Embryology - User contributions [en-gb]

User:Z3389806

2011-10-20T22:44:34Z

Z3389806: /* Lab 12 Assessment */

{{2011Student}}

==Lab Assessments==

===Lab 1 Assessment===

{| style="border: solid 1px #a0a0ff"
|- style="background:#eeeeff"
|'''1. Identify the origin of ''in vitro'' fertilisation and the 2010 Nobel Prize winner associated with this technique.'''
::[[Wikipedia: In vitro fertilisation|''In vitro'' fertilisation]] (IVF) technique was conceptualized by [[Wikipedia: Robert G. Edwards|Sir Robert Geoffrey Edwards]] when he first managed to fertilise a human egg successfully in the laboratory in 1968. This led to the birth of the first baby conceived through IVF, [[WIkipedia: Louise Brown|Louise Brown]], on 25th July 1978. Sir Robert Geoffrey Edwards is also the [[Wikipedia: Nobel Prize in Physiology or Medicine|2010 Nobel Prize]] winner associated with ''in vitro'' fertilisation.

'''2. Identify a recent paper on fertilisation and describe its key findings.'''
::A recent paper on fertilisation is titled “Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during ''in vitro'' fertilisation treatment”<ref>Chen H, Wang W, Mo Y, Ma Y, Ouyang N, Li R, Mai M, He Y, Bodombossou-Djobo MM, Yang D.
'''Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during in vitro fertilisation treatment.''' J Assist Reprod Genet.: 2011 PMID:21717175 [http://www.ncbi.nlm.nih.gov/pubmed/21717175]</ref> by Hong Chen et al. It was reported in the paper that telomerase activity (TA) in the luteinized granulosa cells is positively correlated with clinical pregnancy rate. Clinical pregnancy rate increases with level of TA. This would mean that the success rate of the IVF treatment (resulting in pregnancy) can be predicted by measuring the levels of TA in the granulosa cells.

'''3. Identify 2 congenital anomalies.'''
::The two congenital anomalies are [[wikipedia: Spina bifida|spina bifida]], in which the embryonic neural tube is only partially closed, and [[wikipedia: hydrocephalus|hydrocephalus]], in which there is an unusual accumulation of fluid in the brain.
|}

--[[User:S8600021|Mark Hill]] 00:44, 30 July 2011 (EST) Good wiki coding. Though I am not a fan of Wikipedia linking, should seek scientific references where possible, nobel prize link is better.

===Lab 2 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.'''
::The ZP protein that spermatozoa binds is the zona pelucida glycoprotein 3 (ZP3), also known as the sperm receptor.[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7784]
::Once fertilisation occurs, the oocyte releases enzymes which will alter the terminal carbohydrate residues of ZP3. ZP3 loses the ability to bind sperms, preventing polyspermy.<ref><pubmed>9369183</pubmed></ref>

'''2. Identify a review and a research article related to your group topic.'''
::''Review'': Bassuk AG, Kibar Z. '''Genetic basis of neural tube defects.''' Semin Pediatr Neurol. 2009 Sep;16(3):101-10<ref><pubmed>19778707</pubmed></ref>
::''Research'': De Marco P, Merello E, Cama A, Kibar Z, Capra V.''' Human neural tube defects: Genetic causes and prevention.''' Biofactors. 2011 Jun 14. <ref><pubmed>21674647</pubmed></ref>
|}
--[[User:Z3389806|Nur Sharalyn Abdullah]] 14:20, 10 August 2011 (EST)

===Lab 3 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What is the maternal dietary requirement for late neural development? '''
::The maternal dietary requirement for late neural development is iodine. Iodine is essential in the production of thyroid hormones which play a role in brain development.<ref><pubmed>15107513</pubmed></ref>
::Lack in iodine intake can result in cretinism. The recommended iodine intake during pregnancy is 200-250 micrograms per day.<ref><pubmed>19088150</pubmed></ref>

2. '''Upload a picture relating to your group project.'''

'''Melatonin levels in Huntington's disease patients and controls'''

[[File:Melatonin levels in HD patients and controls.jpg|border]]

The diurnal melatonin rise was significantly delayed in HD patients by about 01:30 h (p = 0.048). The black bar on the abscissa indicates the dark period (23:00–7:30 h).
|}
--Nur Sharalyn Abdullah 12:47, 16 August 2011 (EST)

===Lab 4 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. The allantois, identified in the placental cord, is continuous with what anatomical structure?'''
::The allantois, which originates from the hindgut, is continuous with the bladder.

'''2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.'''
::*Ductus arteriosus: located between pulmonary artery and aortic arch
::*Ductus venosus: located between umbilical vein and inferior vena cava
::*Foramen ovale: located between left atrium and right atrium

'''3. Identify the group project sub-section that you will be researching.'''
::*History
::*Treatment
::*Epidemiology
|}
--Nur Sharalyn Abdullah 21:47, 20 August 2011 (EST)

===Lab 5 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Which side (L/R) is most common for diaphragmatic hernia and why?'''
::The left side is the most common for diaphragmatic hernia. It is thought that this is due to the earlier closure of the right pleuroperitoneal opening.<ref>Moore, K.L. & Persuad, T.V.N. (2008). The Developing Human: clinically oriented embryology (8th ed.). Philadelphia: Saunders, p. 153</ref>
|}
--Z3389806 19:10, 31 August 2011 (EST)

===Lab 6 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What week of development do the palatal shelves fuse?'''
:: The fusion of palatal shelves fuse during week 9 of embryonic development.

'''2. What animal model helped elucidate the neural crest origin and migration of cells?'''
:: The animal model which helped elucidate neural crest origin and migration of cells is the quail-chick chimeras.<ref><pubmed>3058162</pubmed></ref>

'''3. What abnormality results from neural crest not migrating into the cardiac outflow tract?'''
:: Tetralogy of Fallot will be resulted.<ref><pubmed>3568286</pubmed></ref><ref><pubmed>3791607</pubmed></ref>
|}
--Z3389806 22:52, 13 September 2011 (EST)

===Lab 7 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?'''
:: (a) No, satellite cells are not necessary for muscle hypertrophy.
:: (b) Yes, satellite cells are generally involved in hypertrophy.

'''2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?'''
:: Chronic low frequency stimulation subjects the fast muscles to activity of low frequency and thereby, changing the pattern of motor activity imposed upon them. This alters the contractile characteristics of the fast muscles, making it to contract more slowly. This corresponds to the fast to slow fibre type shift.<ref><pubmed>4736724</pubmed></ref>

'''3. Write a comment about the online page on [[Trisomy 21|Trisomy 21]] based upon the group assessment criteria.'''
* ''The frequency of trisomy 21 in the population is approximately 1 in 650 to 1,000 live births, in Australia between 1991-97 there were 2,358 Trisomy 21 (Down) infants.'': it would be better to put this statement under the heading "Prevalence".
* It would be clearer to put the data under "Prevalence" in the form of a table.
* The caption for the table on detection rate of various procedures, "Table data from United Kingdom" is too vague and not clear.
* Choice of headings/sub-headings can be improved. For example, the headings, "Heart Defects" & "Limb Defects" can be sub-headings under "Associated Congenital Abnormalities".
* The sequence of the headings can also be improved. For example, the heading "Recent Findings" should probably be one of the last few headings and should not be just after the introduction as it gives a disjointed feel to the page.
* Reference No. 20 was not formatted properly.
|}
--Z3389806 16:00, 18 September 2011 (EST)

===Lab 8 Assessment===

====Comments on Group Project 1====
'''Strengths:'''
*The alphabetisation of the glossary helps readers to search for terms more easily. I really like this bit.
*The link of some of the words under Etiology to Glossary is really good. The reader can directly find out the meaning of a particular word without scrolling down much.
*All the characteristics and diseases are supported by scientific articles.
*The summaries given for each of the articles under Research gives the reader a gist of each article. It gives the reader a rough idea of where research for Turner Syndrome is heading towards.
*Overall: It has a good flow to the page with headings and sub-headings appropriately placed.
'''Weaknesses:'''
*The wikipage needs to be vetted. There are quite a few grammatical and punctuation errors.
*The placements of some images are disrupting the format of the page e.g the image of “22+23=45”.
*There are duplication in referencing. It will be good to combine the references to only one reference number per article to avoid duplication
*Some of the images did not include copyright statements which allow wiki users to reuse the images e.g. the karyotype image & image on abnormalities.
*Some of the references are just website links. This will need to be corrected.
*History of Turner Syndrome is not available. How was the syndrome first discovered? When was it discovered?
'''Specific corrections:'''
*The second sentence of introduction “It is caused by…survive to term” is a bit too long. Breaking it into two sentences might be better.
*“During normal fetal development, each ovary contain as many as 7 million oocytes”. The word “contain” should be “contains”.
*“The oocytes gradually reduced to 400,000 during menarche and during menopause fewer than 10,000 remains.” Insert the word “are” after “oocytes”.
*Standardise the term “Turner Syndrome”. Either all should be “Turner Syndrome” or “Turner syndrome”
*“…which is complete by the time the infant, is aged 2.” The word “complete” should be “completed”.
*“Genetically menopause” I’m not sure what this means. Is it supposed to be “Genetically-induced menopause”?
*“For example short stature is caused by a deletion of the Xp chromosome and the deletion of Xq causes gonadal dysfunction”. There should be a comma after the word “example”.
*The image on abnormalities associated with Turner Syndrome might be more suitable to be placed under clinical manifestations.

====Comments on Group Project 2====
'''Strengths:'''
*Good placement of sub-headings and headings.
*I like how the introduction gives an overview of the syndrome.
*All images have copyright statements.
'''Weaknesses:'''
*The epidemiology and etiology sections seem like really wordy, overwhelming to read. It is paragraphed but maybe the paragraphs could be more distinct.
*It would be good to link the words that is defined the glossary to the glossary.
*Some of the references are not formatted properly.
'''Specific corrections:'''
*It would be good if introduction immediately started with what is DiGeorge Syndrome instead of leading up with the definition/characteristic of congenital disorder. This definition can be shifted to the glossary
*Just curious, it will be interesting to hear how different the first sound of a DiGeorge baby differs from a normal one.
*”Dianostic Tests” is spelt incorrectly.
*Instead of the sub-heading “Based on symptoms”, it could be “Symptomatic diagnosis”.
*What is “clinodactyly” in the description of the image under “based on symptoms”?
*The link under images for BAC subheading could go under external links section?
*Maybe the table under “Tetralogy of Fallot...in DiGeorge Syndrome” could be vertical instead of horizontal? It will look neater.

====Comments on Group Project 3====
'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

====Comments on Group Project 5====
'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it can be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

====Comments on Group Project 6====
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

====Comments on Group Project 7====
'''Strengths:'''
*The history section was very well done. The block of text above the timeline provided just enough information and captured my interest. The timeline provided adequate summary of the major milestones in research of Angelman Syndrome.
*The glossary section seems decent.
*The student images are really good, especially the mechanism illustrations.
'''Weaknesses:'''
*Lack of use of subheadings. More subheadings can be used to break some of the sections up. It would not look so overwhelming then.
*Format of the overall page is not the best as it can be.
*There is some duplication in references.
'''Specific corrections:'''
*Just curious, why are males more predisposed to early developmental delay?
*It would be good to make the format of the stats under epidemiology consistent. Either fraction or ratio (I prefer ratio :D).
*Maybe for some of the tables, it will look better with an outline border so it is easier to see when the text in the table ends and when text in paragraphs starts.
*Use more subheadings e.g. Under Signs & Symptoms, the subheadings would be “Behavioural Characteristics”, “Communication Skills”, “Clinical & External Characteristics”, etc.
*Section under genetic counselling should come with an explanation or a paragraph of text. It will be good to elaborate further than just a table.

====Comments on Group Project 8====
'''Strengths:'''
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.
*The referencing is well-done with correct formatting and there seemed to be no duplication.
*The external links section is good.
'''Weaknesses:'''
*There are some inconsistencies in formatting.
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.
'''Specific corrections:'''
*Maybe include “frataxin” in the glossary?
*Reference 38 is missing.
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?

