fertilization as it is today. Some early studies have used hamster gametes to prove the possibility of mammalian gametes being fertilized in vitro, done by Yanagimachi and Chang in1963. Chang, in 1959 has also done a study that demonstrated the normal development of a rabbit egg that was fertilized in vitro. Numerous experiments were done using different animals and species which proved the success of in vitro fertilization. Capacitation of the sperm in the uterus of the mother was a significant discovery to in vitro fertilisation. On July 25, 1978, the first successful 'test-tube' baby was born. Dr. Patrick Steptoe, a gynecologist and Dr. Robert Edwards, a physiologist, the team who pioneered the IVF were accredited for their contribution to IVF.

In 2010, Robert Edwards was awarded the 'Nobel prize in physiology or medicine' for his contribution in the development of "In Vitro Fertilization", see [http://www.nobelprize.org/]

(2)Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).

'Genes required for the common miracle of fertilization in Caenorhabditis Elegans' <ref><pubmed>18649278</pubmed></ref>

Fertilization is a result of various sperm-egg interactions and together these interactions lead to gamete fusions and egg activation.This paper describes the identity of genes that are responsible for the interactions between gametes during ferilization and the function of protein products that are produced by these specific genes. The paper focuses on the fertilization process in Caenorhabditis Elegans which is a type of worm. There are two main types of molecules that are essential in fertilization and they are sperm function molecules and egg function molecules. Spe-9 gene produces a single-pass transmembrane molecules with extracellular domain that contain 10 epidermal growth factor and it is responsible for adhesion or ligand receptor functions. Its critical presence on the surface of the sperm allow the sperm to bind to the oocytes during fertilization. Other genes such as Spe-38 is also identified with similar function.

Egg function genes such as egg-1 and egg-2 genes lead to the production of type II transmembrane molecules. Loss of these gene can lead to complete hermaphrodite fertility. Sperms will not be able to enter the oocytes.The main function of these genes is to act as oocyte surface receptor for sperms during fertilization. These discoveries and results in C.elegans provide a blueprint of the genetic control involved in the process of fertilization and encouraged discoveries of similar genes that are involved in fertilization in humans.

--[[User:Z8600021|Mark Hill]] 16:30, 11 September 2012 (EST) Question 1 is answered well and I like that you have discussed earlier research. Question 1 is also answered well, though a 2008 paper is not as recent as I was seeking as an answer. You will need to fix your referencing (ref 1 is blank because it is incorrectly formatted and should only contain the PMID (not PMC number) number without text)'''10/10'''

==lab 2 assessment==
===Degradation of ooctyes by sperm proteasomes===
--[[User:Z8600021|Mark Hill]] 16:49, 11 September 2012 (EST) This should be a sub-heading.

(1)[[File:Degradation_of_oocytes_by_sperm_proteasomes.png‎]]

(2) Rac-1 is a member of the Rho GTPases family of proteins. It was discovered that with the activation of the Rac-1 gene, its protein product can regulate the motility of the human endometrial stromal cells (HESCs) in reponse to the implantation of the embryo in the uterine wall. Rac-1 promotes the lamellipodial protrusion at front of the migrating cells. This protein also encourage the migration of HESCs away from the implantation site which then facilitate the invasion of trophoblast and lead to the inplantation of the embryo into the stromal compartment. <ref><pubmed>PMC2562412</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:32, 11 September 2012 (EST) Question 1 image is well named and contains all the requested information. Though the image is quite small 320 × 399 pixels and a larger version should have been sourced, also png files are quite large 125 KB, jpg are smaller). You have also misinterpreted my request as the file name should be a sub-heading on the file summary page, not here. Question 2 is also relevant to implantation. Rac proteins regulate the actin cytoskeleton and this is further explored in the 3rd year Cell Biology course. '''10/10'''

==Lab 3 assessment==

(1)Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

Answer: Gestational age is classified as the time elapsed from the first day of a women's last menstrual period, and the post-fertilization age is referred as the time since the fertilzation of the egg in the woman's uterus. The main difference is their starting date and gestational age is often two weeks earlier than the post-fertilization age. Clinically, gestational age is often used in describing human development because the start date of the gestational age can be clearly defined while the exact time of fertilization can be confusing. It is also essential for predicting consequences to the development of fetus from toxin exposure of infection during the gestational age.It is also important for evaluation of physical findings such as fetal growth and screening markers.

(2)Identify using histological descriptions at least 3 different types of tissues formed from somites.

3 types of tissues formed from somites:
- dermatome --> Skin are formed from dermatome. There are 3 layers to skin, epidermis which contain stratified squamous cells with epidermal ridges with thick layer of keratin. Dermis layer contain a lot of the vasculature such as blood vessels and glands, there are also dense collagen and irregular elastic fibres. Usually, this layer contains a lot of type I collagen fibre. The last layer is the hypodermis layer where its mainly adipose tissue.

- myotome--> skeletal muscle are developed from myotome. Skeletal muscle has a lot of myocytes and they are long and elongated with multiple nucleus. Their nucleus are often pushed to the periphery of the cells. They also contain myosin and actin which are called the thick and thin filament which cause striation appearance of the muscle cells.

- Sclerotome--> vertebrae and rib cartilages are developed from it, where different type of bone cells are present. The extracellular matrix of bone is formed through inorganic material such as phosphate along with some organic component being collagen fibres and ground substance.

--[[User:Z8600021|Mark Hill]] 16:41, 11 September 2012 (EST) Question 1 has been clearly and correctly answered. Question 2 the somite compartments and major tissues correctly identified. The one error is the answer for dermatome suggests that the epidermis is also a component of this compartment, while it is ectodermal in origin. '''9/10'''

==Lab 4 assessment==

(1)Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

The first invasive prenatal diagnostic techniques is called "chorionic villus sampling" and it involves a catheter passed via the vagina through the cervix and into the uterus to the placenta, under the guidance of ultrasound. There can be other approaches as well such as transvaginal and transabdominal. The catheter will then collect sample of the chorionic villus which is placental tissue. The sample will then be analyse for any chromosomal abnormalities or genetic disorders, and the karotype of the fetus will be determined.

The second technique is "Placental biopsy", it is similiar to the chorionic villus sampling, but it has a transabdominal approach to it. It can be performed at a later stage of the pregnancy. It is used to obtain a rapid result. The karyotype of the fetus can be determined and genetic disorders can be detected such as trisomy 21 and monosomy X.

(2)Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

"Transplantation of microencapsulated umbilical-cord-bloodderived hepatic-like cells for treatment of hepatic failure" [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3051145/?tool=pmcentrez]

The paper aim to investigate intraperitoneal transplantation of microencapsulated hepatic-like cells from human umbilical cord blood for treatment of hepatic failure in rats. There are a few candidates for this experiment but human umbilical cord blood (UCB) cells were thought to be the best as they have some advantages that other cells do not have. The frequencies of UCB hematopoietic stem or progenitor cells is much higher than those from bone marrow and peripheral blood. The paper also mentioned that there are three ways of inducing the UCB cells into hepatocytes-like cells and they are Co-culture with injured liver cell, growth factor-assisted and MNC transplantation.

In the experiment, CD34 cells are isolated from the UCB cells and through the combination of fibroblast growth factor and hepatocyte growth factor, the CD34 cells are induced to hepatocytes-like cells.
It was found that in the cultured cells, the level of human albumin, alpha-fetoprotein and GATA-4 mRNA and albumin positive cells have increased significantly suggesting the transformation of the CD34 cells into hepatic-like cells. The cultured system with growth factors have the ability to convert these UCB cells into hepatocytes phenotype and it is confirmed through PCR and immunohistochemcial staining. Then these hepatic-like cells are encapsulated and transplanted into the abdominal cavity of rats with acute hepatic failure. The transplantation occurs 48 hours after the onset of an acute hepatic failure.The microencapsulation of the cells provide a possibility to overcome the immuno-rejection from the AHF rats.

The result obtained from this experiment was that CD34 cells from the UCB cells can be converted into hepatic-like cells under suitable conditions with appropriate growth factors. The transplantation of these encapsulated hepatic-like cells have resulted in decreased mortality of the AHF rats. But these hepatic-like cells can only offer short term metabolic effect to these AHF rats and cannot interrupt or repair the damaged hepatocytes. Therefore the conclusion of this paper suggests the possibility of UCB cells used in conversion to hepatic-like cells that can temporarily alleviate the symptoms of Acute hepatic failure in rats bur not regenerating healthy hepatocytes. <ref><pubmed>PMC3051145</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:46, 11 September 2012 (EST) Question 1 You have clearly identified 2 invasive techniques diagnostic techniques. I would have liked specific disorders for the first technique, as you have for the second technique. Question 2 this is an excellent description of the paper and technique. You have used the UCB acronym correctly (citing in full the first time), though you still have problems in formatting your reference links, which only require the PMID number to link correctly. '''10/10'''

==Lab 7 assessment==
(1) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?

It is a mononuclear stem cell that are found in mature skeletal muscle fibres and promote their growth, repair and regeneration, they are usually situated between sarcolemma and basement membrane of muscle fibres.

Satellite cells are activated after muscle strains such as trauma, where myogenic regulatory factors will be expressed and they are similar to those produced by muscle precursor cells during muscle development. These cells proliferate and fuse with each other to form myotubes and slowly mature into myofibres. They can also fuse with damaged segments of muscle fibres. These cells can also give rise to new satellite cells. Heavy exercise can induce muscle hypertrophy which also encourage the growth and proliferation of these muscle satellite cells.

(2)In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?

In situations of long term motor nerve damage, since skeletal muscles are activated by these motor nerves, when they are damaged, the muscles will often lose their function and movement. There can be a complete loss of function or only a part of, depending on the severity of the damage to the nerve. When the muscle lose their initiation, they can present symptoms such as muscle twitching, cramping and muscle can become stiff due to the lack of movement. Muscles paralysed by spinal cord injury are usually atrophic, possesses lower tension generating capacity and is less fatigue resistant compared to normal muscles. Upper motor neuron paralysed muscles lose the normal type I (slow) and II (fast) fibre and become predominantly composed of type II (fast glycolytic) fibres. A transitional period can be seen ranging from 1 to 20 months after the injury where there is usually drop in the proportion of slow muscle fibres and a rise in the development of fast fibres.

==Lab 8 assessment==

''Vision''

I really liked the eye image at the top of the project page, it automatically drags my attention towards the page and it clearly shows what the project is going to be focused on. The introduction was good, its not too long but provide sufficient information about the project and as reader, we know what we can expect from the project page. The image used there is very good as well but maybe more labelling and explanation can be included.

Images from the textbook, Atlas of the development of men, both on the development of lens and the formation of optic vesicle, they are really good. I understand that the page is not complete yet, but just looking at these images, a lot of explanation and labelling need to be put in to ensure that readers know what is going on and actually learn from those images. The development of the optic nerve is good. Information provided is clear and precise. The whole process of the development was explained well and used simple terms so that it is very easy to follow and understand but maybe the images need to be labelled more? I saw that this section of the project, only 1-2 references is used? Maybe try to expand the research and include more information from different sources. I really liked the way that most of the images are hand-drawn, this really shows that you understand the process yourself and able to interpret all the knowledge you gathered from resources and produce something that is easy to understand and can actually teach readers about vision development.