====Comments on Group Project 9====
'''Strengths:'''
*Good use of subheadings. It gives the page a structured feel to it.
*For most part of the references, it is good with the initiative to prevent duplication of references.
* I really like the “Specialised Facilities and Supportive Associations” section. Parents who just found out about their child’s condition would probably want to know more and seek help and this would be good for them.
'''Weaknesses:'''
*The history section looks really overwhelming.
*The glossary section is poorly done, with missing definitions for some words. There are other words that should be included in the glossary but was not.
*The image of the typical facial feature of an individual with WS looks similar to the one shown during lecture by Dr Palmer. It would be good to acknowledge what the image drawn was based on.
'''Specific corrections:'''
*It will be good to include an image in either the introduction or history section. At least it will be able to grab some attention.
*Reference 23 is missing its source.
*It will be good to elaborate more on some of the research studies being done to give the readers a feel of the direction in which the research for Williams Syn is gearing towards.

====Comments on Group Project 10====
'''Strengths:'''
*The flow of the page is smooth with appropriate placement of the various headings.
*Clinical manifestation section looks really decent without appearing too verbose but yet sufficient information is given.
*The last image has correct referencing and the copyright statement is also included.
'''Weaknesses:'''
*Some of the references are not formatted properly. There are also a couple of duplications under References.
*Glossary is not complete.
*The formatting for the overall page is not as consistent as it can be.
'''Specific corrections:'''
*Maybe it would be better to have a heading for the genetic condition just on its own and not put it with the introduction heading.
* Maybe future treatments can come under a new heading “future research”?
*It will be good to elaborate more on current treatments.
*Diagnosis can be more detailed.
*Include a timeline under history to summarise that section.
*The copyright statement that allows wikiusers to use the student image after 6 months is not included.

====Comments on Group Project 11====
'''Strengths:'''
*Good use of tables especially under Diagnosis.
*Some of the images are quite good especially on the correcting process (surgery) for cleft palate.
'''Weaknesses:'''
*Placement of headings is not quite appropriate. It gives the page a disjointed feel to it.
*There is a lack of use of subheadings.
*The introduction did not give an overview of the condition.
'''Specific corrections:'''
*Timeline should be a subheading under History section
*Introduction should answer these questions: What is it characterised by? How does it appear on individuals with this condition? What causes it? etc. It will be good to include a picture/ cartoon of an individual with cleft palate and lip.
*Duplication of references should be avoided.
*Some of the references are not formatted correctly.

--Z3389806 12:21, 27 September 2011 (EST)

===Lab 10 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.'''
::Another environmental teratogen that can lead to hearing loss is congenital cytomegalovirus infection.<ref><pubmed>16209862</pubmed></ref>

'''2. Identify 3 factors that contribute to poor neonatal drainage of the middle ear.'''
::The 3 factors are:
::*inflammation (and hence swelling) in the middle ear
::*damage of the tensor palate muscle
::*the (almost) horizontal running of the Eustachian tube

'''3. Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.'''
::A genetic abnormality that affects hearing development is paragangliomas.[http://www.ncbi.nlm.nih.gov/omim/168000 OMIM - Paragangliomas]
|}
--Z3389806 22:24, 6 October 2011 (EST)

===Lab 11 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.'''
::*''Septum primum'' formation from the roof of the atrium separates the right from the left atrium.
::*Perforations of the septum primum gives rise to the ''foramen secundum'' which allows blood flow from right to the left atrium.
::*''Septum secundum'' then forms to the right of the septum primum and incomplete partition of the septum primum gives rise to ''foramen ovale''.

'''2. Identify the cardiac defects that arise through abnormal development of the outflow tract.'''
::*Ventricular Septal Defect
::*Transposition of the Great Vessels
::*Double Outlet Right Ventricle
|}
--Z3389806 13:04, 13 October 2011 (EST)

===Lab 12 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Give examples of 3 systems that continue to develop postnatally.'''
::*Genital development
::*Neural and brain development
::*Musculoskeletal development

'''2. Identify the abnormalities detected by the Guthrie Test and link to one abnormality listed in OMIM.'''
::*Biotinidase Deficiency
::*Congenital Adrenal Hyperplasia (CAH)
::*Congenital Hypothyroidism (CH)
::*Congenital Toxoplasmosis
::*Cystic Fibrosis (CF)
::*Galactosemia (GAL)
::*Homocystinuria
::*Maple Syrup Urine Disease (MSUD)
::*Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)
::*Phenylketonuria (PKU) [http://omim.org/entry/261600 OMIM - PKU]
::*Sickle Cell Disease
|}
--Z3389806 09:42, 21 October 2011 (EST)

==Attendance==

--[[User:Z3389806|Z3389806]] 18:01, 29 July 2011 (EST)

--[[User:Z3389806|Z3389806]] 12:55, 4 August 2011 (EST)

--Z3389806 11:41, 11 August 2011 (EST)

--Z3389806 11:07, 18 August 2011 (EST)

--Z3389806 11:12, 25 August 2011 (EST)

--Z3389806 11:11, 1 September 2011 (EST)

--Z3389806 11:13, 15 September 2011 (EST)

--Z3389806 11:09, 22 September 2011 (EST)

--Z3389806 11:11, 29 September 2011 (EST)

--Z3389806 11:19, 6 October 2011 (EST)

--Z3389806 11:19, 13 October 2011 (EST)

--Z3389806 11:08, 20 October 2011 (EST)

==References==
<references/>

User:Z3389806

2011-10-20T22:43:05Z

Z3389806: /* Lab Assessments */

{{2011Student}}

==Lab Assessments==

===Lab 1 Assessment===

{| style="border: solid 1px #a0a0ff"
|- style="background:#eeeeff"
|'''1. Identify the origin of ''in vitro'' fertilisation and the 2010 Nobel Prize winner associated with this technique.'''
::[[Wikipedia: In vitro fertilisation|''In vitro'' fertilisation]] (IVF) technique was conceptualized by [[Wikipedia: Robert G. Edwards|Sir Robert Geoffrey Edwards]] when he first managed to fertilise a human egg successfully in the laboratory in 1968. This led to the birth of the first baby conceived through IVF, [[WIkipedia: Louise Brown|Louise Brown]], on 25th July 1978. Sir Robert Geoffrey Edwards is also the [[Wikipedia: Nobel Prize in Physiology or Medicine|2010 Nobel Prize]] winner associated with ''in vitro'' fertilisation.

'''2. Identify a recent paper on fertilisation and describe its key findings.'''
::A recent paper on fertilisation is titled “Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during ''in vitro'' fertilisation treatment”<ref>Chen H, Wang W, Mo Y, Ma Y, Ouyang N, Li R, Mai M, He Y, Bodombossou-Djobo MM, Yang D.
'''Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during in vitro fertilisation treatment.''' J Assist Reprod Genet.: 2011 PMID:21717175 [http://www.ncbi.nlm.nih.gov/pubmed/21717175]</ref> by Hong Chen et al. It was reported in the paper that telomerase activity (TA) in the luteinized granulosa cells is positively correlated with clinical pregnancy rate. Clinical pregnancy rate increases with level of TA. This would mean that the success rate of the IVF treatment (resulting in pregnancy) can be predicted by measuring the levels of TA in the granulosa cells.

'''3. Identify 2 congenital anomalies.'''
::The two congenital anomalies are [[wikipedia: Spina bifida|spina bifida]], in which the embryonic neural tube is only partially closed, and [[wikipedia: hydrocephalus|hydrocephalus]], in which there is an unusual accumulation of fluid in the brain.
|}

--[[User:S8600021|Mark Hill]] 00:44, 30 July 2011 (EST) Good wiki coding. Though I am not a fan of Wikipedia linking, should seek scientific references where possible, nobel prize link is better.

===Lab 2 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.'''
::The ZP protein that spermatozoa binds is the zona pelucida glycoprotein 3 (ZP3), also known as the sperm receptor.[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7784]
::Once fertilisation occurs, the oocyte releases enzymes which will alter the terminal carbohydrate residues of ZP3. ZP3 loses the ability to bind sperms, preventing polyspermy.<ref><pubmed>9369183</pubmed></ref>

'''2. Identify a review and a research article related to your group topic.'''
::''Review'': Bassuk AG, Kibar Z. '''Genetic basis of neural tube defects.''' Semin Pediatr Neurol. 2009 Sep;16(3):101-10<ref><pubmed>19778707</pubmed></ref>
::''Research'': De Marco P, Merello E, Cama A, Kibar Z, Capra V.''' Human neural tube defects: Genetic causes and prevention.''' Biofactors. 2011 Jun 14. <ref><pubmed>21674647</pubmed></ref>
|}
--[[User:Z3389806|Nur Sharalyn Abdullah]] 14:20, 10 August 2011 (EST)

===Lab 3 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What is the maternal dietary requirement for late neural development? '''
::The maternal dietary requirement for late neural development is iodine. Iodine is essential in the production of thyroid hormones which play a role in brain development.<ref><pubmed>15107513</pubmed></ref>
::Lack in iodine intake can result in cretinism. The recommended iodine intake during pregnancy is 200-250 micrograms per day.<ref><pubmed>19088150</pubmed></ref>

2. '''Upload a picture relating to your group project.'''

'''Melatonin levels in Huntington's disease patients and controls'''

[[File:Melatonin levels in HD patients and controls.jpg|border]]

The diurnal melatonin rise was significantly delayed in HD patients by about 01:30 h (p = 0.048). The black bar on the abscissa indicates the dark period (23:00–7:30 h).
|}
--Nur Sharalyn Abdullah 12:47, 16 August 2011 (EST)

===Lab 4 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. The allantois, identified in the placental cord, is continuous with what anatomical structure?'''
::The allantois, which originates from the hindgut, is continuous with the bladder.

'''2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.'''
::*Ductus arteriosus: located between pulmonary artery and aortic arch
::*Ductus venosus: located between umbilical vein and inferior vena cava
::*Foramen ovale: located between left atrium and right atrium

'''3. Identify the group project sub-section that you will be researching.'''
::*History
::*Treatment
::*Epidemiology
|}
--Nur Sharalyn Abdullah 21:47, 20 August 2011 (EST)

===Lab 5 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Which side (L/R) is most common for diaphragmatic hernia and why?'''
::The left side is the most common for diaphragmatic hernia. It is thought that this is due to the earlier closure of the right pleuroperitoneal opening.<ref>Moore, K.L. & Persuad, T.V.N. (2008). The Developing Human: clinically oriented embryology (8th ed.). Philadelphia: Saunders, p. 153</ref>
|}
--Z3389806 19:10, 31 August 2011 (EST)

===Lab 6 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What week of development do the palatal shelves fuse?'''
:: The fusion of palatal shelves fuse during week 9 of embryonic development.

'''2. What animal model helped elucidate the neural crest origin and migration of cells?'''
:: The animal model which helped elucidate neural crest origin and migration of cells is the quail-chick chimeras.<ref><pubmed>3058162</pubmed></ref>

'''3. What abnormality results from neural crest not migrating into the cardiac outflow tract?'''
:: Tetralogy of Fallot will be resulted.<ref><pubmed>3568286</pubmed></ref><ref><pubmed>3791607</pubmed></ref>
|}
--Z3389806 22:52, 13 September 2011 (EST)

===Lab 7 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?'''
:: (a) No, satellite cells are not necessary for muscle hypertrophy.
:: (b) Yes, satellite cells are generally involved in hypertrophy.

'''2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?'''
:: Chronic low frequency stimulation subjects the fast muscles to activity of low frequency and thereby, changing the pattern of motor activity imposed upon them. This alters the contractile characteristics of the fast muscles, making it to contract more slowly. This corresponds to the fast to slow fibre type shift.<ref><pubmed>4736724</pubmed></ref>

'''3. Write a comment about the online page on [[Trisomy 21|Trisomy 21]] based upon the group assessment criteria.'''
* ''The frequency of trisomy 21 in the population is approximately 1 in 650 to 1,000 live births, in Australia between 1991-97 there were 2,358 Trisomy 21 (Down) infants.'': it would be better to put this statement under the heading "Prevalence".
* It would be clearer to put the data under "Prevalence" in the form of a table.
* The caption for the table on detection rate of various procedures, "Table data from United Kingdom" is too vague and not clear.
* Choice of headings/sub-headings can be improved. For example, the headings, "Heart Defects" & "Limb Defects" can be sub-headings under "Associated Congenital Abnormalities".
* The sequence of the headings can also be improved. For example, the heading "Recent Findings" should probably be one of the last few headings and should not be just after the introduction as it gives a disjointed feel to the page.
* Reference No. 20 was not formatted properly.
|}
--Z3389806 16:00, 18 September 2011 (EST)

===Lab 8 Assessment===

====Comments on Group Project 1====
'''Strengths:'''
*The alphabetisation of the glossary helps readers to search for terms more easily. I really like this bit.
*The link of some of the words under Etiology to Glossary is really good. The reader can directly find out the meaning of a particular word without scrolling down much.
*All the characteristics and diseases are supported by scientific articles.
*The summaries given for each of the articles under Research gives the reader a gist of each article. It gives the reader a rough idea of where research for Turner Syndrome is heading towards.
*Overall: It has a good flow to the page with headings and sub-headings appropriately placed.
'''Weaknesses:'''
*The wikipage needs to be vetted. There are quite a few grammatical and punctuation errors.
*The placements of some images are disrupting the format of the page e.g the image of “22+23=45”.
*There are duplication in referencing. It will be good to combine the references to only one reference number per article to avoid duplication
*Some of the images did not include copyright statements which allow wiki users to reuse the images e.g. the karyotype image & image on abnormalities.
*Some of the references are just website links. This will need to be corrected.
*History of Turner Syndrome is not available. How was the syndrome first discovered? When was it discovered?
'''Specific corrections:'''
*The second sentence of introduction “It is caused by…survive to term” is a bit too long. Breaking it into two sentences might be better.
*“During normal fetal development, each ovary contain as many as 7 million oocytes”. The word “contain” should be “contains”.
*“The oocytes gradually reduced to 400,000 during menarche and during menopause fewer than 10,000 remains.” Insert the word “are” after “oocytes”.
*Standardise the term “Turner Syndrome”. Either all should be “Turner Syndrome” or “Turner syndrome”
*“…which is complete by the time the infant, is aged 2.” The word “complete” should be “completed”.
*“Genetically menopause” I’m not sure what this means. Is it supposed to be “Genetically-induced menopause”?
*“For example short stature is caused by a deletion of the Xp chromosome and the deletion of Xq causes gonadal dysfunction”. There should be a comma after the word “example”.
*The image on abnormalities associated with Turner Syndrome might be more suitable to be placed under clinical manifestations.

====Comments on Group Project 2====
'''Strengths:'''
*Good placement of sub-headings and headings.
*I like how the introduction gives an overview of the syndrome.
*All images have copyright statements.
'''Weaknesses:'''
*The epidemiology and etiology sections seem like really wordy, overwhelming to read. It is paragraphed but maybe the paragraphs could be more distinct.
*It would be good to link the words that is defined the glossary to the glossary.
*Some of the references are not formatted properly.
'''Specific corrections:'''
*It would be good if introduction immediately started with what is DiGeorge Syndrome instead of leading up with the definition/characteristic of congenital disorder. This definition can be shifted to the glossary
*Just curious, it will be interesting to hear how different the first sound of a DiGeorge baby differs from a normal one.
*”Dianostic Tests” is spelt incorrectly.
*Instead of the sub-heading “Based on symptoms”, it could be “Symptomatic diagnosis”.
*What is “clinodactyly” in the description of the image under “based on symptoms”?
*The link under images for BAC subheading could go under external links section?
*Maybe the table under “Tetralogy of Fallot...in DiGeorge Syndrome” could be vertical instead of horizontal? It will look neater.

====Comments on Group Project 3====
'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

====Comments on Group Project 5====
'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it can be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

====Comments on Group Project 6====
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

====Comments on Group Project 7====
'''Strengths:'''
*The history section was very well done. The block of text above the timeline provided just enough information and captured my interest. The timeline provided adequate summary of the major milestones in research of Angelman Syndrome.
*The glossary section seems decent.
*The student images are really good, especially the mechanism illustrations.
'''Weaknesses:'''
*Lack of use of subheadings. More subheadings can be used to break some of the sections up. It would not look so overwhelming then.
*Format of the overall page is not the best as it can be.
*There is some duplication in references.
'''Specific corrections:'''
*Just curious, why are males more predisposed to early developmental delay?
*It would be good to make the format of the stats under epidemiology consistent. Either fraction or ratio (I prefer ratio :D).
*Maybe for some of the tables, it will look better with an outline border so it is easier to see when the text in the table ends and when text in paragraphs starts.
*Use more subheadings e.g. Under Signs & Symptoms, the subheadings would be “Behavioural Characteristics”, “Communication Skills”, “Clinical & External Characteristics”, etc.
*Section under genetic counselling should come with an explanation or a paragraph of text. It will be good to elaborate further than just a table.

====Comments on Group Project 8====
'''Strengths:'''
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.
*The referencing is well-done with correct formatting and there seemed to be no duplication.
*The external links section is good.
'''Weaknesses:'''
*There are some inconsistencies in formatting.
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.
'''Specific corrections:'''
*Maybe include “frataxin” in the glossary?
*Reference 38 is missing.
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?

====Comments on Group Project 9====
'''Strengths:'''
*Good use of subheadings. It gives the page a structured feel to it.
*For most part of the references, it is good with the initiative to prevent duplication of references.
* I really like the “Specialised Facilities and Supportive Associations” section. Parents who just found out about their child’s condition would probably want to know more and seek help and this would be good for them.
'''Weaknesses:'''
*The history section looks really overwhelming.
*The glossary section is poorly done, with missing definitions for some words. There are other words that should be included in the glossary but was not.
*The image of the typical facial feature of an individual with WS looks similar to the one shown during lecture by Dr Palmer. It would be good to acknowledge what the image drawn was based on.
'''Specific corrections:'''
*It will be good to include an image in either the introduction or history section. At least it will be able to grab some attention.
*Reference 23 is missing its source.
*It will be good to elaborate more on some of the research studies being done to give the readers a feel of the direction in which the research for Williams Syn is gearing towards.

====Comments on Group Project 10====
'''Strengths:'''
*The flow of the page is smooth with appropriate placement of the various headings.
*Clinical manifestation section looks really decent without appearing too verbose but yet sufficient information is given.
*The last image has correct referencing and the copyright statement is also included.
'''Weaknesses:'''
*Some of the references are not formatted properly. There are also a couple of duplications under References.
*Glossary is not complete.
*The formatting for the overall page is not as consistent as it can be.
'''Specific corrections:'''
*Maybe it would be better to have a heading for the genetic condition just on its own and not put it with the introduction heading.
* Maybe future treatments can come under a new heading “future research”?
*It will be good to elaborate more on current treatments.
*Diagnosis can be more detailed.
*Include a timeline under history to summarise that section.
*The copyright statement that allows wikiusers to use the student image after 6 months is not included.

====Comments on Group Project 11====
'''Strengths:'''
*Good use of tables especially under Diagnosis.
*Some of the images are quite good especially on the correcting process (surgery) for cleft palate.
'''Weaknesses:'''
*Placement of headings is not quite appropriate. It gives the page a disjointed feel to it.
*There is a lack of use of subheadings.
*The introduction did not give an overview of the condition.
'''Specific corrections:'''
*Timeline should be a subheading under History section
*Introduction should answer these questions: What is it characterised by? How does it appear on individuals with this condition? What causes it? etc. It will be good to include a picture/ cartoon of an individual with cleft palate and lip.
*Duplication of references should be avoided.
*Some of the references are not formatted correctly.

--Z3389806 12:21, 27 September 2011 (EST)

===Lab 10 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.'''
::Another environmental teratogen that can lead to hearing loss is congenital cytomegalovirus infection.<ref><pubmed>16209862</pubmed></ref>

'''2. Identify 3 factors that contribute to poor neonatal drainage of the middle ear.'''
::The 3 factors are:
::*inflammation (and hence swelling) in the middle ear
::*damage of the tensor palate muscle
::*the (almost) horizontal running of the Eustachian tube

'''3. Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.'''
::A genetic abnormality that affects hearing development is paragangliomas.[http://www.ncbi.nlm.nih.gov/omim/168000 OMIM - Paragangliomas]
|}
--Z3389806 22:24, 6 October 2011 (EST)

===Lab 11 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.'''
::*''Septum primum'' formation from the roof of the atrium separates the right from the left atrium.
::*Perforations of the septum primum gives rise to the ''foramen secundum'' which allows blood flow from right to the left atrium.
::*''Septum secundum'' then forms to the right of the septum primum and incomplete partition of the septum primum gives rise to ''foramen ovale''.

'''2. Identify the cardiac defects that arise through abnormal development of the outflow tract.'''
::*Ventricular Septal Defect
::*Transposition of the Great Vessels
::*Double Outlet Right Ventricle
|}
--Z3389806 13:04, 13 October 2011 (EST)

===Lab 12 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Give examples of 3 systems that continue to develop postnatally.'''
::*Genital development
::*Neural and brain development
::*Musculoskeletal development

'''2. Identify the abnormalities detected by the Guthrie Test and link to one abnormality listed in OMIM.'''
::*Biotinidase Deficiency
::*Congenital Adrenal Hyperplasia (CAH)
::*Congenital Hypothyroidism (CH)
::*Congenital Toxoplasmosis
::*Cystic Fibrosis (CF)
::*Galactosemia (GAL)
::*Homocystinuria
::*Maple Syrup Urine Disease (MSUD)
::*Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)
::*Phenylketonuria (PKU) ([http://omim.org/entry/261600 OMIM])
::*Sickle Cell Disease
|}
--Z3389806 09:42, 21 October 2011 (EST)

==Attendance==

--[[User:Z3389806|Z3389806]] 18:01, 29 July 2011 (EST)

--[[User:Z3389806|Z3389806]] 12:55, 4 August 2011 (EST)

--Z3389806 11:41, 11 August 2011 (EST)

--Z3389806 11:07, 18 August 2011 (EST)

--Z3389806 11:12, 25 August 2011 (EST)

--Z3389806 11:11, 1 September 2011 (EST)

--Z3389806 11:13, 15 September 2011 (EST)

--Z3389806 11:09, 22 September 2011 (EST)

--Z3389806 11:11, 29 September 2011 (EST)

--Z3389806 11:19, 6 October 2011 (EST)

--Z3389806 11:19, 13 October 2011 (EST)

--Z3389806 11:08, 20 October 2011 (EST)

==References==
<references/>

User:Z3389806

2011-10-20T00:08:35Z

Z3389806: /* Attendance */

{{2011Student}}

==Lab Assessments==

===Lab 1 Assessment===

{| style="border: solid 1px #a0a0ff"
|- style="background:#eeeeff"
|'''1. Identify the origin of ''in vitro'' fertilisation and the 2010 Nobel Prize winner associated with this technique.'''
::[[Wikipedia: In vitro fertilisation|''In vitro'' fertilisation]] (IVF) technique was conceptualized by [[Wikipedia: Robert G. Edwards|Sir Robert Geoffrey Edwards]] when he first managed to fertilise a human egg successfully in the laboratory in 1968. This led to the birth of the first baby conceived through IVF, [[WIkipedia: Louise Brown|Louise Brown]], on 25th July 1978. Sir Robert Geoffrey Edwards is also the [[Wikipedia: Nobel Prize in Physiology or Medicine|2010 Nobel Prize]] winner associated with ''in vitro'' fertilisation.

'''2. Identify a recent paper on fertilisation and describe its key findings.'''
::A recent paper on fertilisation is titled “Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during ''in vitro'' fertilisation treatment”<ref>Chen H, Wang W, Mo Y, Ma Y, Ouyang N, Li R, Mai M, He Y, Bodombossou-Djobo MM, Yang D.
'''Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during in vitro fertilisation treatment.''' J Assist Reprod Genet.: 2011 PMID:21717175 [http://www.ncbi.nlm.nih.gov/pubmed/21717175]</ref> by Hong Chen et al. It was reported in the paper that telomerase activity (TA) in the luteinized granulosa cells is positively correlated with clinical pregnancy rate. Clinical pregnancy rate increases with level of TA. This would mean that the success rate of the IVF treatment (resulting in pregnancy) can be predicted by measuring the levels of TA in the granulosa cells.

'''3. Identify 2 congenital anomalies.'''
::The two congenital anomalies are [[wikipedia: Spina bifida|spina bifida]], in which the embryonic neural tube is only partially closed, and [[wikipedia: hydrocephalus|hydrocephalus]], in which there is an unusual accumulation of fluid in the brain.
|}

--[[User:S8600021|Mark Hill]] 00:44, 30 July 2011 (EST) Good wiki coding. Though I am not a fan of Wikipedia linking, should seek scientific references where possible, nobel prize link is better.