There is a glossary at the end of the page which includes all the scientific terms, maybe expand this section a little bit more. Some scientific words are not included such as mesenchyme, as a science student, maybe we will understand these words but for the general public, they may not. That's why it is essential to have a glossary. I thought having an image gallery was a good idea, in that way, people can concentrate on only the image aspect of the project without all the text in between, allowing a different approach in looking at this project. Referencing of the project overall was good, except there is one citing error, no.13? But this should be quite easy to fix. In terms of variety of resources used, i thought was quite narrow, with the majority resources being websites and lab material from the course. Maybe use more journal articles and reviews to expand the depth of the information presented. The structure and the lay out of the page is very clear with consistent headings and sub-headings, which makes the page very easy to read and follow.

Overall, the project page is looking good.There are just some minor parts to be completed and maybe a little bit more research needs to be done. :) hope this helps.
--Z3331330 18:35, 23 September 2012 (EST)

''Somatosensory''

The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?
The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

''Taste''

The introduction is very detailed but did not mention anything about the development of the taste. But I thought the mechanisms behind sweet and salty tastes are very interesting. Maybe do the same for the other 3 tastes? The image of the basic 5 tastes is a bit small, maybe upload a bigger version of the image. Also, the image is lacking some reference, copyright information and a student image template.

The type II receptor section is pretty good and descriptive but it does not really relate to the development of the taste. The taste map is a very eye-catchy image and it would be really useful if it had all the needed information such as the copyright notice. The timeline of the gustatory system is very well-presented and easy to read. I understand the project is not completed yet, therefore more images are still to be put in. Only 2 references have been used in the timeline section, maybe try to research more and use different resources. There are some citing error but it should be quite easy to fix.

Histories of discoveries section is very detailed and easy to read but the referencing needs to be fixed. The adult tongue and taste bud section is very clear and precise and contain a lot of useful information but it does not really relate to the research topic, should beware of going off-track. The hand-drawn diagram of the taste bud is impressive and easy to understand but again lacking in some referencing information such as who drew it. The abnormalities section is good and well-researched and it is interesting to know about which gene or receptors will effect the development of taste and sensation. Maybe the abnormalities section can be included into the current research section because abnormalities are repeated in the current research section below. There are detailed definitions of terms in the glossary which is good because it really helps the reader to understand more about the research topic.

Overall, the page is looking good. The main thing that needs to be fixed will be the images that are already on the page, they need the correct and essential information with them when uploaded on the page or else, they will get deleted and there will be no images on the page and the nice balance of images and text now will be gone. There seem to be a lot of anatomy and biology of the taste system but not a lot of information about their development. Although there is a timeline of development but i think more information is needed. Referencing is pretty good with only one or two minor citing error but it should be easy to fix. Structure of the page is clear and simple with headings and sub-headings being consistent, making the page easy to read and follow. Hope this helps :)

''Olfaction''

The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.
The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

''Hearing''

Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

==Lab 9 assessment==

(1)Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.

'Stam2 expression pattern during embryo development.'<ref><pubmed>22143071</pubmed></ref>

Signal transduction adaptor molecules 1 and 2 (STAM1 and STAM2). They are both involved in the endosomal sorting of the cargo proteins for trafficking towards the lysosome. STAM2 is activated by tyrosine phosphorylation and can also be stimulated by various cytokines and growth factors. It is involved in the regulation of endocytosis and also regulation of intracellular signal transduction for DNA synthesis through JAK2 and JAK3 tyrosine kinases.

In the paper, a mouse line have been created to enable the expression of STAM2 to be observed by X-gal histochemistry. At around embryonic day 16.5, it is evident that STAM2 is expressed in the heart, testes, olfactory bulbs, trigeminal and dorsal root ganglia, pituitary and medulla of the adrenal glands. Around embryonic day 18.5, the expression of STAM2 become much stronger, especially in areas of testes, ovaries, lungs, kidneys, urogenital sinus, pituitary and adrenal glands. Near the end of gestation, STAM2 expression is confined to regions such as nervous tissue, and endocrine organs like pituitary and adrenal glands and they are already highly secretory active at this stage of embryonic development. This paper demonstrates a very strong correlation between the development of the adrenal glands and the expression of STAM2.

(2)Identify the embryonic layers and tissues that contribute to the developing teeth.

Teeth are formed from cells that derived from the ectoderm of the first branchial arch and the ectomesenchyme of the neural crest and also mesoderm.It is organized into 3 parts, the enamel organ, the dental papilla and the dental follicle. The enamel organ give rise to ameloblasts which produce enamel and the reduced enamel epithelium and ultimately determines the root shape of the tooth.The dental papilla contains cells that develop into odontoblasts which determines the crown shape of a tooth. Mesenchymal cells in the dental papilla are for the formation of tooth pulp. The dental follicle contribute to cementoblasts which form the cementum of the tooth, osteoblasts which give rise to the alveolar bone and fibroblasts give rise to periodontal ligamtns.

===References===
<references/>

2012 Group Project 5

2012-09-26T01:50:16Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.
[[Sensory_-_Vision_Development|blah]]

[[:File:Historic_retina_drawing.jpg|historic picture]]

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
----
'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>
[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

'''New Research Development for LCA'''

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name= genes>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name= genes/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-26T01:47:42Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.
[[Sensory_-_Vision_Development|blah]]

[[:File:Historic_retina_drawing.jpg|historic picture]]

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>
[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

'''New Research Development for LCA'''

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref><ref name=anophthalmia>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name=anophthalmia/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-26T01:44:07Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.
[[Sensory_-_Vision_Development|blah]]

[[:File:Historic_retina_drawing.jpg|historic picture]]

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
----
The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name=PMID20301552/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
----

====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
----

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-26T01:43:10Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.
[[Sensory_-_Vision_Development|blah]]

[[:File:Historic_retina_drawing.jpg|historic picture]]

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
----
'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause [[#Glossary|anterior segment dysgenesis]] and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an [[#Glossary|Autosomal recessive]] pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with [[#Glossary|Retinitis Pigmentosia]] which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as [[#Glossary|Bardet-Biedl syndrome]] and [[#Glossary|Senior-Loken syndrome]] for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced [[#Glossary|Electroretinogram (ERG)]] measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref>Bardakjian T, Weiss A, Schneider AS. Anophthalmia / Microphthalmia Overview. 2004 Jan 29 [Updated 2007 Feb 15]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993 http://www.ncbi.nlm.nih.gov/books/NBK1378/</ref><pubmed>20301552</pubmed></ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name=PMID20301552/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of [[#Glossay|uveal effusions]] and [[#Glossary|choroidal detachments]], and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-26T01:26:58Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.
[[Sensory_-_Vision_Development|blah]]

[[:File:Historic_retina_drawing.jpg|historic picture]]

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
----
'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
----
'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name=PMID20301552><pubmed>20301552</pubmed></ref><ref name=PMID21825993><pubmed>21825993</pubmed></ref><ref name=PMID18039390><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name=PMID21825993 /> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name=PMID20301552/><ref name="PMID21825993"/><ref name=PMID18039390 />Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-26T01:23:49Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.
[[Sensory_-_Vision_Development|blah]]

[[:File:Historic_retina_drawing.jpg|historic picture]]

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and [[#Glossary|Albinism]]
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993</pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552"/><ref name="PMID21825993"/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488</pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-26T01:21:39Z

Z3331330: /* Abnormal Lens Development */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.
[[Sensory_-_Vision_Development|blah]]

[[:File:Historic_retina_drawing.jpg|historic picture]]

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
----
The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-26T01:21:07Z

Z3331330: /* Abnormal Lens Development */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.
[[Sensory_-_Vision_Development|blah]]

[[:File:Historic_retina_drawing.jpg|historic picture]]

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''

[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
----
The condition of anophthalmia refers to complete absence of the globe in the presence of ocular [[#Glossary|adnexa]] (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
----

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-26T01:19:04Z

Z3331330: /* Abnormal Lens Development */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.
[[Sensory_-_Vision_Development|blah]]

[[:File:Historic_retina_drawing.jpg|historic picture]]

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
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'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png|400px]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
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'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
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'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Disorders==

Major ocular disorders can be split into two separate sections based on the way in which they originated.
*Genetic disorders are cause when there is a mutation to genes which allow for ocular development.
*Environmental disorders are caused when external factors disrupt the mechanisms or genes involved in ocular development

===Genetic Ocular Disorders===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- [[#Glossary|Human adeno-associated virus (AAV)]] was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
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The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
----

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

File:Images of congenital hereditary cataracts due to mutations of crystallin genes.png

2012-09-26T01:06:25Z

Z3331330:

Slit-lamp photographs of the eye of the proband. Slit lamp photographs of the eye of the proband (III:3). A: Front view of the eye of the proband, showing cataract phenotype. B: Slit lamp view of the len of the proband. Lens opacities were mainly located in the nuclear area of lenses as well as in the embryonal and fetal areas.

Images of congenital hereditary cataracts from crystallin mutations<ref>Chen, Q, Ma,J,Yan,M,Mothobi,ME, Liu,Y, Zheng, F, '''A novel mutation in CRYAB associated with autosomal dominant congenital nuclear cataract in a Chinese family''' 2009 Mol Vis, vol:15,pp.1359–1365.[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC2709425/?tool=pmcentrez]</ref>
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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

[[File:Images of congenital hereditary cataracts due to mutations of crystallin genes.png|300px]]
===reference===
<references/>

{{Template:Student Image}}

2012 Group Project 5

2012-09-26T00:59:36Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref name=PMC1233106><pubmed>PMC1233106</pubmed></ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref name=PMC1233106/><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref name=PMC1233106/>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===
----
'''Overview of Normal Lens Development'''

As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage.<ref name=PMID10627820><pubmed>10627820</pubmed></ref> <ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref name=PMID10627820/>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref name=PMID10627820/> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===
----
'''Overview of Normal Corneal Development'''

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===
----
'''Overview of Normal Retinal Development'''

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic Ocular Disorders===
----
====Leber Congenital Amaurosis====
----
Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[#Abnormal Retinal Development|Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Clinical Manifestation'''

As stated above Leber was the first to identify the clinical appreance of LCA which are still used today. While sufferers of LCA can be blind from birth or suffer sever visual loss during infancy, other manifestations found in sufferers of LCA can include all or some of the following<ref name=PMID15231395/>:
*Wandering Nystagmus <ref name=PMID15231395/>
*Amaurotic pupils <ref name=PMID15231395/>
*Pigmentary Retinopathy <ref name=PMID15231395/>

'''Research Timeline of LCA'''

From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1965'''- Human adeno-associated virus (AAV) was discovered. This discovery is important as it has become an important research avenue for retinal regeneration therapies<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''Treatment'''

To date there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>

'''New Research Development for LCA'''

[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

A current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
----
The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental Ocular Disorders===
----

====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref name=PMID2910286><pubmed>2910286</pubmed></ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref name="PMID8735731"><pubmed>8735731</pubmed></ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref name="PMID8735731"/> Premature delivery is increased by 12.4% also. <ref name="PMID8735731"/>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref name="PMID8735731"/> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref name=PMID2910286/>

====Fetal alcohol syndrome====
----

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

*'''Adeno-Assocaited virus (AAV)''' - A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Adnexa''' - Accessory anatomical parts

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

----

{{2012Projects}}

User:Z3331330

2012-09-26T00:08:17Z

Z3331330: /* Lab Attendance */

==Lab Attendance==

Lab 1--[[User:Z3331330|Z3331330]] 11:49, 25 July 2012 (EST)
Lab 2--[[User:Z3331330|Z3331330]] 10:41, 1 August 2012 (EST)
Lab 3--[[User:Z3331330|Z3331330]] 13:00, 8 August 2012 (EST)
Lab 4--[[User:Z3331330|Z3331330]] 10:07, 15 August 2012 (EST)
Lab 5--[[User:Z3331330|Z3331330]] 10:08, 22 August 2012 (EST)
Lab 6--[[User:Z3331330|Z3331330]] 10:10, 29 August 2012 (EST)
Lab 7--[[User:Z3331330|Z3331330]] 10:05, 12 September 2012 (EST)
Lab 8--[[User:Z3331330|Z3331330]] 10:03, 19 September 2012 (EST)
Lab 9--[[User:Z3331330|Z3331330]] 10:08, 26 September 2012 (EST)

==Lab 1 Assessment==
(1)Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique and add a correctly formatted link to the Nobel page.