===Lab 2 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.'''
::The ZP protein that spermatozoa binds is the zona pelucida glycoprotein 3 (ZP3), also known as the sperm receptor.[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7784]
::Once fertilisation occurs, the oocyte releases enzymes which will alter the terminal carbohydrate residues of ZP3. ZP3 loses the ability to bind sperms, preventing polyspermy.<ref><pubmed>9369183</pubmed></ref>

'''2. Identify a review and a research article related to your group topic.'''
::''Review'': Bassuk AG, Kibar Z. '''Genetic basis of neural tube defects.''' Semin Pediatr Neurol. 2009 Sep;16(3):101-10<ref><pubmed>19778707</pubmed></ref>
::''Research'': De Marco P, Merello E, Cama A, Kibar Z, Capra V.''' Human neural tube defects: Genetic causes and prevention.''' Biofactors. 2011 Jun 14. <ref><pubmed>21674647</pubmed></ref>
|}
--[[User:Z3389806|Nur Sharalyn Abdullah]] 14:20, 10 August 2011 (EST)

===Lab 3 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What is the maternal dietary requirement for late neural development? '''
::The maternal dietary requirement for late neural development is iodine. Iodine is essential in the production of thyroid hormones which play a role in brain development.<ref><pubmed>15107513</pubmed></ref>
::Lack in iodine intake can result in cretinism. The recommended iodine intake during pregnancy is 200-250 micrograms per day.<ref><pubmed>19088150</pubmed></ref>

2. '''Upload a picture relating to your group project.'''

'''Melatonin levels in Huntington's disease patients and controls'''

[[File:Melatonin levels in HD patients and controls.jpg|border]]

The diurnal melatonin rise was significantly delayed in HD patients by about 01:30 h (p = 0.048). The black bar on the abscissa indicates the dark period (23:00–7:30 h).
|}
--Nur Sharalyn Abdullah 12:47, 16 August 2011 (EST)

===Lab 4 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. The allantois, identified in the placental cord, is continuous with what anatomical structure?'''
::The allantois, which originates from the hindgut, is continuous with the bladder.

'''2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.'''
::*Ductus arteriosus: located between pulmonary artery and aortic arch
::*Ductus venosus: located between umbilical vein and inferior vena cava
::*Foramen ovale: located between left atrium and right atrium

'''3. Identify the group project sub-section that you will be researching.'''
::*History
::*Treatment
::*Epidemiology
|}
--Nur Sharalyn Abdullah 21:47, 20 August 2011 (EST)

===Lab 5 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Which side (L/R) is most common for diaphragmatic hernia and why?'''
::The left side is the most common for diaphragmatic hernia. It is thought that this is due to the earlier closure of the right pleuroperitoneal opening.<ref>Moore, K.L. & Persuad, T.V.N. (2008). The Developing Human: clinically oriented embryology (8th ed.). Philadelphia: Saunders, p. 153</ref>
|}
--Z3389806 19:10, 31 August 2011 (EST)

===Lab 6 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What week of development do the palatal shelves fuse?'''
:: The fusion of palatal shelves fuse during week 9 of embryonic development.

'''2. What animal model helped elucidate the neural crest origin and migration of cells?'''
:: The animal model which helped elucidate neural crest origin and migration of cells is the quail-chick chimeras.<ref><pubmed>3058162</pubmed></ref>

'''3. What abnormality results from neural crest not migrating into the cardiac outflow tract?'''
:: Tetralogy of Fallot will be resulted.<ref><pubmed>3568286</pubmed></ref><ref><pubmed>3791607</pubmed></ref>
|}
--Z3389806 22:52, 13 September 2011 (EST)

===Lab 7 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?'''
:: (a) No, satellite cells are not necessary for muscle hypertrophy.
:: (b) Yes, satellite cells are generally involved in hypertrophy.

'''2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?'''
:: Chronic low frequency stimulation subjects the fast muscles to activity of low frequency and thereby, changing the pattern of motor activity imposed upon them. This alters the contractile characteristics of the fast muscles, making it to contract more slowly. This corresponds to the fast to slow fibre type shift.<ref><pubmed>4736724</pubmed></ref>

'''3. Write a comment about the online page on [[Trisomy 21|Trisomy 21]] based upon the group assessment criteria.'''
* ''The frequency of trisomy 21 in the population is approximately 1 in 650 to 1,000 live births, in Australia between 1991-97 there were 2,358 Trisomy 21 (Down) infants.'': it would be better to put this statement under the heading "Prevalence".
* It would be clearer to put the data under "Prevalence" in the form of a table.
* The caption for the table on detection rate of various procedures, "Table data from United Kingdom" is too vague and not clear.
* Choice of headings/sub-headings can be improved. For example, the headings, "Heart Defects" & "Limb Defects" can be sub-headings under "Associated Congenital Abnormalities".
* The sequence of the headings can also be improved. For example, the heading "Recent Findings" should probably be one of the last few headings and should not be just after the introduction as it gives a disjointed feel to the page.
* Reference No. 20 was not formatted properly.
|}
--Z3389806 16:00, 18 September 2011 (EST)

===Lab 8 Assessment===

====Comments on Group Project 1====
'''Strengths:'''
*The alphabetisation of the glossary helps readers to search for terms more easily. I really like this bit.
*The link of some of the words under Etiology to Glossary is really good. The reader can directly find out the meaning of a particular word without scrolling down much.
*All the characteristics and diseases are supported by scientific articles.
*The summaries given for each of the articles under Research gives the reader a gist of each article. It gives the reader a rough idea of where research for Turner Syndrome is heading towards.
*Overall: It has a good flow to the page with headings and sub-headings appropriately placed.
'''Weaknesses:'''
*The wikipage needs to be vetted. There are quite a few grammatical and punctuation errors.
*The placements of some images are disrupting the format of the page e.g the image of “22+23=45”.
*There are duplication in referencing. It will be good to combine the references to only one reference number per article to avoid duplication
*Some of the images did not include copyright statements which allow wiki users to reuse the images e.g. the karyotype image & image on abnormalities.
*Some of the references are just website links. This will need to be corrected.
*History of Turner Syndrome is not available. How was the syndrome first discovered? When was it discovered?
'''Specific corrections:'''
*The second sentence of introduction “It is caused by…survive to term” is a bit too long. Breaking it into two sentences might be better.
*“During normal fetal development, each ovary contain as many as 7 million oocytes”. The word “contain” should be “contains”.
*“The oocytes gradually reduced to 400,000 during menarche and during menopause fewer than 10,000 remains.” Insert the word “are” after “oocytes”.
*Standardise the term “Turner Syndrome”. Either all should be “Turner Syndrome” or “Turner syndrome”
*“…which is complete by the time the infant, is aged 2.” The word “complete” should be “completed”.
*“Genetically menopause” I’m not sure what this means. Is it supposed to be “Genetically-induced menopause”?
*“For example short stature is caused by a deletion of the Xp chromosome and the deletion of Xq causes gonadal dysfunction”. There should be a comma after the word “example”.
*The image on abnormalities associated with Turner Syndrome might be more suitable to be placed under clinical manifestations.

====Comments on Group Project 2====
'''Strengths:'''
*Good placement of sub-headings and headings.
*I like how the introduction gives an overview of the syndrome.
*All images have copyright statements.
'''Weaknesses:'''
*The epidemiology and etiology sections seem like really wordy, overwhelming to read. It is paragraphed but maybe the paragraphs could be more distinct.
*It would be good to link the words that is defined the glossary to the glossary.
*Some of the references are not formatted properly.
'''Specific corrections:'''
*It would be good if introduction immediately started with what is DiGeorge Syndrome instead of leading up with the definition/characteristic of congenital disorder. This definition can be shifted to the glossary
*Just curious, it will be interesting to hear how different the first sound of a DiGeorge baby differs from a normal one.
*”Dianostic Tests” is spelt incorrectly.
*Instead of the sub-heading “Based on symptoms”, it could be “Symptomatic diagnosis”.
*What is “clinodactyly” in the description of the image under “based on symptoms”?
*The link under images for BAC subheading could go under external links section?
*Maybe the table under “Tetralogy of Fallot...in DiGeorge Syndrome” could be vertical instead of horizontal? It will look neater.

====Comments on Group Project 3====
'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

====Comments on Group Project 5====
'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it can be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

====Comments on Group Project 6====
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

====Comments on Group Project 7====
'''Strengths:'''
*The history section was very well done. The block of text above the timeline provided just enough information and captured my interest. The timeline provided adequate summary of the major milestones in research of Angelman Syndrome.
*The glossary section seems decent.
*The student images are really good, especially the mechanism illustrations.
'''Weaknesses:'''
*Lack of use of subheadings. More subheadings can be used to break some of the sections up. It would not look so overwhelming then.
*Format of the overall page is not the best as it can be.
*There is some duplication in references.
'''Specific corrections:'''
*Just curious, why are males more predisposed to early developmental delay?
*It would be good to make the format of the stats under epidemiology consistent. Either fraction or ratio (I prefer ratio :D).
*Maybe for some of the tables, it will look better with an outline border so it is easier to see when the text in the table ends and when text in paragraphs starts.
*Use more subheadings e.g. Under Signs & Symptoms, the subheadings would be “Behavioural Characteristics”, “Communication Skills”, “Clinical & External Characteristics”, etc.
*Section under genetic counselling should come with an explanation or a paragraph of text. It will be good to elaborate further than just a table.

====Comments on Group Project 8====
'''Strengths:'''
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.
*The referencing is well-done with correct formatting and there seemed to be no duplication.
*The external links section is good.
'''Weaknesses:'''
*There are some inconsistencies in formatting.
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.
'''Specific corrections:'''
*Maybe include “frataxin” in the glossary?
*Reference 38 is missing.
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?

====Comments on Group Project 9====
'''Strengths:'''
*Good use of subheadings. It gives the page a structured feel to it.
*For most part of the references, it is good with the initiative to prevent duplication of references.
* I really like the “Specialised Facilities and Supportive Associations” section. Parents who just found out about their child’s condition would probably want to know more and seek help and this would be good for them.
'''Weaknesses:'''
*The history section looks really overwhelming.
*The glossary section is poorly done, with missing definitions for some words. There are other words that should be included in the glossary but was not.
*The image of the typical facial feature of an individual with WS looks similar to the one shown during lecture by Dr Palmer. It would be good to acknowledge what the image drawn was based on.
'''Specific corrections:'''
*It will be good to include an image in either the introduction or history section. At least it will be able to grab some attention.
*Reference 23 is missing its source.
*It will be good to elaborate more on some of the research studies being done to give the readers a feel of the direction in which the research for Williams Syn is gearing towards.

====Comments on Group Project 10====
'''Strengths:'''
*The flow of the page is smooth with appropriate placement of the various headings.
*Clinical manifestation section looks really decent without appearing too verbose but yet sufficient information is given.
*The last image has correct referencing and the copyright statement is also included.
'''Weaknesses:'''
*Some of the references are not formatted properly. There are also a couple of duplications under References.
*Glossary is not complete.
*The formatting for the overall page is not as consistent as it can be.
'''Specific corrections:'''
*Maybe it would be better to have a heading for the genetic condition just on its own and not put it with the introduction heading.
* Maybe future treatments can come under a new heading “future research”?
*It will be good to elaborate more on current treatments.
*Diagnosis can be more detailed.
*Include a timeline under history to summarise that section.
*The copyright statement that allows wikiusers to use the student image after 6 months is not included.

====Comments on Group Project 11====
'''Strengths:'''
*Good use of tables especially under Diagnosis.
*Some of the images are quite good especially on the correcting process (surgery) for cleft palate.
'''Weaknesses:'''
*Placement of headings is not quite appropriate. It gives the page a disjointed feel to it.
*There is a lack of use of subheadings.
*The introduction did not give an overview of the condition.
'''Specific corrections:'''
*Timeline should be a subheading under History section
*Introduction should answer these questions: What is it characterised by? How does it appear on individuals with this condition? What causes it? etc. It will be good to include a picture/ cartoon of an individual with cleft palate and lip.
*Duplication of references should be avoided.
*Some of the references are not formatted correctly.