Many studies and experiments were conducted and they all contributed to the development of In Vitro Fertilization as it is today. Some early studies have used hamster gametes to prove the possibility of mammalian gametes being fertilized in vitro, done by Yanagimachi and Chang in1963. Chang, in 1959 has also done a study that demonstrated the normal development of a rabbit egg that was fertilized in vitro. Numerous experiments were done using different animals and species which proved the success of in vitro fertilization. Capacitation of the sperm in the uterus of the mother was a significant discovery to in vitro fertilisation. On July 25, 1978, the first successful 'test-tube' baby was born. Dr. Patrick Steptoe, a gynecologist and Dr. Robert Edwards, a physiologist, the team who pioneered the IVF were accredited for their contribution to IVF.

In 2010, Robert Edwards was awarded the 'Nobel prize in physiology or medicine' for his contribution in the development of "In Vitro Fertilization", see [http://www.nobelprize.org/]

(2)Identify and add a PubMed reference link to a recent paper on fertilisation and describe its key findings (1-2 paragraphs).

'Genes required for the common miracle of fertilization in Caenorhabditis Elegans' <ref><pubmed>18649278</pubmed></ref>

Fertilization is a result of various sperm-egg interactions and together these interactions lead to gamete fusions and egg activation.This paper describes the identity of genes that are responsible for the interactions between gametes during ferilization and the function of protein products that are produced by these specific genes. The paper focuses on the fertilization process in Caenorhabditis Elegans which is a type of worm. There are two main types of molecules that are essential in fertilization and they are sperm function molecules and egg function molecules. Spe-9 gene produces a single-pass transmembrane molecules with extracellular domain that contain 10 epidermal growth factor and it is responsible for adhesion or ligand receptor functions. Its critical presence on the surface of the sperm allow the sperm to bind to the oocytes during fertilization. Other genes such as Spe-38 is also identified with similar function.

Egg function genes such as egg-1 and egg-2 genes lead to the production of type II transmembrane molecules. Loss of these gene can lead to complete hermaphrodite fertility. Sperms will not be able to enter the oocytes.The main function of these genes is to act as oocyte surface receptor for sperms during fertilization. These discoveries and results in C.elegans provide a blueprint of the genetic control involved in the process of fertilization and encouraged discoveries of similar genes that are involved in fertilization in humans.

--[[User:Z8600021|Mark Hill]] 16:30, 11 September 2012 (EST) Question 1 is answered well and I like that you have discussed earlier research. Question 1 is also answered well, though a 2008 paper is not as recent as I was seeking as an answer. You will need to fix your referencing (ref 1 is blank because it is incorrectly formatted and should only contain the PMID (not PMC number) number without text)'''10/10'''

==lab 2 assessment==
===Degradation of ooctyes by sperm proteasomes===
--[[User:Z8600021|Mark Hill]] 16:49, 11 September 2012 (EST) This should be a sub-heading.

(1)[[File:Degradation_of_oocytes_by_sperm_proteasomes.png‎]]

(2) Rac-1 is a member of the Rho GTPases family of proteins. It was discovered that with the activation of the Rac-1 gene, its protein product can regulate the motility of the human endometrial stromal cells (HESCs) in reponse to the implantation of the embryo in the uterine wall. Rac-1 promotes the lamellipodial protrusion at front of the migrating cells. This protein also encourage the migration of HESCs away from the implantation site which then facilitate the invasion of trophoblast and lead to the inplantation of the embryo into the stromal compartment. <ref><pubmed>PMC2562412</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:32, 11 September 2012 (EST) Question 1 image is well named and contains all the requested information. Though the image is quite small 320 × 399 pixels and a larger version should have been sourced, also png files are quite large 125 KB, jpg are smaller). You have also misinterpreted my request as the file name should be a sub-heading on the file summary page, not here. Question 2 is also relevant to implantation. Rac proteins regulate the actin cytoskeleton and this is further explored in the 3rd year Cell Biology course. '''10/10'''

==Lab 3 assessment==

(1)Identify the difference between "gestational age" and "post-fertilisation age" and explain why clinically "gestational age" is used in describing human development.

Answer: Gestational age is classified as the time elapsed from the first day of a women's last menstrual period, and the post-fertilization age is referred as the time since the fertilzation of the egg in the woman's uterus. The main difference is their starting date and gestational age is often two weeks earlier than the post-fertilization age. Clinically, gestational age is often used in describing human development because the start date of the gestational age can be clearly defined while the exact time of fertilization can be confusing. It is also essential for predicting consequences to the development of fetus from toxin exposure of infection during the gestational age.It is also important for evaluation of physical findings such as fetal growth and screening markers.

(2)Identify using histological descriptions at least 3 different types of tissues formed from somites.

3 types of tissues formed from somites:
- dermatome --> Skin are formed from dermatome. There are 3 layers to skin, epidermis which contain stratified squamous cells with epidermal ridges with thick layer of keratin. Dermis layer contain a lot of the vasculature such as blood vessels and glands, there are also dense collagen and irregular elastic fibres. Usually, this layer contains a lot of type I collagen fibre. The last layer is the hypodermis layer where its mainly adipose tissue.

- myotome--> skeletal muscle are developed from myotome. Skeletal muscle has a lot of myocytes and they are long and elongated with multiple nucleus. Their nucleus are often pushed to the periphery of the cells. They also contain myosin and actin which are called the thick and thin filament which cause striation appearance of the muscle cells.

- Sclerotome--> vertebrae and rib cartilages are developed from it, where different type of bone cells are present. The extracellular matrix of bone is formed through inorganic material such as phosphate along with some organic component being collagen fibres and ground substance.

--[[User:Z8600021|Mark Hill]] 16:41, 11 September 2012 (EST) Question 1 has been clearly and correctly answered. Question 2 the somite compartments and major tissues correctly identified. The one error is the answer for dermatome suggests that the epidermis is also a component of this compartment, while it is ectodermal in origin. '''9/10'''

==Lab 4 assessment==

(1)Identify the 2 invasive prenatal diagnostic techniques related to the placenta and 2 abnormalities that can be identified with these techniques.

The first invasive prenatal diagnostic techniques is called "chorionic villus sampling" and it involves a catheter passed via the vagina through the cervix and into the uterus to the placenta, under the guidance of ultrasound. There can be other approaches as well such as transvaginal and transabdominal. The catheter will then collect sample of the chorionic villus which is placental tissue. The sample will then be analyse for any chromosomal abnormalities or genetic disorders, and the karotype of the fetus will be determined.

The second technique is "Placental biopsy", it is similiar to the chorionic villus sampling, but it has a transabdominal approach to it. It can be performed at a later stage of the pregnancy. It is used to obtain a rapid result. The karyotype of the fetus can be determined and genetic disorders can be detected such as trisomy 21 and monosomy X.

(2)Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.

"Transplantation of microencapsulated umbilical-cord-bloodderived hepatic-like cells for treatment of hepatic failure" [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3051145/?tool=pmcentrez]

The paper aim to investigate intraperitoneal transplantation of microencapsulated hepatic-like cells from human umbilical cord blood for treatment of hepatic failure in rats. There are a few candidates for this experiment but human umbilical cord blood (UCB) cells were thought to be the best as they have some advantages that other cells do not have. The frequencies of UCB hematopoietic stem or progenitor cells is much higher than those from bone marrow and peripheral blood. The paper also mentioned that there are three ways of inducing the UCB cells into hepatocytes-like cells and they are Co-culture with injured liver cell, growth factor-assisted and MNC transplantation.

In the experiment, CD34 cells are isolated from the UCB cells and through the combination of fibroblast growth factor and hepatocyte growth factor, the CD34 cells are induced to hepatocytes-like cells.
It was found that in the cultured cells, the level of human albumin, alpha-fetoprotein and GATA-4 mRNA and albumin positive cells have increased significantly suggesting the transformation of the CD34 cells into hepatic-like cells. The cultured system with growth factors have the ability to convert these UCB cells into hepatocytes phenotype and it is confirmed through PCR and immunohistochemcial staining. Then these hepatic-like cells are encapsulated and transplanted into the abdominal cavity of rats with acute hepatic failure. The transplantation occurs 48 hours after the onset of an acute hepatic failure.The microencapsulation of the cells provide a possibility to overcome the immuno-rejection from the AHF rats.

The result obtained from this experiment was that CD34 cells from the UCB cells can be converted into hepatic-like cells under suitable conditions with appropriate growth factors. The transplantation of these encapsulated hepatic-like cells have resulted in decreased mortality of the AHF rats. But these hepatic-like cells can only offer short term metabolic effect to these AHF rats and cannot interrupt or repair the damaged hepatocytes. Therefore the conclusion of this paper suggests the possibility of UCB cells used in conversion to hepatic-like cells that can temporarily alleviate the symptoms of Acute hepatic failure in rats bur not regenerating healthy hepatocytes. <ref><pubmed>PMC3051145</pubmed></ref>

--[[User:Z8600021|Mark Hill]] 16:46, 11 September 2012 (EST) Question 1 You have clearly identified 2 invasive techniques diagnostic techniques. I would have liked specific disorders for the first technique, as you have for the second technique. Question 2 this is an excellent description of the paper and technique. You have used the UCB acronym correctly (citing in full the first time), though you still have problems in formatting your reference links, which only require the PMID number to link correctly. '''10/10'''

==Lab 7 assessment==
(1) Provide a one sentence definition of a muscle satellite cell (b) In one paragraph, briefly discuss two examples of when satellite cells are activated ?

It is a mononuclear stem cell that are found in mature skeletal muscle fibres and promote their growth, repair and regeneration, they are usually situated between sarcolemma and basement membrane of muscle fibres.

Satellite cells are activated after muscle strains such as trauma, where myogenic regulatory factors will be expressed and they are similar to those produced by muscle precursor cells during muscle development. These cells proliferate and fuse with each other to form myotubes and slowly mature into myofibres. They can also fuse with damaged segments of muscle fibres. These cells can also give rise to new satellite cells. Heavy exercise can induce muscle hypertrophy which also encourage the growth and proliferation of these muscle satellite cells.

(2)In one brief paragraph, describe what happens to skeletal muscle fibre type and size when the innervating motor nerve sustains long term damage such as in spinal cord injury?

In situations of long term motor nerve damage, since skeletal muscles are activated by these motor nerves, when they are damaged, the muscles will often lose their function and movement. There can be a complete loss of function or only a part of, depending on the severity of the damage to the nerve. When the muscle lose their initiation, they can present symptoms such as muscle twitching, cramping and muscle can become stiff due to the lack of movement. Muscles paralysed by spinal cord injury are usually atrophic, possesses lower tension generating capacity and is less fatigue resistant compared to normal muscles. Upper motor neuron paralysed muscles lose the normal type I (slow) and II (fast) fibre and become predominantly composed of type II (fast glycolytic) fibres. A transitional period can be seen ranging from 1 to 20 months after the injury where there is usually drop in the proportion of slow muscle fibres and a rise in the development of fast fibres.

==Lab 8 assessment==

''Vision''

I really liked the eye image at the top of the project page, it automatically drags my attention towards the page and it clearly shows what the project is going to be focused on. The introduction was good, its not too long but provide sufficient information about the project and as reader, we know what we can expect from the project page. The image used there is very good as well but maybe more labelling and explanation can be included.

Images from the textbook, Atlas of the development of men, both on the development of lens and the formation of optic vesicle, they are really good. I understand that the page is not complete yet, but just looking at these images, a lot of explanation and labelling need to be put in to ensure that readers know what is going on and actually learn from those images. The development of the optic nerve is good. Information provided is clear and precise. The whole process of the development was explained well and used simple terms so that it is very easy to follow and understand but maybe the images need to be labelled more? I saw that this section of the project, only 1-2 references is used? Maybe try to expand the research and include more information from different sources. I really liked the way that most of the images are hand-drawn, this really shows that you understand the process yourself and able to interpret all the knowledge you gathered from resources and produce something that is easy to understand and can actually teach readers about vision development.

There is a glossary at the end of the page which includes all the scientific terms, maybe expand this section a little bit more. Some scientific words are not included such as mesenchyme, as a science student, maybe we will understand these words but for the general public, they may not. That's why it is essential to have a glossary. I thought having an image gallery was a good idea, in that way, people can concentrate on only the image aspect of the project without all the text in between, allowing a different approach in looking at this project. Referencing of the project overall was good, except there is one citing error, no.13? But this should be quite easy to fix. In terms of variety of resources used, i thought was quite narrow, with the majority resources being websites and lab material from the course. Maybe use more journal articles and reviews to expand the depth of the information presented. The structure and the lay out of the page is very clear with consistent headings and sub-headings, which makes the page very easy to read and follow.

Overall, the project page is looking good.There are just some minor parts to be completed and maybe a little bit more research needs to be done. :) hope this helps.
--Z3331330 18:35, 23 September 2012 (EST)

''Somatosensory''

The introduction is very detailed and precise, and it really prepares the readers for what is going to be covered within the project. I thought it was a good introduction but the referencing needs to be fixed up because it looks really different too all the other parts of the project. I do not think that style of in-text citation is needed for the purpose of this project. The histories of discoveries will look better if it is in dot-points, it would be so much easier to read.

In the central somatosensory differentiation section, you mentioned that there are three components, but to me, only the primary somatosensory cortex has been extensively researched, i think more research should be done on the other two components. There is an imbalance of information between the three components. Also, I can see that only 2 references have been used in this entire section, maybe this is why there is an imbalance of information. Using a large variety of resources will definitely expand your knowledge and enable you to put in more information in this section. I thought the hand-drawn image was impressive but the colour is a bit vague and hard to see. A larger version of the image should be uploaded so that it is easier to see.

The "making connection" section has very good description on the physiology and the signalling process of CNS but I do not really understand the stages? Are they the stage events that are involved in embryonic development? Some more detailed explanation is needed here, and maybe some images will help?
The touch section has some good information but again only 2 references have been used which shows the need for further research. Images should be put in here because right now it is very crowded with text. Also, the same problem keeps occurring throughout the project, I feel like there are lots of information about the function of different components of the somatosensory system but not how they are developed. Make sure you do not go off track. There are some weird referencing in the hot/cold section which needs fixing up. There are nothing in the glossary, scientific terms and definition should be put here because not everyone will understand the terms used within the project page. The structure of the project was good though, very clear and simple which makes the page very easy to follow.

Overall, the page is looking good but maybe more research should be done and more images should be put in to balance with the large amount of text. Also, keeping the information related to the research topic will be a huge aspect to focus on. Hope this helps :)

''Taste''

The introduction is very detailed but did not mention anything about the development of the taste. But I thought the mechanisms behind sweet and salty tastes are very interesting. Maybe do the same for the other 3 tastes? The image of the basic 5 tastes is a bit small, maybe upload a bigger version of the image. Also, the image is lacking some reference, copyright information and a student image template.

The type II receptor section is pretty good and descriptive but it does not really relate to the development of the taste. The taste map is a very eye-catchy image and it would be really useful if it had all the needed information such as the copyright notice. The timeline of the gustatory system is very well-presented and easy to read. I understand the project is not completed yet, therefore more images are still to be put in. Only 2 references have been used in the timeline section, maybe try to research more and use different resources. There are some citing error but it should be quite easy to fix.

Histories of discoveries section is very detailed and easy to read but the referencing needs to be fixed. The adult tongue and taste bud section is very clear and precise and contain a lot of useful information but it does not really relate to the research topic, should beware of going off-track. The hand-drawn diagram of the taste bud is impressive and easy to understand but again lacking in some referencing information such as who drew it. The abnormalities section is good and well-researched and it is interesting to know about which gene or receptors will effect the development of taste and sensation. Maybe the abnormalities section can be included into the current research section because abnormalities are repeated in the current research section below. There are detailed definitions of terms in the glossary which is good because it really helps the reader to understand more about the research topic.

Overall, the page is looking good. The main thing that needs to be fixed will be the images that are already on the page, they need the correct and essential information with them when uploaded on the page or else, they will get deleted and there will be no images on the page and the nice balance of images and text now will be gone. There seem to be a lot of anatomy and biology of the taste system but not a lot of information about their development. Although there is a timeline of development but i think more information is needed. Referencing is pretty good with only one or two minor citing error but it should be easy to fix. Structure of the page is clear and simple with headings and sub-headings being consistent, making the page easy to read and follow. Hope this helps :)

''Olfaction''

The introduction is quite small but very precise, indicating the function and the components of the olfactory system but maybe include one or two sentences in the introduction telling readers that it is actually about the development of the olfactory system, not just the function and components of it. After all, introduction is meant to show others what your project is about. The hand-drawn image there is very nice but maybe more information need to be provided other than just labelling parts of it. Along with the image, there are the important informations such as the copyright notice which is good to see.

The history of discoveries section is very well-researched but it will be easier to read if it was in a table. The timeline, i thought was very good because there are a lot of useful information about the development of olfaction which relates to the research topic. The developmental process is explained in quite simple terms but i notice some of the scientific terms in the timeline are not explained in the glossary, this makes it a little bit hard to understand the whole process. It is very interesting that a youtube link has been included in the structure section, this is really a good peer teaching but make sure you referenced the video correctly to avoid plagiarism. The section on Kallman's syndrome is quite interesting but the structure of that section is a bit messy, maybe try clarifying and tidy it up a lit. But i can see that a lot of research effort has been put into it which is good and the variety of resources used in the section is very broad. More images should be put here because right now, there is just a huge block of text in the section. Images will balance out the heavy text load and attract readers more.
The current research section contains a lot of useful information and it relates to the research topic well. Again, images should be put here because right now, there are just small blocks of text in the section without any images, this maybe a little bit boring for readers.

Overall, the project looks well-researched and relates pretty well to the research topic. The balance of the images and text still needs to be fixed but in terms of the text and information on the page, i think it is pretty sufficient and in-depth especially the timeline of development and current research section. There are some terms in the glossary which is good but maybe more terms should be added. The structure of the page is good, very easy to follow. There are a few external links which is always good to put there for anyone that are interested by the topic and want some further information about it. Referencing is good, there is only one minor citing error (no.7), but it should be easy to fix. Hope this helps :)

''Hearing''

Good use of image, it attracts my attention straight away and it is very relaxing to look at a funny image before reading the text. Introduction is precise and to point, clearly identifying the purpose of the project and gives a general overview of what the readers will see or learn from the project. The timeline for history is good, but maybe indicate what kind of history is it? The adult anatomy and histology section is good but the heading should be "adult ear anatomy and histology"? I like it how the ear is divided into outer ear, middle ear and inner ear and then it is further divided into components that are included in these 3 different parts of the ear. This makes the structure of the ear very easy to understand and we can locate the different structure of the ear much easily. The image used in this section is very good with clearly labelled structures, the image also contained all the important information and referenced correctly but you forgot to include the student image template.

The development section is well-researched and contain a lot of information. More images should be put in to balance out the heavy text load in the section but the information provided is very in-depth and precise. The developmental process is explained in simple terms but i noticed that there is an imbalance in terms of research and information between middle ear and the other two. Maybe more research should be done on the middle ear. The summary of the inner idea was a good idea because it clearly points out the main points that readers should know, should consider do something similar for both the outer and middle ear.

The abnormal hearing section is well-researched and interesting. It is very nice to know about the association between gene mutation and its influence on hearing development. Maybe some images should be put here to balance out the text a bit. The table of genetic syndrome is very nice, maybe you can consider putting the gene mutations into table as well. The environmental section is nice and well-researched but maybe images should be put here because right now it is pretty boring just going through all the text. And there are just some weird reference under each infections but i think this can be fixed soon. Structural malformation of the ear table is nice as well, clearly showing all the important information. It will look even better when all the images are put in.

Overall, i thought the project is really good. Contained a lot of useful information and a lot of research effort has been put in, all the information are related to the research topic. The tables work really well and the structure of the page is easy to follow. Referencing is generally good but maybe get rid of some of the random citations in sections. More images should be put in to balance out the heavy text but I thought it was a very well-researched project. Hope this helps :)

===References===
<references/>

2012 Group Project 5

2012-09-24T13:16:06Z

Z3331330: /* Glossary */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===

''Overview of normal lens development:'' As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref><ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===

''Overview of normal corneal development:'' The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===

''Overview of retinal development:'' The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic===
----
====Leber Congenital Amaurosis====
----
Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. These manifestations are: sever visual loss at/near birth, wandering nystagmus, amaurotic pupils, and pigmentary retinopathy<ref name=PMID15231395/>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Research Timeline'''
----
From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1932-34'''- George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology <ref name=neinih/>
*'''1965'''- Human adeno-associated virus (AAV) was discovered.<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''New Research Development'''
----
[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

While there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>, a current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

----

====Anophthalmia and Microphthalmia====

The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> Premature delivery is increased by 12.4% also. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

* '''Anterior segment dysgenesis''' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

* '''Adnexa''' - Accessory anatomical parts

* '''Choroidal detachment''' - A separation of the choroid from the sclera

* '''Uveal effusion''' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body
Adeno-Assocaited virus (AAV): A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

* '''Albinism''' - Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

* '''Autosomal recessive inheritance''' - gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

* '''Bardet-Biedl Syndrome''' - ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

* '''Electroretinography (ERG)''' - technique by which the electrical response of the retina is measured.