--Z3389806 12:21, 27 September 2011 (EST)

===Lab 10 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.'''
::Another environmental teratogen that can lead to hearing loss is congenital cytomegalovirus infection.<ref><pubmed>16209862</pubmed></ref>

'''2. Identify 3 factors that contribute to poor neonatal drainage of the middle ear.'''
::The 3 factors are:
::*inflammation (and hence swelling) in the middle ear
::*damage of the tensor palate muscle
::*the (almost) horizontal running of the Eustachian tube

'''3. Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.'''
::A genetic abnormality that affects hearing development is paragangliomas.[http://www.ncbi.nlm.nih.gov/omim/168000 OMIM - Paragangliomas]
|}
--Z3389806 22:24, 6 October 2011 (EST)

===Lab 11 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.'''
::*''Septum primum'' formation from the roof of the atrium separates the right from the left atrium.
::*Perforations of the septum primum gives rise to the ''foramen secundum'' which allows blood flow from right to the left atrium.
::*''Septum secundum'' then forms to the right of the septum primum and incomplete partition of the septum primum gives rise to ''foramen ovale''.

'''2. Identify the cardiac defects that arise through abnormal development of the outflow tract.'''
::*Ventricular Septal Defect
::*Transposition of the Great Vessels
::*Double Outlet Right Ventricle
|}
--Z3389806 13:04, 13 October 2011 (EST)

==Attendance==

--[[User:Z3389806|Z3389806]] 18:01, 29 July 2011 (EST)

--[[User:Z3389806|Z3389806]] 12:55, 4 August 2011 (EST)

--Z3389806 11:41, 11 August 2011 (EST)

--Z3389806 11:07, 18 August 2011 (EST)

--Z3389806 11:12, 25 August 2011 (EST)

--Z3389806 11:11, 1 September 2011 (EST)

--Z3389806 11:13, 15 September 2011 (EST)

--Z3389806 11:09, 22 September 2011 (EST)

--Z3389806 11:11, 29 September 2011 (EST)

--Z3389806 11:19, 6 October 2011 (EST)

--Z3389806 11:19, 13 October 2011 (EST)

--Z3389806 11:08, 20 October 2011 (EST)

==References==
<references/>

User:Z3389806

2011-10-13T02:08:08Z

Z3389806: /* Lab 11 Assessment */

{{2011Student}}

==Lab Assessments==

===Lab 1 Assessment===

{| style="border: solid 1px #a0a0ff"
|- style="background:#eeeeff"
|'''1. Identify the origin of ''in vitro'' fertilisation and the 2010 Nobel Prize winner associated with this technique.'''
::[[Wikipedia: In vitro fertilisation|''In vitro'' fertilisation]] (IVF) technique was conceptualized by [[Wikipedia: Robert G. Edwards|Sir Robert Geoffrey Edwards]] when he first managed to fertilise a human egg successfully in the laboratory in 1968. This led to the birth of the first baby conceived through IVF, [[WIkipedia: Louise Brown|Louise Brown]], on 25th July 1978. Sir Robert Geoffrey Edwards is also the [[Wikipedia: Nobel Prize in Physiology or Medicine|2010 Nobel Prize]] winner associated with ''in vitro'' fertilisation.

'''2. Identify a recent paper on fertilisation and describe its key findings.'''
::A recent paper on fertilisation is titled “Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during ''in vitro'' fertilisation treatment”<ref>Chen H, Wang W, Mo Y, Ma Y, Ouyang N, Li R, Mai M, He Y, Bodombossou-Djobo MM, Yang D.
'''Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during in vitro fertilisation treatment.''' J Assist Reprod Genet.: 2011 PMID:21717175 [http://www.ncbi.nlm.nih.gov/pubmed/21717175]</ref> by Hong Chen et al. It was reported in the paper that telomerase activity (TA) in the luteinized granulosa cells is positively correlated with clinical pregnancy rate. Clinical pregnancy rate increases with level of TA. This would mean that the success rate of the IVF treatment (resulting in pregnancy) can be predicted by measuring the levels of TA in the granulosa cells.

'''3. Identify 2 congenital anomalies.'''
::The two congenital anomalies are [[wikipedia: Spina bifida|spina bifida]], in which the embryonic neural tube is only partially closed, and [[wikipedia: hydrocephalus|hydrocephalus]], in which there is an unusual accumulation of fluid in the brain.
|}

--[[User:S8600021|Mark Hill]] 00:44, 30 July 2011 (EST) Good wiki coding. Though I am not a fan of Wikipedia linking, should seek scientific references where possible, nobel prize link is better.

===Lab 2 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.'''
::The ZP protein that spermatozoa binds is the zona pelucida glycoprotein 3 (ZP3), also known as the sperm receptor.[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7784]
::Once fertilisation occurs, the oocyte releases enzymes which will alter the terminal carbohydrate residues of ZP3. ZP3 loses the ability to bind sperms, preventing polyspermy.<ref><pubmed>9369183</pubmed></ref>

'''2. Identify a review and a research article related to your group topic.'''
::''Review'': Bassuk AG, Kibar Z. '''Genetic basis of neural tube defects.''' Semin Pediatr Neurol. 2009 Sep;16(3):101-10<ref><pubmed>19778707</pubmed></ref>
::''Research'': De Marco P, Merello E, Cama A, Kibar Z, Capra V.''' Human neural tube defects: Genetic causes and prevention.''' Biofactors. 2011 Jun 14. <ref><pubmed>21674647</pubmed></ref>
|}
--[[User:Z3389806|Nur Sharalyn Abdullah]] 14:20, 10 August 2011 (EST)

===Lab 3 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What is the maternal dietary requirement for late neural development? '''
::The maternal dietary requirement for late neural development is iodine. Iodine is essential in the production of thyroid hormones which play a role in brain development.<ref><pubmed>15107513</pubmed></ref>
::Lack in iodine intake can result in cretinism. The recommended iodine intake during pregnancy is 200-250 micrograms per day.<ref><pubmed>19088150</pubmed></ref>

2. '''Upload a picture relating to your group project.'''

'''Melatonin levels in Huntington's disease patients and controls'''

[[File:Melatonin levels in HD patients and controls.jpg|border]]

The diurnal melatonin rise was significantly delayed in HD patients by about 01:30 h (p = 0.048). The black bar on the abscissa indicates the dark period (23:00–7:30 h).
|}
--Nur Sharalyn Abdullah 12:47, 16 August 2011 (EST)

===Lab 4 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. The allantois, identified in the placental cord, is continuous with what anatomical structure?'''
::The allantois, which originates from the hindgut, is continuous with the bladder.

'''2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.'''
::*Ductus arteriosus: located between pulmonary artery and aortic arch
::*Ductus venosus: located between umbilical vein and inferior vena cava
::*Foramen ovale: located between left atrium and right atrium

'''3. Identify the group project sub-section that you will be researching.'''
::*History
::*Treatment
::*Epidemiology
|}
--Nur Sharalyn Abdullah 21:47, 20 August 2011 (EST)

===Lab 5 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Which side (L/R) is most common for diaphragmatic hernia and why?'''
::The left side is the most common for diaphragmatic hernia. It is thought that this is due to the earlier closure of the right pleuroperitoneal opening.<ref>Moore, K.L. & Persuad, T.V.N. (2008). The Developing Human: clinically oriented embryology (8th ed.). Philadelphia: Saunders, p. 153</ref>
|}
--Z3389806 19:10, 31 August 2011 (EST)

===Lab 6 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What week of development do the palatal shelves fuse?'''
:: The fusion of palatal shelves fuse during week 9 of embryonic development.

'''2. What animal model helped elucidate the neural crest origin and migration of cells?'''
:: The animal model which helped elucidate neural crest origin and migration of cells is the quail-chick chimeras.<ref><pubmed>3058162</pubmed></ref>

'''3. What abnormality results from neural crest not migrating into the cardiac outflow tract?'''
:: Tetralogy of Fallot will be resulted.<ref><pubmed>3568286</pubmed></ref><ref><pubmed>3791607</pubmed></ref>
|}
--Z3389806 22:52, 13 September 2011 (EST)

===Lab 7 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?'''
:: (a) No, satellite cells are not necessary for muscle hypertrophy.
:: (b) Yes, satellite cells are generally involved in hypertrophy.

'''2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?'''
:: Chronic low frequency stimulation subjects the fast muscles to activity of low frequency and thereby, changing the pattern of motor activity imposed upon them. This alters the contractile characteristics of the fast muscles, making it to contract more slowly. This corresponds to the fast to slow fibre type shift.<ref><pubmed>4736724</pubmed></ref>

'''3. Write a comment about the online page on [[Trisomy 21|Trisomy 21]] based upon the group assessment criteria.'''
* ''The frequency of trisomy 21 in the population is approximately 1 in 650 to 1,000 live births, in Australia between 1991-97 there were 2,358 Trisomy 21 (Down) infants.'': it would be better to put this statement under the heading "Prevalence".
* It would be clearer to put the data under "Prevalence" in the form of a table.
* The caption for the table on detection rate of various procedures, "Table data from United Kingdom" is too vague and not clear.
* Choice of headings/sub-headings can be improved. For example, the headings, "Heart Defects" & "Limb Defects" can be sub-headings under "Associated Congenital Abnormalities".
* The sequence of the headings can also be improved. For example, the heading "Recent Findings" should probably be one of the last few headings and should not be just after the introduction as it gives a disjointed feel to the page.
* Reference No. 20 was not formatted properly.
|}
--Z3389806 16:00, 18 September 2011 (EST)

===Lab 8 Assessment===

====Comments on Group Project 1====
'''Strengths:'''
*The alphabetisation of the glossary helps readers to search for terms more easily. I really like this bit.
*The link of some of the words under Etiology to Glossary is really good. The reader can directly find out the meaning of a particular word without scrolling down much.
*All the characteristics and diseases are supported by scientific articles.
*The summaries given for each of the articles under Research gives the reader a gist of each article. It gives the reader a rough idea of where research for Turner Syndrome is heading towards.
*Overall: It has a good flow to the page with headings and sub-headings appropriately placed.
'''Weaknesses:'''
*The wikipage needs to be vetted. There are quite a few grammatical and punctuation errors.
*The placements of some images are disrupting the format of the page e.g the image of “22+23=45”.
*There are duplication in referencing. It will be good to combine the references to only one reference number per article to avoid duplication
*Some of the images did not include copyright statements which allow wiki users to reuse the images e.g. the karyotype image & image on abnormalities.
*Some of the references are just website links. This will need to be corrected.
*History of Turner Syndrome is not available. How was the syndrome first discovered? When was it discovered?
'''Specific corrections:'''
*The second sentence of introduction “It is caused by…survive to term” is a bit too long. Breaking it into two sentences might be better.
*“During normal fetal development, each ovary contain as many as 7 million oocytes”. The word “contain” should be “contains”.
*“The oocytes gradually reduced to 400,000 during menarche and during menopause fewer than 10,000 remains.” Insert the word “are” after “oocytes”.
*Standardise the term “Turner Syndrome”. Either all should be “Turner Syndrome” or “Turner syndrome”
*“…which is complete by the time the infant, is aged 2.” The word “complete” should be “completed”.
*“Genetically menopause” I’m not sure what this means. Is it supposed to be “Genetically-induced menopause”?
*“For example short stature is caused by a deletion of the Xp chromosome and the deletion of Xq causes gonadal dysfunction”. There should be a comma after the word “example”.
*The image on abnormalities associated with Turner Syndrome might be more suitable to be placed under clinical manifestations.

====Comments on Group Project 2====
'''Strengths:'''
*Good placement of sub-headings and headings.
*I like how the introduction gives an overview of the syndrome.
*All images have copyright statements.
'''Weaknesses:'''
*The epidemiology and etiology sections seem like really wordy, overwhelming to read. It is paragraphed but maybe the paragraphs could be more distinct.
*It would be good to link the words that is defined the glossary to the glossary.
*Some of the references are not formatted properly.
'''Specific corrections:'''
*It would be good if introduction immediately started with what is DiGeorge Syndrome instead of leading up with the definition/characteristic of congenital disorder. This definition can be shifted to the glossary
*Just curious, it will be interesting to hear how different the first sound of a DiGeorge baby differs from a normal one.
*”Dianostic Tests” is spelt incorrectly.
*Instead of the sub-heading “Based on symptoms”, it could be “Symptomatic diagnosis”.
*What is “clinodactyly” in the description of the image under “based on symptoms”?
*The link under images for BAC subheading could go under external links section?
*Maybe the table under “Tetralogy of Fallot...in DiGeorge Syndrome” could be vertical instead of horizontal? It will look neater.