* '''Retinitis Pigmentosa (RP)''' - an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

* '''Senior-Løken Syndrome''' - Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-24T13:11:05Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===

''Overview of normal lens development:'' As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref><ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===

''Overview of normal corneal development:'' The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===

''Overview of retinal development:'' The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. These manifestations are: sever visual loss at/near birth, wandering nystagmus, amaurotic pupils, and pigmentary retinopathy<ref name=PMID15231395/>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Research Timeline'''
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From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1932-34'''- George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology <ref name=neinih/>
*'''1965'''- Human adeno-associated virus (AAV) was discovered.<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''New Research Development'''
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[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

While there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>, a current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

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====Anophthalmia and Microphthalmia====

The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> Premature delivery is increased by 12.4% also. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

''Anterior segment dysgenesis'' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

''Adnexa'' - Accessory anatomical parts

''Choroidal detachment'' - A separation of the choroid from the sclera

''Uveal effusion'' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body
Adeno-Assocaited virus (AAV): A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

Albinism: Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

Autosomal recessive inheritance: gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

Bardet-Biedl Syndrome: ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

Electroretinography (ERG): technique by which the electrical response of the retina is measured.

Retinitis Pigmentosa (RP): an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

Senior-Løken Syndrome: Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-24T13:10:19Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===

''Overview of normal lens development:'' As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref><ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===

''Overview of normal corneal development:'' The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===

''Overview of retinal development:'' The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. These manifestations are: sever visual loss at/near birth, wandering nystagmus, amaurotic pupils, and pigmentary retinopathy<ref name=PMID15231395/>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Research Timeline'''
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From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1932-34'''- George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology <ref name=neinih/>
*'''1965'''- Human adeno-associated virus (AAV) was discovered.<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''New Research Development'''
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[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

While there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>, a current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

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====Anophthalmia and Microphthalmia====

The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> Premature delivery is increased by 12.4% also. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

''Anterior segment dysgenesis'' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

''Adnexa'' - Accessory anatomical parts

''Choroidal detachment'' - A separation of the choroid from the sclera

''Uveal effusion'' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body
Adeno-Assocaited virus (AAV): A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

Albinism: Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

Autosomal recessive inheritance: gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

Bardet-Biedl Syndrome: ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

Electroretinography (ERG): technique by which the electrical response of the retina is measured.

Retinitis Pigmentosa (RP): an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

Senior-Løken Syndrome: Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-24T13:09:36Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===

''Overview of normal lens development:'' As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref><ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===

''Overview of normal corneal development:'' The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===

''Overview of retinal development:'' The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic===
----
====Leber Congenital Amaurosis====
----
Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. These manifestations are: sever visual loss at/near birth, wandering nystagmus, amaurotic pupils, and pigmentary retinopathy<ref name=PMID15231395/>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Research Timeline'''
----
From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1932-34'''- George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology <ref name=neinih/>
*'''1965'''- Human adeno-associated virus (AAV) was discovered.<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''New Research Development'''
----
[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

While there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>, a current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====

The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> Premature delivery is increased by 12.4% also. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

''Anterior segment dysgenesis'' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

''Adnexa'' - Accessory anatomical parts

''Choroidal detachment'' - A separation of the choroid from the sclera

''Uveal effusion'' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body
Adeno-Assocaited virus (AAV): A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

Albinism: Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

Autosomal recessive inheritance: gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

Bardet-Biedl Syndrome: ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

Electroretinography (ERG): technique by which the electrical response of the retina is measured.

Retinitis Pigmentosa (RP): an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

Senior-Løken Syndrome: Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-24T13:08:34Z

Z3331330: /* Anophthalmia and Microphthalmia */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===

''Overview of normal lens development:'' As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref><ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===

''Overview of normal corneal development:'' The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===

''Overview of retinal development:'' The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. These manifestations are: sever visual loss at/near birth, wandering nystagmus, amaurotic pupils, and pigmentary retinopathy<ref name=PMID15231395/>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Research Timeline'''
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From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1932-34'''- George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology <ref name=neinih/>
*'''1965'''- Human adeno-associated virus (AAV) was discovered.<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''New Research Development'''
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[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

While there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>, a current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====

The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> Premature delivery is increased by 12.4% also. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>

====Fetal alcohol syndrome====
----

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

''Anterior segment dysgenesis'' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

''Adnexa'' - Accessory anatomical parts

''Choroidal detachment'' - A separation of the choroid from the sclera

''Uveal effusion'' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body
Adeno-Assocaited virus (AAV): A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

Albinism: Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

Autosomal recessive inheritance: gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

Bardet-Biedl Syndrome: ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

Electroretinography (ERG): technique by which the electrical response of the retina is measured.

Retinitis Pigmentosa (RP): an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

Senior-Løken Syndrome: Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-24T13:07:25Z

Z3331330: /* Leber Congenital Amaurosis */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===

''Overview of normal lens development:'' As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref><ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===

''Overview of normal corneal development:'' The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===

''Overview of retinal development:'' The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. These manifestations are: sever visual loss at/near birth, wandering nystagmus, amaurotic pupils, and pigmentary retinopathy<ref name=PMID15231395/>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Research Timeline'''
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From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1932-34'''- George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology <ref name=neinih/>
*'''1965'''- Human adeno-associated virus (AAV) was discovered.<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''New Research Development'''
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[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|left|Fundus of LCA patient with RPE65 mutation]]

While there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>, a current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
----

The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> Premature delivery is increased by 12.4% also. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

''Anterior segment dysgenesis'' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

''Adnexa'' - Accessory anatomical parts

''Choroidal detachment'' - A separation of the choroid from the sclera

''Uveal effusion'' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body
Adeno-Assocaited virus (AAV): A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

Albinism: Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

Autosomal recessive inheritance: gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

Bardet-Biedl Syndrome: ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

Electroretinography (ERG): technique by which the electrical response of the retina is measured.

Retinitis Pigmentosa (RP): an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

Senior-Løken Syndrome: Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-24T13:04:31Z

Z3331330: /* Abnormal Retinal Development */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===

''Overview of normal lens development:'' As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref><ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===

''Overview of normal corneal development:'' The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===

''Overview of retinal development:'' The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic===
----
====Leber Congenital Amaurosis====
----
Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. These manifestations are: sever visual loss at/near birth, wandering nystagmus, amaurotic pupils, and pigmentary retinopathy<ref name=PMID15231395/>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Research Timeline'''
----
From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1932-34'''- George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology <ref name=neinih/>
*'''1965'''- Human adeno-associated virus (AAV) was discovered.<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''New Research Development'''
----
[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|right|Fundus of LCA patient with RPE65 mutation]]While there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>, a current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
----

The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> Premature delivery is increased by 12.4% also. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

''Anterior segment dysgenesis'' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

''Adnexa'' - Accessory anatomical parts

''Choroidal detachment'' - A separation of the choroid from the sclera

''Uveal effusion'' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body
Adeno-Assocaited virus (AAV): A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

Albinism: Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

Autosomal recessive inheritance: gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

Bardet-Biedl Syndrome: ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

Electroretinography (ERG): technique by which the electrical response of the retina is measured.

Retinitis Pigmentosa (RP): an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

Senior-Løken Syndrome: Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-24T13:03:28Z

Z3331330: /* Abnormal Corneal Development */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===

''Overview of normal lens development:'' As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref><ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===

''Overview of normal corneal development:'' The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to Corneal hereditary endothelial dystrophy.]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. These manifestations are: sever visual loss at/near birth, wandering nystagmus, amaurotic pupils, and pigmentary retinopathy<ref name=PMID15231395/>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Research Timeline'''
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From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1932-34'''- George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology <ref name=neinih/>
*'''1965'''- Human adeno-associated virus (AAV) was discovered.<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''New Research Development'''
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[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|right|Fundus of LCA patient with RPE65 mutation]]While there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>, a current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
----

The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> Premature delivery is increased by 12.4% also. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>

====Fetal alcohol syndrome====
----

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

''Anterior segment dysgenesis'' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

''Adnexa'' - Accessory anatomical parts

''Choroidal detachment'' - A separation of the choroid from the sclera

''Uveal effusion'' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body
Adeno-Assocaited virus (AAV): A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

Albinism: Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

Autosomal recessive inheritance: gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

Bardet-Biedl Syndrome: ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

Electroretinography (ERG): technique by which the electrical response of the retina is measured.

Retinitis Pigmentosa (RP): an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

Senior-Løken Syndrome: Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-24T13:01:25Z

Z3331330: /* Abnormal Corneal Development */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===

''Overview of normal lens development:'' As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref><ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===

''Overview of normal corneal development:'' The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to CHED]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic===
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====Leber Congenital Amaurosis====
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Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. These manifestations are: sever visual loss at/near birth, wandering nystagmus, amaurotic pupils, and pigmentary retinopathy<ref name=PMID15231395/>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Research Timeline'''
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From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1932-34'''- George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology <ref name=neinih/>
*'''1965'''- Human adeno-associated virus (AAV) was discovered.<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''New Research Development'''
----
[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|right|Fundus of LCA patient with RPE65 mutation]]While there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>, a current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
----

The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
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Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> Premature delivery is increased by 12.4% also. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

''Anterior segment dysgenesis'' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

''Adnexa'' - Accessory anatomical parts

''Choroidal detachment'' - A separation of the choroid from the sclera

''Uveal effusion'' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body
Adeno-Assocaited virus (AAV): A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

Albinism: Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

Autosomal recessive inheritance: gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

Bardet-Biedl Syndrome: ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

Electroretinography (ERG): technique by which the electrical response of the retina is measured.

Retinitis Pigmentosa (RP): an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

Senior-Løken Syndrome: Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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{{2012Projects}}

2012 Group Project 5

2012-09-24T13:00:21Z

Z3331330: /* Abnormal Lens Development */

=Abnormal Vision=

==Introduction==
The development of the eye occurs with the optic placode at a Carnegie stage 12 embryo (week 4). The development of the eye is very sensitive and requires accurate, co-ordinated associations of many different factors, both genetic and environmental. During this time any malfunction of development or disturbance of developmental factors such as gene mutations will create an abnormality of the eye. Abnormalities in vision can be acquired by environmental means, like that of Fetal Alcohol Syndrome or by Genetics such as the abnormalities discussed on this page. People with congenital vision abnormalities experience a lot of inconvenience and current technology generally cannot replace the abnormal eye for example in the case of microphthalmia (development of abnormally small eye) and anophthalmia (the absence of eyeball in the orbit). Normally, treatment or management of these conditions focus heavily on improving the appearance of the patients rather than improving their vision. The purpose of this page is to give a brief overview of the development of the eye, association between genes and the development of the eye and abnormalities that can occur under environmental influence. By understanding the factors that contribute to abnormal vision development, treatments or cures maybe developed in the future and these conditions can be better managed.