====Comments on Group Project 3====
'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

====Comments on Group Project 5====
'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it can be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

====Comments on Group Project 6====
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

====Comments on Group Project 7====
'''Strengths:'''
*The history section was very well done. The block of text above the timeline provided just enough information and captured my interest. The timeline provided adequate summary of the major milestones in research of Angelman Syndrome.
*The glossary section seems decent.
*The student images are really good, especially the mechanism illustrations.
'''Weaknesses:'''
*Lack of use of subheadings. More subheadings can be used to break some of the sections up. It would not look so overwhelming then.
*Format of the overall page is not the best as it can be.
*There is some duplication in references.
'''Specific corrections:'''
*Just curious, why are males more predisposed to early developmental delay?
*It would be good to make the format of the stats under epidemiology consistent. Either fraction or ratio (I prefer ratio :D).
*Maybe for some of the tables, it will look better with an outline border so it is easier to see when the text in the table ends and when text in paragraphs starts.
*Use more subheadings e.g. Under Signs & Symptoms, the subheadings would be “Behavioural Characteristics”, “Communication Skills”, “Clinical & External Characteristics”, etc.
*Section under genetic counselling should come with an explanation or a paragraph of text. It will be good to elaborate further than just a table.

====Comments on Group Project 8====
'''Strengths:'''
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.
*The referencing is well-done with correct formatting and there seemed to be no duplication.
*The external links section is good.
'''Weaknesses:'''
*There are some inconsistencies in formatting.
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.
'''Specific corrections:'''
*Maybe include “frataxin” in the glossary?
*Reference 38 is missing.
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?

====Comments on Group Project 9====
'''Strengths:'''
*Good use of subheadings. It gives the page a structured feel to it.
*For most part of the references, it is good with the initiative to prevent duplication of references.
* I really like the “Specialised Facilities and Supportive Associations” section. Parents who just found out about their child’s condition would probably want to know more and seek help and this would be good for them.
'''Weaknesses:'''
*The history section looks really overwhelming.
*The glossary section is poorly done, with missing definitions for some words. There are other words that should be included in the glossary but was not.
*The image of the typical facial feature of an individual with WS looks similar to the one shown during lecture by Dr Palmer. It would be good to acknowledge what the image drawn was based on.
'''Specific corrections:'''
*It will be good to include an image in either the introduction or history section. At least it will be able to grab some attention.
*Reference 23 is missing its source.
*It will be good to elaborate more on some of the research studies being done to give the readers a feel of the direction in which the research for Williams Syn is gearing towards.

====Comments on Group Project 10====
'''Strengths:'''
*The flow of the page is smooth with appropriate placement of the various headings.
*Clinical manifestation section looks really decent without appearing too verbose but yet sufficient information is given.
*The last image has correct referencing and the copyright statement is also included.
'''Weaknesses:'''
*Some of the references are not formatted properly. There are also a couple of duplications under References.
*Glossary is not complete.
*The formatting for the overall page is not as consistent as it can be.
'''Specific corrections:'''
*Maybe it would be better to have a heading for the genetic condition just on its own and not put it with the introduction heading.
* Maybe future treatments can come under a new heading “future research”?
*It will be good to elaborate more on current treatments.
*Diagnosis can be more detailed.
*Include a timeline under history to summarise that section.
*The copyright statement that allows wikiusers to use the student image after 6 months is not included.

====Comments on Group Project 11====
'''Strengths:'''
*Good use of tables especially under Diagnosis.
*Some of the images are quite good especially on the correcting process (surgery) for cleft palate.
'''Weaknesses:'''
*Placement of headings is not quite appropriate. It gives the page a disjointed feel to it.
*There is a lack of use of subheadings.
*The introduction did not give an overview of the condition.
'''Specific corrections:'''
*Timeline should be a subheading under History section
*Introduction should answer these questions: What is it characterised by? How does it appear on individuals with this condition? What causes it? etc. It will be good to include a picture/ cartoon of an individual with cleft palate and lip.
*Duplication of references should be avoided.
*Some of the references are not formatted correctly.

--Z3389806 12:21, 27 September 2011 (EST)

===Lab 10 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.'''
::Another environmental teratogen that can lead to hearing loss is congenital cytomegalovirus infection.<ref><pubmed>16209862</pubmed></ref>

'''2. Identify 3 factors that contribute to poor neonatal drainage of the middle ear.'''
::The 3 factors are:
::*inflammation (and hence swelling) in the middle ear
::*damage of the tensor palate muscle
::*the (almost) horizontal running of the Eustachian tube

'''3. Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.'''
::A genetic abnormality that affects hearing development is paragangliomas.[http://www.ncbi.nlm.nih.gov/omim/168000 OMIM - Paragangliomas]
|}
--Z3389806 22:24, 6 October 2011 (EST)

===Lab 11 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.'''
::*''Septum primum'' formation from the roof of the atrium separates the right from the left atrium.
::*Perforations of the septum primum gives rise to the ''foramen secundum'' which allows blood flow from right to the left atrium.
::*''Septum secundum'' then forms to the right of the septum primum and incomplete partition of the septum primum gives rise to ''foramen ovale''.

'''2. Identify the cardiac defects that arise through abnormal development of the outflow tract.'''
::*Ventricular Septal Defect
::*Transposition of the Great Vessels
::*Double Outlet Right Ventricle
|}
--Z3389806 13:04, 13 October 2011 (EST)

==Attendance==

--[[User:Z3389806|Z3389806]] 18:01, 29 July 2011 (EST)

--[[User:Z3389806|Z3389806]] 12:55, 4 August 2011 (EST)

--Z3389806 11:41, 11 August 2011 (EST)

--Z3389806 11:07, 18 August 2011 (EST)

--Z3389806 11:12, 25 August 2011 (EST)

--Z3389806 11:11, 1 September 2011 (EST)

--Z3389806 11:13, 15 September 2011 (EST)

--Z3389806 11:09, 22 September 2011 (EST)

--Z3389806 11:11, 29 September 2011 (EST)

--Z3389806 11:19, 6 October 2011 (EST)

--Z3389806 11:19, 13 October 2011 (EST)

==References==
<references/>

User:Z3389806

2011-10-13T02:05:23Z

Z3389806: /* Lab 11 Assessment */

{{2011Student}}

==Lab Assessments==

===Lab 1 Assessment===

{| style="border: solid 1px #a0a0ff"
|- style="background:#eeeeff"
|'''1. Identify the origin of ''in vitro'' fertilisation and the 2010 Nobel Prize winner associated with this technique.'''
::[[Wikipedia: In vitro fertilisation|''In vitro'' fertilisation]] (IVF) technique was conceptualized by [[Wikipedia: Robert G. Edwards|Sir Robert Geoffrey Edwards]] when he first managed to fertilise a human egg successfully in the laboratory in 1968. This led to the birth of the first baby conceived through IVF, [[WIkipedia: Louise Brown|Louise Brown]], on 25th July 1978. Sir Robert Geoffrey Edwards is also the [[Wikipedia: Nobel Prize in Physiology or Medicine|2010 Nobel Prize]] winner associated with ''in vitro'' fertilisation.

'''2. Identify a recent paper on fertilisation and describe its key findings.'''
::A recent paper on fertilisation is titled “Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during ''in vitro'' fertilisation treatment”<ref>Chen H, Wang W, Mo Y, Ma Y, Ouyang N, Li R, Mai M, He Y, Bodombossou-Djobo MM, Yang D.
'''Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during in vitro fertilisation treatment.''' J Assist Reprod Genet.: 2011 PMID:21717175 [http://www.ncbi.nlm.nih.gov/pubmed/21717175]</ref> by Hong Chen et al. It was reported in the paper that telomerase activity (TA) in the luteinized granulosa cells is positively correlated with clinical pregnancy rate. Clinical pregnancy rate increases with level of TA. This would mean that the success rate of the IVF treatment (resulting in pregnancy) can be predicted by measuring the levels of TA in the granulosa cells.

'''3. Identify 2 congenital anomalies.'''
::The two congenital anomalies are [[wikipedia: Spina bifida|spina bifida]], in which the embryonic neural tube is only partially closed, and [[wikipedia: hydrocephalus|hydrocephalus]], in which there is an unusual accumulation of fluid in the brain.
|}

--[[User:S8600021|Mark Hill]] 00:44, 30 July 2011 (EST) Good wiki coding. Though I am not a fan of Wikipedia linking, should seek scientific references where possible, nobel prize link is better.

===Lab 2 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.'''
::The ZP protein that spermatozoa binds is the zona pelucida glycoprotein 3 (ZP3), also known as the sperm receptor.[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7784]
::Once fertilisation occurs, the oocyte releases enzymes which will alter the terminal carbohydrate residues of ZP3. ZP3 loses the ability to bind sperms, preventing polyspermy.<ref><pubmed>9369183</pubmed></ref>

'''2. Identify a review and a research article related to your group topic.'''
::''Review'': Bassuk AG, Kibar Z. '''Genetic basis of neural tube defects.''' Semin Pediatr Neurol. 2009 Sep;16(3):101-10<ref><pubmed>19778707</pubmed></ref>
::''Research'': De Marco P, Merello E, Cama A, Kibar Z, Capra V.''' Human neural tube defects: Genetic causes and prevention.''' Biofactors. 2011 Jun 14. <ref><pubmed>21674647</pubmed></ref>
|}
--[[User:Z3389806|Nur Sharalyn Abdullah]] 14:20, 10 August 2011 (EST)

===Lab 3 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What is the maternal dietary requirement for late neural development? '''
::The maternal dietary requirement for late neural development is iodine. Iodine is essential in the production of thyroid hormones which play a role in brain development.<ref><pubmed>15107513</pubmed></ref>
::Lack in iodine intake can result in cretinism. The recommended iodine intake during pregnancy is 200-250 micrograms per day.<ref><pubmed>19088150</pubmed></ref>

2. '''Upload a picture relating to your group project.'''

'''Melatonin levels in Huntington's disease patients and controls'''

[[File:Melatonin levels in HD patients and controls.jpg|border]]

The diurnal melatonin rise was significantly delayed in HD patients by about 01:30 h (p = 0.048). The black bar on the abscissa indicates the dark period (23:00–7:30 h).
|}
--Nur Sharalyn Abdullah 12:47, 16 August 2011 (EST)

===Lab 4 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. The allantois, identified in the placental cord, is continuous with what anatomical structure?'''
::The allantois, which originates from the hindgut, is continuous with the bladder.

'''2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.'''
::*Ductus arteriosus: located between pulmonary artery and aortic arch
::*Ductus venosus: located between umbilical vein and inferior vena cava
::*Foramen ovale: located between left atrium and right atrium

'''3. Identify the group project sub-section that you will be researching.'''
::*History
::*Treatment
::*Epidemiology
|}
--Nur Sharalyn Abdullah 21:47, 20 August 2011 (EST)

===Lab 5 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Which side (L/R) is most common for diaphragmatic hernia and why?'''
::The left side is the most common for diaphragmatic hernia. It is thought that this is due to the earlier closure of the right pleuroperitoneal opening.<ref>Moore, K.L. & Persuad, T.V.N. (2008). The Developing Human: clinically oriented embryology (8th ed.). Philadelphia: Saunders, p. 153</ref>
|}
--Z3389806 19:10, 31 August 2011 (EST)

===Lab 6 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What week of development do the palatal shelves fuse?'''
:: The fusion of palatal shelves fuse during week 9 of embryonic development.

'''2. What animal model helped elucidate the neural crest origin and migration of cells?'''
:: The animal model which helped elucidate neural crest origin and migration of cells is the quail-chick chimeras.<ref><pubmed>3058162</pubmed></ref>

'''3. What abnormality results from neural crest not migrating into the cardiac outflow tract?'''
:: Tetralogy of Fallot will be resulted.<ref><pubmed>3568286</pubmed></ref><ref><pubmed>3791607</pubmed></ref>
|}
--Z3389806 22:52, 13 September 2011 (EST)

===Lab 7 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?'''
:: (a) No, satellite cells are not necessary for muscle hypertrophy.
:: (b) Yes, satellite cells are generally involved in hypertrophy.