==Normal Eye Development==

The normal early development of the eye begins with the optic primordium and sulcus developing in the neural folds at Carnegie stage 10 or around 22 days. Stage 11, or 24 days, sees the rostral neuropore closing and the optic vesicle forming from the optic sulcus. Only at stage 12 will you see the beginning formation of the optic placode as the optic vesicle sits near the surface ectoderm.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name=PMID1100417><pubmed>1100417</pubmed></ref><ref name="PMID6650859"><pubmed>6650859</pubmed></ref>At stage 13, 28 days, a thickened surface ectoderm layer has developed on top of the optic vesicle, we know this to be the lens disc. The retinal disc (soon to be optic cup) has appeared on the wall of the optic vesicle.<ref name=PMID1100417/> As development continues through to Carnegie stage 14, the retinal disc is invaginated to form then optic cup and the lens pit forms. This lens pit closes in stage 15 and the optic cup and lens vesicle seem to bulge and press against the surface as the primary vitreous body begins to form.<ref name=PMID1100417/> <ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref><ref name="PMID6650859 "/>
This contour of the optic cup progresses until it is quite noticeable in stage 16, small grooves can also be seen above and below the eye. The retina differentiates at around stage 17 and the primary lens fibers obliterate the cavity of the lens vesicle filling the space at stage 18. The pupillary membrane and the layers of the cornea develop from stages 19-21. At stage 20 the retinal nerve fiber layer appears and grow towards the brain.<ref name=PMID1100417/>
As the grooves above and below the eye develop and deepen in stage 17-19, eyelid folds develop, which soon turn into actual eyelids at around stage 19 and continue to develop further and grow slowly at stage 22. The eyelids close completely at stage 23.<ref> Anthony A. Pearson '''The Development of the Eyelids''' Journal of Anatomy: 1980, 130, 1, pp. 35-42 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1233106/]</ref>

==Abnormal Development==

Abnormalities can occur in different parts of the eye. In the section below, we have focused on abnormalities that developed in the lens, cornea and retina and have included genes that are associated with the abnormalities. Also, a general overview on the role of each genes and what is their impact on the structure of the eye when mutated is given.

===Abnormal Lens Development===

''Overview of normal lens development:'' As stated above, the lens originates from the ectoderm on top of the optic vesicle, it also requires a large portion of the head ectoderm surrounding this area before interacting with the optic vesicle. The vesicle is more involved with the correct positioning and lens formation at this stage. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref><ref name="PMID7789273"><pubmed>7789273</pubmed></ref>As the optic vesicle grows rapidly, the lens placode moves almost on top of the vesicle just close enough for a small gap to show. From this a network of fibrin adheres one surface to the other and the lens placode thickens and both sufaces start to invaginate becoming the lens pit and optic vesicle. The lens pit then detatches after deepening further and becomes the lens vesicle. From here the cells of the lens differentiate into primary fibres in the posterior half of the vesicle and epithelium in the anterior half. Rapid growth occurs with cell division occurring mostly in the epithelium region called the germinative zone with the daughter cells moving to the transitional zone where they mature and differentiate into fibre cells which continues throughout life. <ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref>

*Pax-6 Genes
Most of the development of the lens occurs as a result of the Pax-6 gene. <ref name="PMID7789273 "/><ref> McAvoy, J W '''Lens Development''' Eye (The Royal College of Ophthalmologists) 1999 vol:13 3b pp.25 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/eye/journal/v13/n3b/pdf/eye1999117a.pdf] </ref> It is expressed in early developing optic vesicle and lens placode which is during the 4th and 5th week of human eye development. <ref>Mihelec, M, St Heaps, L, Flaherty, M '''Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma.'''Twin Research and Human Genetics 2008 vol:11 pp.412-21 [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/18637741]</ref>It is responsible for the embryonic and postnatal development of the lens epithelium, and in particular, the ectoderm in embryonic development. And a variety of abnormalities can occur as a result of a mutation from this gene, Peters' anomaly (Corneal Opacity) and aniridia (lack of Iris) <ref> Glaser, T Et al '''Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene''' Nature Genetics 1992 vol:2:3 pp.232 [http://www.nature.com.wwwproxy0.library.unsw.edu.au/ng/journal/v2/n3/pdf/ng1192-232.pdf] </ref> are just some, as well as an abnormal cortical plate formations.<ref name="PMID7789273 "/> Within a few days of development, it is easy to distinguish an abnormality with the forebrain and the shape of the optic vesicle, as development continues there is an absence of a thickened ectodermal surface, lens placode, lens pit and the optic vesicle becomes distorted. As the ectodermal surface did not thicken, there is then no developing lens thus, Pax-6 gene is absolutely essential in the development of the lens. <ref name="PMID7789273 "/>

*FOX genes
Another gene that may have an important role in the development of the lens is FOXe3 (Forkhead box protein E3) and FOXe4 (Forkhead box protein E4). They are expressed in the lens and they aid in the formation of the lens. Mutation of FOXe3 gene will cause anterior segment dysgenesis and result in cataracts formation as part of the dysgenesis.<ref name="PMID18035564"><pubmed>18035564</pubmed></ref><ref name="PMID15855758"><pubmed>15855758</pubmed></ref>FOXe3 can be detected in the first embryonic days 8.5, in two distinctive area of the cephallic neural folds. Both FOXe3 and FOXe4 are not as important as the Pax-6 gene, but it plays a very essential role in the control of proliferation and differentiation of the anterior len epithelium and it is evident that, the loss of these two genes will lead to anterior segment dysgenesis. <ref name="PMID15855758 "/>

*Crystalline genes

'''Images of congenital hereditary cataracts from mutations of crystallin genes'''
[[Image:Images_of_congenital_hereditary_cataracts_due_to_mutations_of_crystallin_genes.png]]

Cataracts of the eye can be defined as any opacity of the crystalline lens in which congenital cataract is especially important because it has the potential for inducing abnormal visual development and resulting in permanent blindness. Inherited cataracts contribute the most to congenital cataracts especially in developed countries.<ref name="PMID18035564 "/><ref name="PMID17460281 "><pubmed>17460281 </pubmed></ref> Crystalline genes in the human body codes for major structural proteins in the lens, they are considered important due to their high level of expression in the lens and their functions in maintaining lens transparency. There is a strong relationship between their mutation and the development of congenital cataracts.<ref name="PMID17460281 "/> One example of crystalline gene is βγ-crystallins. When this gene is mutated, major abnormalities in the protein structure can occur and result in the presence of an unstable protein that is able to precipitate from solution and protein denaturation and precipitation that will eventually lead to cataract formation.<ref name="PMID18035564 "/>Mutations in the αA-crystallin gene have also been implicated both in autosomal recessive and autosomal dominant cataract. One would expect that αB-crystallin would have a similar effect on cataracts formation but experiments suggested that cataracts formation is dominated by mutations in αA-crystallin gene with the abnormal protein having a toxic effect on lens cells. The mutant protein also inhibit the functioning of normal αA-crystallin protein.<ref name="PMID18035564" />

===Abnormal Corneal Development===

The corneal Development begins at around Carnegie Stage 15 with the surface ectoderm differentiating into the anterior epithelieum of the cornea, at this stage it has its own basement membrane. At stage 18 the posterior epithelium of the cornea begins to form and by stage 19, is easily recogniseable. <ref name="PMID6650859 "/> Stage 20 sees the developing cornea with an anterior epithelium, a postepithelial layer, and a posterior epithelium. The postepithelial layer will develop further to become the substantia propria of the cornea in stage 21 via cells invading the layer. This process is finished in stage 22 and at stage 2 the cornea consists of an anterior epithelium and a basement membrane, the substntia propria and the posterior epithelium. <ref name="PMID6650859 "/>

*SCL4A11 gene
Congenital Autosomal recessive corneal endothelial dystrophy type 2(CHED2) is associated with mutations in SLC4A11, Solute Carrier family 4 (sodium borate cotransporter) member 11). This gene is located on chromosome 20p13-12. Mutation of this gene cause disorder of the cornea that is characterised by diffuse bilateral corneal clouding and they are often edematous and have a ground glass appearance that is evident at birth or in the neotal period and can cause the impairment of vision and require corneal transplantation.<ref name="PMID16825429 "><pubmed>16825429 </pubmed></ref><ref><pubmed>18474783</pubmed></ref><ref><pubmed>21855542</pubmed></ref>

[[Image:Appearance_of_cornea_due_to_CHED.png|thumb|right|Appearance of cornea due to CHED]]SLC4A11 is an electrogenic Na/borate cotransporter and it can stimulate cell growth and proliferation by increasing intracellular borate and activating the MAPK pathway.<ref name="PMID16825429 "/>The ion transporter SLC4A11 promote sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions. It has been shown that SLC4A11 is expressed in the endothelial cells of the cornea, and mutation of the gene will cause increased sodium concentrations in the stroma, thus resulting in morphological changes of the cornea. The mutated gene also result in the death of endothelial cells and loss of barrier function, eventually secondary corneal edema. <ref name="PMID16767101 "><pubmed>16767101 </pubmed></ref>.Some other studies have shown that borate can lead to the phosphorylation of both MAP-kinase and extracellular signalling kinases, and these are part of the mitogen activated protein kinase cascade (MAPK). MAPKs are important in the regulation of cell cycle and growth, a less regulated MAPK pathway can lead to major characteristics that are presented in CHED2 such as the morphology of the eye. <ref name="PMID16767101 "/>

===Abnormal Retinal Development===

The retina is of neuro-ectodermal origin<ref name="PMID15231395"><pubmed>15231395</pubmed></ref> and is derived from the optic cup (stage 17). The optic cup is divided into the neural retina and the retinal pigmental epithelium. The neural retina is light sensitive, the region from which the photoreceptors and cell bodies of the neurons are located.
As the retina is the part of the eye from which the brain receives the most visual information there are many abnormalities which can occur here during development. In various research avenues for Leber Congenital Amaurosis (to be discussed later) the following genes have been found to be involved in retinal development, they are as follows : RPE65 for retinoid metabolism, GUCY2D phototransduction, CRX photoreceptor outer segment development, RPGRIP1 disk morphogenesis, CRB1 zonula adherens formation and AIPL1 cell-cycle progression.<ref name="PMID15231395 "/>

*CRX gene
An example of one of these gene expressions is CRX. CRX is expressed abundantly in photoreceptor cells and is an important regulator of various photoreceptor specific genes and key enzymes for melanin synthesis. <ref name="PMID14625556"><pubmed>14625556</pubmed></ref> While it has been determined that CRX is important in terminal differentiation of the photoreceptors, using a mouse model, in which the otx2 was conditionally knocked out there was a complete loss of retinal photoreceptors and thus it has been found that otx2 is essential for CRX transcription as it is an upstream regulator of CRX expression<ref name="PMID14625556 "/>. Otx2 expression covers most of the fore and midbrain neuro-epithelium and subsequently the retinal region<ref name="PMID14625556 "/>

*RPE65
RPE65 is an enzyme located in the retinal pigment epithelium (RPE)which is a catalyst during a crutial part of the visual cycle. It permits photoreceptors pigments to absorb photons which maintain sight<ref><pubmed>PMC2940541</pubmed></ref>.

*Retinal Pigment Epithelium and Albinism
[[Image:Albino_fundus.jpg‎|thumb|right|Comparison between fundus in Albinism and Normal eye]]
Some research suggests that Retinal Pigment Epithelium (RPE) has a regulatory effect upon neural retina development<ref name="PMID9775209"><pubmed>9775209</pubmed></ref>. A melanin related agent, has been suggested to be important in retinal development and maintenance during maturity as in albinism there is a reduction in melanin and retinal abnormalities are present. <ref name="PMID9775209 "/>The Tyrosinase gene controls melanin production and acts a catalyst in DOPA production from tyrosine and is a regulator of cell cycles.<ref name="PMID9775209 "/> Although there is evidence for a relationship between DOPA and retinal mitosis the mechanisms responsible are not so easily identifiable.<ref name="PMID9775209 "/>
When melanin is absent a variety of retinal disorders such as abnormal connection between the eye and brain, undeveloped central retina and rod defects can occur, this reduction and/or absence of melanin is commonly caused by Albinism which also has reduced cell density is also abnormally low with ganglion cells of the retina decreased by 25%.<ref name="PMID9775209 "/> Other eye defects caused by Albinism are absent Fovea, undeveloped Macula region and abnormal chiasmatic projections to name a few<ref name="PMID9775209 "/>

==Ocular Manifestations==

Major ocular disorders can be split into two separate sections based on the way in which they originated.

===Genetic===
----
====Leber Congenital Amaurosis====
----
Leber Congenital Amaurosis (LCA) is an inherited retinal degenerative disorder that causes blindness or loss of sight at birth.<ref name=lca>Evans, J. (2012). Leber Congenital Amaurosis. Retrieved 2012, from Foundation Fighting Blindness[http://www.blindness.org/index.php?view=article&catid=38%3Aother-retinal-diseases&id=253%3Aleber-congenital-amaurosis&option=com_content&Itemid=88]</ref> LCA has an Autosomal recessive pattern of inheritance where there is a 25% chance for a child to contract LCA.<ref name=lca/>

LCA was first recognized by Dr Theodor Leber in 1869. He published the paper ''Ueber Retinitis pigmentosa und angeborene Amaurosa'' (About Retinitis pigmentosa and congenital Amaurosa) in '''Archiv fur Ophthalmologie''' (now known as Graefes Archive of clinical and experimental ophthalmology).<ref>Leber, T. (1869). Ueber Retinitis pigmentosa und angeborene Amaurosa. Archiv fur Ophthalmologie , 1-25.[http://www.springerlink.com/content/rmj766pjrq130011/]</ref> In his research Leber describes a set of clinical manifestations in children he studied at the Ilvesheim School for the blind in Germany with Retinitis Pigmentosia which are used still today as a diagnostic technique for LCA <ref name=PMID15231395><pubmed>15231395</pubmed></ref>. These manifestations are: sever visual loss at/near birth, wandering nystagmus, amaurotic pupils, and pigmentary retinopathy<ref name=PMID15231395/>. In his paper Leber classified this disease as being a part of the Retinitis Pigmentosia group of optical disorder, placing great emphasis upon the high incidence of hereditary factors<ref name=PMID15231395/>. As stated in the section on [[Abnormal Retinal Development]] out of the eighteen genes <ref name=PMIDPMC3283211><pubmed>PMC3283211</pubmed></ref> found that contribute to LCA, six of them have been linked to specific sections to retinal development<ref name=PMID15231395/>. As a result making a differential diagnosis on congential blindness can be difficult as LCA can overlap with many other disorders such as Bardet-Biedl syndrome and Senior-Loken syndrome for example<ref name=PMIDPMC3283211/>.
An important diagnostic technique was recognised by Franeschetti and Dieterle of non-detectable or severely reduced electroretinogram (ERG) measured in early progression of LCA<ref name=PMID15231395/>. The measurement of ERG has become a prerequisite diagnostic protocol for LCA<ref name=PMID15231395/>.

CEP290 gene mutation is the most common cause of LCA and accounts for 6-22% of all cases<ref name=PMIDPMC3283211/>. This mutation is a slow progressive form of LCA and has a relatively normal optic disc with sclera ring. Abnormalities associated with CEP290 mutation include salt and pepper aspect of fundus with Macular degeneration causes typical Retinitis Pigmentosa appearance in second decade and Mild lobar retinal pigment epithelium atrophy<ref name=PMIDPMC3283211/>. Clinical signs associated with CEP290 include sluggish pupillary reflexes and juvenile cataracts<ref name=PMIDPMC3283211/>.

'''Research Timeline'''
----
From 1869-2009, the major contributers to LCA research and consequently to retinal regeneration therapy research: "Courtesy: National Eye Institute, National Institutes of Health (NEI/NIH)."

*'''1869'''- Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood <ref name=neinih>http://www.nei.nih.gov/lca/timeline.asp</ref>
*'''1932-34'''- George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology <ref name=neinih/>
*'''1965'''- Human adeno-associated virus (AAV) was discovered.<ref name=neinih/>
*'''1984'''- Drs. Nicolas Muzyczka and Paul Hermonat publish an article on adeno-associated virus (AAV) expresses that it can be used to introduce foreign DNA into human and murine tissue culture cells.<ref name=neinih/>
*'''1990'''- Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.<ref name=neinih/>
*'''1993'''- Dr. T. Michael Redmond of the NEI's Laboratory, cloned RPE65, a protein necessary for processing vitamin A in the visual cycle.<ref name=neinih/>
*'''1997'''- RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis.<ref name=neinih/>
*'''1998'''- Dr. T. Michael Redmond's team in the NEI's Laboratory use the knockout mouse model to establish RPE65’s role in vitamin A metabolism. RPE65 gene mutation was discovered as causing ''congenital blindness'' in Briard dogs.<ref name=neinih/>
*'''2001'''- Gene transfer RPE65 therapy used to restore vision in a Briard Dog by researchers at the University of Pennsylvania and University of Florida supported by the NEI.<ref name=neinih/>
*'''2005'''- Restored vision in Briard dog persists longer than four years following RPE65 gene transfer <ref name=neinih/>
*'''2007'''- NEI-supported RPE65 human clinical trial began. This study was designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.<ref name=neinih/>
*'''2009'''- One-year results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and the New England Journal of Medicine. All three patients remained healthy and maintained previous visual gains. One patient also noticed a visual improvement that helped her perform daily tasks. Results from early LCA clinical studies represent one of the first steps toward the use of gene transfer therapy for an inherited form of blindness.<ref name=neinih/>

'''New Research Development'''
----
[[Image:Leber Congential Amaurosis Fundus.jpg|thumb|right|Fundus of LCA patient with RPE65 mutation]]While there is no effective treatment for LCA <ref name=PMID18441371><pubmed>18441371</pubmed></ref>, a current field of research for LCA and in turn retinal restoration is that of using an altered version of the adeno-associated virus. In 2001 study on dogs with early and a similar impairment to that of LCA in children<ref name=PMID11326284><pubmed>11326284</pubmed></ref>. The recombinant adeno-associated virus serotype 2 (rAVV2) vector to carry the human RPE65 has restored vision in this model<ref name=PMIDPMC2940541><pubmed>PMC2940541</pubmed></ref>. The virus was injected intra ocular, into 3 dogs with LCA and the results were assessed by ERG<ref name=PMID11326284/>. As a result of this experiment retinal function improved in eyes compared with the same eyes before treatment<ref name=PMID11326284/>. This experiment is a proof of concept study being the first to show gene therapy can restore vision<ref name=PMID11326284/>. In clinical trials undertaken in 2008 leads to improvement in visual function and the AVV has no immediate adverse effects on patients and it is suggested that these procedures would benefit children with LCA than adults<ref name=PMID18441371/>.

====Anophthalmia and Microphthalmia====
----

The condition of anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Microphthalmia is defined as a globe with a total axial length (TAL) that is at least two standard deviations below the mean for age.<ref name="PMID20301552"><pubmed>20301552</pubmed></ref><ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390"><pubmed>18039390</pubmed></ref>Anophthalmia and Micropthalmia, these two ocular manifestations have a combined incidence of approximately 2/10000 births and can be developed as unilateral or bilateral. <ref name="PMID21825993 "/> The development of both Anaophthalmia and Microphthalmia can be isolated, associated with other abnormalities or can be part of a well defined syndrome.The aetiology of these two conditions can be very complex with genetic, environmental causes both identified.<ref name="PMID20301552 "/><ref name="PMID21825993 "/><ref name="PMID18039390 "/>Some risks factors for these conditions are idenitifed such as maternal age over 40, multiple births, infants of low birth weight and low gestational age.<ref><pubmed>16007635</pubmed></ref><ref><pubmed>8921488 </pubmed></ref><ref><pubmed>16498668</pubmed></ref>There are many causes of these two conditions including chromosomal, part of a syndrome, single gene disorder and environmental. Only single gene disorder as an aetiology of these two conditions will be discussed in detail, where the accumulative mutations of several genes eventually result in the development of anophthalmia and microphthalmia.[[Image:Clinical_appearance_of_anophthalmia_and_microphthalmia.png‎|thumb|right|Clinical appearance of anophthalmia and microphthalmia (upper picture: anophthalmia, lower picture:microphthalmia)]]

'''Clinical description'''

Anophthalmia is a condition that result in the absence of ocular tissue in the orbit. Simple microphthalmia is condition where patient present with structurally normal, small eyes. In both conditions, there is increased incidence of uveal effusions and choroidal detachments, and this is thought to be due to the increased thickness of the sclera and changes in blood flow that results from anophthalmia and microphthalmia. Complex micropthlamia occurs when microphthalmia is complicated with other ocular disorders. Both Anterior and posterior segment can be affected by complex microphthalmia <ref name="PMID18039390 "/>

'''Genetic cause (Single gene disorders)'''

There are various causes to the development of Anophthalmia and microphthalmia, the roles of several genes involved in the ocular development have been identified. Also, some well-defined syndrome have been proved to be related with these two conditions, such as matthew-wood syndrome and Fraser syndrom. Genes that are responsible for these conditions include, PAX6, RAX, CHX10, SOX2, OXT2 and FOXE3. These are the main contributor to the development of anophthalmia and microphthalmia. <ref name="PMID21825993"><pubmed>21825993 </pubmed></ref><ref name="PMID18039390 "/>

'''Summary of genes associated with anophthalmia and microphthalmia'''

[[File:Summary_of_the_genes_associated_with_anophthalmia_and_microphthalmia.png‎]]

''SOX-2''

'''A patient with microphthalmia with deletion of SOX2 gene'''

[[Image:Unilateral_microphthalmia_patient_with_delection_of_SOX2_gene.png]]