'''2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?'''
:: Chronic low frequency stimulation subjects the fast muscles to activity of low frequency and thereby, changing the pattern of motor activity imposed upon them. This alters the contractile characteristics of the fast muscles, making it to contract more slowly. This corresponds to the fast to slow fibre type shift.<ref><pubmed>4736724</pubmed></ref>

'''3. Write a comment about the online page on [[Trisomy 21|Trisomy 21]] based upon the group assessment criteria.'''
* ''The frequency of trisomy 21 in the population is approximately 1 in 650 to 1,000 live births, in Australia between 1991-97 there were 2,358 Trisomy 21 (Down) infants.'': it would be better to put this statement under the heading "Prevalence".
* It would be clearer to put the data under "Prevalence" in the form of a table.
* The caption for the table on detection rate of various procedures, "Table data from United Kingdom" is too vague and not clear.
* Choice of headings/sub-headings can be improved. For example, the headings, "Heart Defects" & "Limb Defects" can be sub-headings under "Associated Congenital Abnormalities".
* The sequence of the headings can also be improved. For example, the heading "Recent Findings" should probably be one of the last few headings and should not be just after the introduction as it gives a disjointed feel to the page.
* Reference No. 20 was not formatted properly.
|}
--Z3389806 16:00, 18 September 2011 (EST)

===Lab 8 Assessment===

====Comments on Group Project 1====
'''Strengths:'''
*The alphabetisation of the glossary helps readers to search for terms more easily. I really like this bit.
*The link of some of the words under Etiology to Glossary is really good. The reader can directly find out the meaning of a particular word without scrolling down much.
*All the characteristics and diseases are supported by scientific articles.
*The summaries given for each of the articles under Research gives the reader a gist of each article. It gives the reader a rough idea of where research for Turner Syndrome is heading towards.
*Overall: It has a good flow to the page with headings and sub-headings appropriately placed.
'''Weaknesses:'''
*The wikipage needs to be vetted. There are quite a few grammatical and punctuation errors.
*The placements of some images are disrupting the format of the page e.g the image of “22+23=45”.
*There are duplication in referencing. It will be good to combine the references to only one reference number per article to avoid duplication
*Some of the images did not include copyright statements which allow wiki users to reuse the images e.g. the karyotype image & image on abnormalities.
*Some of the references are just website links. This will need to be corrected.
*History of Turner Syndrome is not available. How was the syndrome first discovered? When was it discovered?
'''Specific corrections:'''
*The second sentence of introduction “It is caused by…survive to term” is a bit too long. Breaking it into two sentences might be better.
*“During normal fetal development, each ovary contain as many as 7 million oocytes”. The word “contain” should be “contains”.
*“The oocytes gradually reduced to 400,000 during menarche and during menopause fewer than 10,000 remains.” Insert the word “are” after “oocytes”.
*Standardise the term “Turner Syndrome”. Either all should be “Turner Syndrome” or “Turner syndrome”
*“…which is complete by the time the infant, is aged 2.” The word “complete” should be “completed”.
*“Genetically menopause” I’m not sure what this means. Is it supposed to be “Genetically-induced menopause”?
*“For example short stature is caused by a deletion of the Xp chromosome and the deletion of Xq causes gonadal dysfunction”. There should be a comma after the word “example”.
*The image on abnormalities associated with Turner Syndrome might be more suitable to be placed under clinical manifestations.

====Comments on Group Project 2====
'''Strengths:'''
*Good placement of sub-headings and headings.
*I like how the introduction gives an overview of the syndrome.
*All images have copyright statements.
'''Weaknesses:'''
*The epidemiology and etiology sections seem like really wordy, overwhelming to read. It is paragraphed but maybe the paragraphs could be more distinct.
*It would be good to link the words that is defined the glossary to the glossary.
*Some of the references are not formatted properly.
'''Specific corrections:'''
*It would be good if introduction immediately started with what is DiGeorge Syndrome instead of leading up with the definition/characteristic of congenital disorder. This definition can be shifted to the glossary
*Just curious, it will be interesting to hear how different the first sound of a DiGeorge baby differs from a normal one.
*”Dianostic Tests” is spelt incorrectly.
*Instead of the sub-heading “Based on symptoms”, it could be “Symptomatic diagnosis”.
*What is “clinodactyly” in the description of the image under “based on symptoms”?
*The link under images for BAC subheading could go under external links section?
*Maybe the table under “Tetralogy of Fallot...in DiGeorge Syndrome” could be vertical instead of horizontal? It will look neater.

====Comments on Group Project 3====
'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

====Comments on Group Project 5====
'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it can be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

====Comments on Group Project 6====
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

====Comments on Group Project 7====
'''Strengths:'''
*The history section was very well done. The block of text above the timeline provided just enough information and captured my interest. The timeline provided adequate summary of the major milestones in research of Angelman Syndrome.
*The glossary section seems decent.
*The student images are really good, especially the mechanism illustrations.
'''Weaknesses:'''
*Lack of use of subheadings. More subheadings can be used to break some of the sections up. It would not look so overwhelming then.
*Format of the overall page is not the best as it can be.
*There is some duplication in references.
'''Specific corrections:'''
*Just curious, why are males more predisposed to early developmental delay?
*It would be good to make the format of the stats under epidemiology consistent. Either fraction or ratio (I prefer ratio :D).
*Maybe for some of the tables, it will look better with an outline border so it is easier to see when the text in the table ends and when text in paragraphs starts.
*Use more subheadings e.g. Under Signs & Symptoms, the subheadings would be “Behavioural Characteristics”, “Communication Skills”, “Clinical & External Characteristics”, etc.
*Section under genetic counselling should come with an explanation or a paragraph of text. It will be good to elaborate further than just a table.

====Comments on Group Project 8====
'''Strengths:'''
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.
*The referencing is well-done with correct formatting and there seemed to be no duplication.
*The external links section is good.
'''Weaknesses:'''
*There are some inconsistencies in formatting.
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.
'''Specific corrections:'''
*Maybe include “frataxin” in the glossary?
*Reference 38 is missing.
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?

====Comments on Group Project 9====
'''Strengths:'''
*Good use of subheadings. It gives the page a structured feel to it.
*For most part of the references, it is good with the initiative to prevent duplication of references.
* I really like the “Specialised Facilities and Supportive Associations” section. Parents who just found out about their child’s condition would probably want to know more and seek help and this would be good for them.
'''Weaknesses:'''
*The history section looks really overwhelming.
*The glossary section is poorly done, with missing definitions for some words. There are other words that should be included in the glossary but was not.
*The image of the typical facial feature of an individual with WS looks similar to the one shown during lecture by Dr Palmer. It would be good to acknowledge what the image drawn was based on.
'''Specific corrections:'''
*It will be good to include an image in either the introduction or history section. At least it will be able to grab some attention.
*Reference 23 is missing its source.
*It will be good to elaborate more on some of the research studies being done to give the readers a feel of the direction in which the research for Williams Syn is gearing towards.

====Comments on Group Project 10====
'''Strengths:'''
*The flow of the page is smooth with appropriate placement of the various headings.
*Clinical manifestation section looks really decent without appearing too verbose but yet sufficient information is given.
*The last image has correct referencing and the copyright statement is also included.
'''Weaknesses:'''
*Some of the references are not formatted properly. There are also a couple of duplications under References.
*Glossary is not complete.
*The formatting for the overall page is not as consistent as it can be.
'''Specific corrections:'''
*Maybe it would be better to have a heading for the genetic condition just on its own and not put it with the introduction heading.
* Maybe future treatments can come under a new heading “future research”?
*It will be good to elaborate more on current treatments.
*Diagnosis can be more detailed.
*Include a timeline under history to summarise that section.
*The copyright statement that allows wikiusers to use the student image after 6 months is not included.

====Comments on Group Project 11====
'''Strengths:'''
*Good use of tables especially under Diagnosis.
*Some of the images are quite good especially on the correcting process (surgery) for cleft palate.
'''Weaknesses:'''
*Placement of headings is not quite appropriate. It gives the page a disjointed feel to it.
*There is a lack of use of subheadings.
*The introduction did not give an overview of the condition.
'''Specific corrections:'''
*Timeline should be a subheading under History section
*Introduction should answer these questions: What is it characterised by? How does it appear on individuals with this condition? What causes it? etc. It will be good to include a picture/ cartoon of an individual with cleft palate and lip.
*Duplication of references should be avoided.
*Some of the references are not formatted correctly.

--Z3389806 12:21, 27 September 2011 (EST)

===Lab 10 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.'''
::Another environmental teratogen that can lead to hearing loss is congenital cytomegalovirus infection.<ref><pubmed>16209862</pubmed></ref>

'''2. Identify 3 factors that contribute to poor neonatal drainage of the middle ear.'''
::The 3 factors are:
::*inflammation (and hence swelling) in the middle ear
::*damage of the tensor palate muscle
::*the (almost) horizontal running of the Eustachian tube

'''3. Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.'''
::A genetic abnormality that affects hearing development is paragangliomas.[http://www.ncbi.nlm.nih.gov/omim/168000 OMIM - Paragangliomas]
|}
--Z3389806 22:24, 6 October 2011 (EST)

===Lab 11 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.'''
::*''Septum primum'' formation from the roof of the atrium separates the right from the left atrium.
::*Perforations of the septum primum gives rise to the ''foramen secundum'' which allows blood flow from right to the left atrium.
::*''Septum secundum'' then forms to the right of the septum primum and incomplete partition of the septum primum gives rise to ''foramen ovale''.

'''2. Identify the cardiac defects that arise through abnormal development of the outflow tract.'''
::*Transposition of the Great Vessels
|}
--Z3389806 13:04, 13 October 2011 (EST)

==Attendance==

--[[User:Z3389806|Z3389806]] 18:01, 29 July 2011 (EST)

--[[User:Z3389806|Z3389806]] 12:55, 4 August 2011 (EST)

--Z3389806 11:41, 11 August 2011 (EST)

--Z3389806 11:07, 18 August 2011 (EST)

--Z3389806 11:12, 25 August 2011 (EST)

--Z3389806 11:11, 1 September 2011 (EST)

--Z3389806 11:13, 15 September 2011 (EST)

--Z3389806 11:09, 22 September 2011 (EST)

--Z3389806 11:11, 29 September 2011 (EST)

--Z3389806 11:19, 6 October 2011 (EST)

--Z3389806 11:19, 13 October 2011 (EST)

==References==
<references/>

User:Z3389806

2011-10-13T02:03:57Z

Z3389806: /* Lab 10 Assessment */

{{2011Student}}

==Lab Assessments==

===Lab 1 Assessment===

{| style="border: solid 1px #a0a0ff"
|- style="background:#eeeeff"
|'''1. Identify the origin of ''in vitro'' fertilisation and the 2010 Nobel Prize winner associated with this technique.'''
::[[Wikipedia: In vitro fertilisation|''In vitro'' fertilisation]] (IVF) technique was conceptualized by [[Wikipedia: Robert G. Edwards|Sir Robert Geoffrey Edwards]] when he first managed to fertilise a human egg successfully in the laboratory in 1968. This led to the birth of the first baby conceived through IVF, [[WIkipedia: Louise Brown|Louise Brown]], on 25th July 1978. Sir Robert Geoffrey Edwards is also the [[Wikipedia: Nobel Prize in Physiology or Medicine|2010 Nobel Prize]] winner associated with ''in vitro'' fertilisation.

'''2. Identify a recent paper on fertilisation and describe its key findings.'''
::A recent paper on fertilisation is titled “Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during ''in vitro'' fertilisation treatment”<ref>Chen H, Wang W, Mo Y, Ma Y, Ouyang N, Li R, Mai M, He Y, Bodombossou-Djobo MM, Yang D.
'''Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during in vitro fertilisation treatment.''' J Assist Reprod Genet.: 2011 PMID:21717175 [http://www.ncbi.nlm.nih.gov/pubmed/21717175]</ref> by Hong Chen et al. It was reported in the paper that telomerase activity (TA) in the luteinized granulosa cells is positively correlated with clinical pregnancy rate. Clinical pregnancy rate increases with level of TA. This would mean that the success rate of the IVF treatment (resulting in pregnancy) can be predicted by measuring the levels of TA in the granulosa cells.