The image above shows a patient with microphthalmia and from his gene sequence, it was discovered that the SOX2 gene has been deleted and it is indicated by the red arrow on the image. His parents gene sequence is shown underneath his and shows the presence of the normal SOX2 gene. <ref><pubmed>20454695</pubmed></ref>The SOX-2 gene has been identified as the major causative gene of the two conditions, it is located on the location 3q26.3-q27. It is an important transcription factor responsible for the maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells.<ref name="PMID18039390 "/>Although, SOX2 gene mutation is quite rare with an estimated frequency of 1 in 250,000 births, they are still considered the most common genetic cause of anophthalmia and microphthalmia to date. <ref name="PMID22005280"><pubmed>22005280</pubmed></ref>Mutations in the SOX-2 gene is often associated with ocular malformations, they are variable in types but mostly bilateral and severe, it can also lead to mild dysmorphic facial features, genital abnormalities in males, learning disabilities, and motor delay as part of anaophthalmia syndrome. Some addtional features of SOX2 mutation are cataracts, coloboma, optic nerve hypoplasia. <ref name="PMID19921648"><pubmed>19921648</pubmed></ref>This gene is highly expressed during lens induction and play an important role in the growth and maintenance of the developing lens. <ref><pubmed>15812812</pubmed></ref>SOX2 expression in humans are also seen in area of neural retina, optic stalk and lens, further suggesting its importance to the development of the eye.<ref name="PMID22005280 "/>

SOX2 gene also co-operates with other genes to ensure normal lens development such as the PAX 6 gene and they mutually induce each other.<ref name="PMID22005280 "/>It has been demonstrated in chicks, the co-regulation of these two gene drive lens induction in chicks, suggesting that lens induction failure in humans can be due to these genes. The lens induction is also mediated by the interaction of the two genes through their action on the γ-crystallin gene. The three genes SOX2, PAX6 and FOXE3 are all highly express in the retinal area of the developing eye, their accumulated mutations may cause failure of retinal differentiation and related to the development of anophthalmia and microphthalmia.<ref name="PMID18039390 "/>

''PAX6''

'''Comparison of phenotypes between normal and PAX6 mutant across different animals'''

[[Image:Comparison_of_phenotypes_with_PAX6_gene_mutation_in_different_animals.png]]

The PAX6 gene mentioned before in the abnormal lens development section has already been stated of its importance in lens development, located on chromosome 11p13.The mutation of this gene cause alterantion to the developing lens and the pit of the optic vesicle. Through the use of differentiation marker, this gene has also been proved to be expressed by corneal epithelial cells and can regulate their differentiation.<ref name="PMID22005280 "/><ref><pubmed>19347868</pubmed></ref>As mentioned in the section before, PAX6 co-regulates with SOX-2 for lens induction and the induction is also mediated through their interaction on the γ-crystallin gene.<ref name="PMID18039390 "/> Overall, the PAX6 gene is a major gene involved in the normal development of the eye, any mutation of this gene will cause abnormalities to the eye one way or the other.

''OTX2''

OTX2 is a homeobox-containing trancription factor gene that plays a key role in the development of head structures in vertebrates. The protein products of OTX2 and SOX2 have been shown to co-regulate the expression of the RAX gene which is also essential in eye development. Mutations in OTX2 is associated with unilateral or bilateral anophthalmia and microphthamia, along with other abnormalities such as pituitary defects and significant developmental delays. <ref name="PMID21825993 "/>

''RAX''

The establishment and proliferation of retinal progenitor cells are mainly regulated by the RAX gene. <ref name="PMID18039390 "/> The transcription of this gene starts in the anterior neural plate and then simultaneously in the eye field and the ventral forebrain. <ref name="PMID19921648"/> Mutation of this gene will bring failure of lens induction in eye development, along with other genes such as PAX6, CHX10, OTX2.<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>

''CHX10''

The role of this gene is the proliferation of neuroretinal progenitor cells and the mutation of this gene will lead to microphthalmia, cataract and iris coloboma. <ref name="PMID21825993 "/>

''FOXE3''

THe FOXE3 gene is responsible for lens development in vertebrates and a mutation of this gene will lead to lens agenesis, it is a transcription factor that is critical for the regulation of lens fibre differentiation, also in promoting the growth and survival of the lens epithelium cells. <ref><pubmed>20216939</pubmed></ref>
<ref name="PMID18039390 "/> <ref name="PMID21825993 "/>In humans, mutations of this gene is associated with variable phenotypes such as anterior segment abnomalities, cataracts and microphthalmia. <ref><pubmed>20140963 </pubmed></ref>

'''Management'''

''Conservative''

In unilateral cases of both anophthalmia and microphthalmia, the good eye must be protected with any visual deficit managed well. <ref name="PMID18039390 "/>

''Surgical''
[[Image:Ocular prosthesis.png|thumb|right|ocular prosthesis]]
Congenital anophthalmia and microphthalmia result in small volume orbit when compared to age-related controls and this will potentially lead to the appearance of hemifacial asymmetry. And the removal of the globe will produce a reduction in orbital volume. Mild or moderate micropthalmia is generally managed with insertion of a conformer which is a prosthetic eye , not painted, increasing in size periodically to ensure normal orbit growth. There are many others implants of the orbits that are inflatable or expandable, often increase in size periodically to ensure the normal development of the orbital bone such as endo-orbital volume replacement, volume replacement and static orbital implants. <ref name="PMID18039390 "/>

Ideal treatment for anophthalmic patients would be simultaneous expansion of the eyelids, socket and orbital bones, and this type of treatment should begin right after birth. Socket expansion with self-inflating expanders is also a useful technique, along with conformers.<ref><pubmed>21730840</pubmed></ref>

'''Prognosis'''

The therapy tries to maximise vision for patients with micropthalmia, and rather to enhance the appearance rather than improving the sight.<ref name="PMID18039390 "/>

===Environmental===
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====Chorioretinal Scars Caused by Congenital Varicella Syndrome====
----
Chorioretinal Scars are scars within the eye that have penetrated the choroid and the retina giving the back of the eye a white, black or pinky appearance rather than that of a healthy eye on examination. This scar or scars damage significant parts of the retina and can cause a cloudiness or even a substantial lack of vision. They are usually described in three sites, Juxapapillary, Peripheral or Macular with macular being the most common. After possible finding of these scars at birth, it is extremely common for the scars to worsen and enlarge with age.

Chorioretinal scars can be caused by a number of diseases during development within the uterus, most commonly seen after contracting the congenital varicella syndrome, rubella. syphilis, and toxoplasmosis. In rarer cases it can be seen after contraction of the herpes simplex.
The Congenital Varicella Syndrome or Fetal Varicella Syndrome is the common chicken pox virus which is transferred from the mother to the fetus after she contracts the syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>
The risk of this transference is around 1.3%<ref> Boussault, P et al '''Chronic Varicella-Zoster Skin Infection Complicating the Congenital Varicella Syndrome''' Pediatric Dermatology 2007 vol:24:4 pp. 429 [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1525-1470.2007.00471.x/pdf] </ref> if the mother has it during the 1st and half way through the 2nd trimester. in 1996 , seven in every 10000 pregnancies were affected by the Varicella Syndrome. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> The reason for such a low number is because most women have usually already had the virus as a child, so their chances of getting it again are greatly reduced if not totally reduced. Fetal death caused by congenital varicella syndrome is very low at 0.8%. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> Premature delivery is increased by 12.4% also. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref>

However, pregnancies that are affected by Congenital Varicella Syndrome are usually left with some morphological anomalies such as growth retardation(39%), gastro-intestinal lesions(23%), problems with skeletal development (68%), ocular abnomalities (68%) and many more. <ref> Dufour, P et al. '''Varicella and Pregnancy''' European Journal of Obstetrics & Gynecology and Reproductive Biology, 1996 vol:66:2 pp.119 [http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/0301211596023950] </ref> For those born with ocular problems, the most obvious abnormality is the presence of chorioretinal scarring, but there are also many other abnormalities that are sometimes overlooked. Including atrophy of the optic discs, congenital cataracts, and Horner's Syndrome. <ref> Lambert, S et al '''Ocular Manifestations of the Congenital Varicella Syndrome''' Archives of Ophthalmology 1989 vol:107:1 pp.52 [http://archopht.jamanetwork.com.wwwproxy0.library.unsw.edu.au/article.aspx?articleid=637630] </ref>

====Fetal alcohol syndrome====
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Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption chronically during pregnancy, eye abnormalities have been shown to occur in over 90% of children that were exposed to FAS prenatally.<ref name="PMID19907681"><pubmed>19907681</pubmed></ref> FAS has been estimated with a frequency of 0.97 cases in 1000 births<ref name="PMID11825849"><pubmed>11825849</pubmed></ref>

Some of the defects result from FAS include coloboma which is the failure of closure of choroid fissure that should be closed during the 7th week of development, hypoplasia of the optic nerve resulting in an abnormal small size of the nerve, increasing abnormal shaping of retinal vessels, short palpebral fissure length, anterior segment abnormalities and microphthalmia. It is also an environmental aetiology for the condition, microphthalmia.<ref name="PMID19907681 "/><ref><pubmed>18571671</pubmed></ref> Alcohol may produce its effect by interacting with cell membranes and receptors of cells and by changing the morphology and function of the proteins that regulate signal transduction, gene expression, cell differentiation and proliferation, impacting on the development of the prenatal eye. Demonstrated in some animal studies, malformations result from FAS are caused by the effects of ethanol on embryos prior to or during gastrulation and neurulation during embryonic development, inducing the development of small neural plates, abnormal migration of mesodermal cells and malformations of the cranial- facial area. <ref><pubmed>8857698</pubmed></ref>Another study on animal suggested, ethanol can alter the normal patterns of recruitment and loss of neural progenitor (Stem cells) which is especially important in neurogenesis. A strong correlation has been shown between ethanol dose being exposed to neuroblasts at their highest activity level and the damage to neuroretinogenesis and optic nerve development. <ref name="PMID11825849"/>

==Glossary==

''Anterior segment dysgenesis'' - Failure of the normal development of the tissues in the anterior compartment of the eye including the cornea, iris, ciliary body, sclera, conjunctiva and lens.

''Adnexa'' - Accessory anatomical parts

''Choroidal detachment'' - A separation of the choroid from the sclera

''Uveal effusion'' - An abnormal accumulation of serous fluid in the outer layer of the choroid and ciliary body
Adeno-Assocaited virus (AAV): A small virus which affects humans and primates. It causes mild immune response and is an important part of gene therapy research.

Albinism: Congenital disorder characterized by an absence of pigmentation in skin, eye and hair. This is due to a non expression of Melanin

Autosomal recessive inheritance: gene inheritance by which the gene is carried on one of the 22 non sex determining chromosomes and both parents must be carriers of the gene for a child to inherit. There is a 1 in 4 chance of inheritance and a 2 in 4 chance of becoming a unaffected carrier

Bardet-Biedl Syndrome: ciliopathic genetic disorder which main clinical feature id rod-cone dystrophy onset during childhood.

Electroretinography (ERG): technique by which the electrical response of the retina is measured.

Retinitis Pigmentosa (RP): an inherited degenerative eye disorder which causes impairment and blindness and is characterised by many symptoms including Night Blindness.

Senior-Løken Syndrome: Rare Congenital recessive inherited eye disorder. Discovered in 1961 and is a progressive disorder

== References ==
<references/>

==External Links==
{{External Links}}

[http://www.nei.nih.gov/ National Eye Institute]

--[[User:Z8600021|Mark Hill]] 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.

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