'''3. Identify 2 congenital anomalies.'''
::The two congenital anomalies are [[wikipedia: Spina bifida|spina bifida]], in which the embryonic neural tube is only partially closed, and [[wikipedia: hydrocephalus|hydrocephalus]], in which there is an unusual accumulation of fluid in the brain.
|}

--[[User:S8600021|Mark Hill]] 00:44, 30 July 2011 (EST) Good wiki coding. Though I am not a fan of Wikipedia linking, should seek scientific references where possible, nobel prize link is better.

===Lab 2 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.'''
::The ZP protein that spermatozoa binds is the zona pelucida glycoprotein 3 (ZP3), also known as the sperm receptor.[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7784]
::Once fertilisation occurs, the oocyte releases enzymes which will alter the terminal carbohydrate residues of ZP3. ZP3 loses the ability to bind sperms, preventing polyspermy.<ref><pubmed>9369183</pubmed></ref>

'''2. Identify a review and a research article related to your group topic.'''
::''Review'': Bassuk AG, Kibar Z. '''Genetic basis of neural tube defects.''' Semin Pediatr Neurol. 2009 Sep;16(3):101-10<ref><pubmed>19778707</pubmed></ref>
::''Research'': De Marco P, Merello E, Cama A, Kibar Z, Capra V.''' Human neural tube defects: Genetic causes and prevention.''' Biofactors. 2011 Jun 14. <ref><pubmed>21674647</pubmed></ref>
|}
--[[User:Z3389806|Nur Sharalyn Abdullah]] 14:20, 10 August 2011 (EST)

===Lab 3 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What is the maternal dietary requirement for late neural development? '''
::The maternal dietary requirement for late neural development is iodine. Iodine is essential in the production of thyroid hormones which play a role in brain development.<ref><pubmed>15107513</pubmed></ref>
::Lack in iodine intake can result in cretinism. The recommended iodine intake during pregnancy is 200-250 micrograms per day.<ref><pubmed>19088150</pubmed></ref>

2. '''Upload a picture relating to your group project.'''

'''Melatonin levels in Huntington's disease patients and controls'''

[[File:Melatonin levels in HD patients and controls.jpg|border]]

The diurnal melatonin rise was significantly delayed in HD patients by about 01:30 h (p = 0.048). The black bar on the abscissa indicates the dark period (23:00–7:30 h).
|}
--Nur Sharalyn Abdullah 12:47, 16 August 2011 (EST)

===Lab 4 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. The allantois, identified in the placental cord, is continuous with what anatomical structure?'''
::The allantois, which originates from the hindgut, is continuous with the bladder.

'''2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.'''
::*Ductus arteriosus: located between pulmonary artery and aortic arch
::*Ductus venosus: located between umbilical vein and inferior vena cava
::*Foramen ovale: located between left atrium and right atrium

'''3. Identify the group project sub-section that you will be researching.'''
::*History
::*Treatment
::*Epidemiology
|}
--Nur Sharalyn Abdullah 21:47, 20 August 2011 (EST)

===Lab 5 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Which side (L/R) is most common for diaphragmatic hernia and why?'''
::The left side is the most common for diaphragmatic hernia. It is thought that this is due to the earlier closure of the right pleuroperitoneal opening.<ref>Moore, K.L. & Persuad, T.V.N. (2008). The Developing Human: clinically oriented embryology (8th ed.). Philadelphia: Saunders, p. 153</ref>
|}
--Z3389806 19:10, 31 August 2011 (EST)

===Lab 6 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What week of development do the palatal shelves fuse?'''
:: The fusion of palatal shelves fuse during week 9 of embryonic development.

'''2. What animal model helped elucidate the neural crest origin and migration of cells?'''
:: The animal model which helped elucidate neural crest origin and migration of cells is the quail-chick chimeras.<ref><pubmed>3058162</pubmed></ref>

'''3. What abnormality results from neural crest not migrating into the cardiac outflow tract?'''
:: Tetralogy of Fallot will be resulted.<ref><pubmed>3568286</pubmed></ref><ref><pubmed>3791607</pubmed></ref>
|}
--Z3389806 22:52, 13 September 2011 (EST)

===Lab 7 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?'''
:: (a) No, satellite cells are not necessary for muscle hypertrophy.
:: (b) Yes, satellite cells are generally involved in hypertrophy.

'''2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?'''
:: Chronic low frequency stimulation subjects the fast muscles to activity of low frequency and thereby, changing the pattern of motor activity imposed upon them. This alters the contractile characteristics of the fast muscles, making it to contract more slowly. This corresponds to the fast to slow fibre type shift.<ref><pubmed>4736724</pubmed></ref>

'''3. Write a comment about the online page on [[Trisomy 21|Trisomy 21]] based upon the group assessment criteria.'''
* ''The frequency of trisomy 21 in the population is approximately 1 in 650 to 1,000 live births, in Australia between 1991-97 there were 2,358 Trisomy 21 (Down) infants.'': it would be better to put this statement under the heading "Prevalence".
* It would be clearer to put the data under "Prevalence" in the form of a table.
* The caption for the table on detection rate of various procedures, "Table data from United Kingdom" is too vague and not clear.
* Choice of headings/sub-headings can be improved. For example, the headings, "Heart Defects" & "Limb Defects" can be sub-headings under "Associated Congenital Abnormalities".
* The sequence of the headings can also be improved. For example, the heading "Recent Findings" should probably be one of the last few headings and should not be just after the introduction as it gives a disjointed feel to the page.
* Reference No. 20 was not formatted properly.
|}
--Z3389806 16:00, 18 September 2011 (EST)

===Lab 8 Assessment===

====Comments on Group Project 1====
'''Strengths:'''
*The alphabetisation of the glossary helps readers to search for terms more easily. I really like this bit.
*The link of some of the words under Etiology to Glossary is really good. The reader can directly find out the meaning of a particular word without scrolling down much.
*All the characteristics and diseases are supported by scientific articles.
*The summaries given for each of the articles under Research gives the reader a gist of each article. It gives the reader a rough idea of where research for Turner Syndrome is heading towards.
*Overall: It has a good flow to the page with headings and sub-headings appropriately placed.
'''Weaknesses:'''
*The wikipage needs to be vetted. There are quite a few grammatical and punctuation errors.
*The placements of some images are disrupting the format of the page e.g the image of “22+23=45”.
*There are duplication in referencing. It will be good to combine the references to only one reference number per article to avoid duplication
*Some of the images did not include copyright statements which allow wiki users to reuse the images e.g. the karyotype image & image on abnormalities.
*Some of the references are just website links. This will need to be corrected.
*History of Turner Syndrome is not available. How was the syndrome first discovered? When was it discovered?
'''Specific corrections:'''
*The second sentence of introduction “It is caused by…survive to term” is a bit too long. Breaking it into two sentences might be better.
*“During normal fetal development, each ovary contain as many as 7 million oocytes”. The word “contain” should be “contains”.
*“The oocytes gradually reduced to 400,000 during menarche and during menopause fewer than 10,000 remains.” Insert the word “are” after “oocytes”.
*Standardise the term “Turner Syndrome”. Either all should be “Turner Syndrome” or “Turner syndrome”
*“…which is complete by the time the infant, is aged 2.” The word “complete” should be “completed”.
*“Genetically menopause” I’m not sure what this means. Is it supposed to be “Genetically-induced menopause”?
*“For example short stature is caused by a deletion of the Xp chromosome and the deletion of Xq causes gonadal dysfunction”. There should be a comma after the word “example”.
*The image on abnormalities associated with Turner Syndrome might be more suitable to be placed under clinical manifestations.

====Comments on Group Project 2====
'''Strengths:'''
*Good placement of sub-headings and headings.
*I like how the introduction gives an overview of the syndrome.
*All images have copyright statements.
'''Weaknesses:'''
*The epidemiology and etiology sections seem like really wordy, overwhelming to read. It is paragraphed but maybe the paragraphs could be more distinct.
*It would be good to link the words that is defined the glossary to the glossary.
*Some of the references are not formatted properly.
'''Specific corrections:'''
*It would be good if introduction immediately started with what is DiGeorge Syndrome instead of leading up with the definition/characteristic of congenital disorder. This definition can be shifted to the glossary
*Just curious, it will be interesting to hear how different the first sound of a DiGeorge baby differs from a normal one.
*”Dianostic Tests” is spelt incorrectly.
*Instead of the sub-heading “Based on symptoms”, it could be “Symptomatic diagnosis”.
*What is “clinodactyly” in the description of the image under “based on symptoms”?
*The link under images for BAC subheading could go under external links section?
*Maybe the table under “Tetralogy of Fallot...in DiGeorge Syndrome” could be vertical instead of horizontal? It will look neater.

====Comments on Group Project 3====
'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

====Comments on Group Project 5====
'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it can be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

====Comments on Group Project 6====
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

====Comments on Group Project 7====
'''Strengths:'''
*The history section was very well done. The block of text above the timeline provided just enough information and captured my interest. The timeline provided adequate summary of the major milestones in research of Angelman Syndrome.
*The glossary section seems decent.
*The student images are really good, especially the mechanism illustrations.
'''Weaknesses:'''
*Lack of use of subheadings. More subheadings can be used to break some of the sections up. It would not look so overwhelming then.
*Format of the overall page is not the best as it can be.
*There is some duplication in references.
'''Specific corrections:'''
*Just curious, why are males more predisposed to early developmental delay?
*It would be good to make the format of the stats under epidemiology consistent. Either fraction or ratio (I prefer ratio :D).
*Maybe for some of the tables, it will look better with an outline border so it is easier to see when the text in the table ends and when text in paragraphs starts.
*Use more subheadings e.g. Under Signs & Symptoms, the subheadings would be “Behavioural Characteristics”, “Communication Skills”, “Clinical & External Characteristics”, etc.
*Section under genetic counselling should come with an explanation or a paragraph of text. It will be good to elaborate further than just a table.

====Comments on Group Project 8====
'''Strengths:'''
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.
*The referencing is well-done with correct formatting and there seemed to be no duplication.
*The external links section is good.
'''Weaknesses:'''
*There are some inconsistencies in formatting.
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.
'''Specific corrections:'''
*Maybe include “frataxin” in the glossary?
*Reference 38 is missing.
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?

====Comments on Group Project 9====
'''Strengths:'''
*Good use of subheadings. It gives the page a structured feel to it.
*For most part of the references, it is good with the initiative to prevent duplication of references.
* I really like the “Specialised Facilities and Supportive Associations” section. Parents who just found out about their child’s condition would probably want to know more and seek help and this would be good for them.
'''Weaknesses:'''
*The history section looks really overwhelming.
*The glossary section is poorly done, with missing definitions for some words. There are other words that should be included in the glossary but was not.
*The image of the typical facial feature of an individual with WS looks similar to the one shown during lecture by Dr Palmer. It would be good to acknowledge what the image drawn was based on.
'''Specific corrections:'''
*It will be good to include an image in either the introduction or history section. At least it will be able to grab some attention.
*Reference 23 is missing its source.
*It will be good to elaborate more on some of the research studies being done to give the readers a feel of the direction in which the research for Williams Syn is gearing towards.

====Comments on Group Project 10====
'''Strengths:'''
*The flow of the page is smooth with appropriate placement of the various headings.
*Clinical manifestation section looks really decent without appearing too verbose but yet sufficient information is given.
*The last image has correct referencing and the copyright statement is also included.
'''Weaknesses:'''
*Some of the references are not formatted properly. There are also a couple of duplications under References.
*Glossary is not complete.
*The formatting for the overall page is not as consistent as it can be.
'''Specific corrections:'''
*Maybe it would be better to have a heading for the genetic condition just on its own and not put it with the introduction heading.
* Maybe future treatments can come under a new heading “future research”?
*It will be good to elaborate more on current treatments.
*Diagnosis can be more detailed.
*Include a timeline under history to summarise that section.
*The copyright statement that allows wikiusers to use the student image after 6 months is not included.

====Comments on Group Project 11====
'''Strengths:'''
*Good use of tables especially under Diagnosis.
*Some of the images are quite good especially on the correcting process (surgery) for cleft palate.
'''Weaknesses:'''
*Placement of headings is not quite appropriate. It gives the page a disjointed feel to it.
*There is a lack of use of subheadings.
*The introduction did not give an overview of the condition.
'''Specific corrections:'''
*Timeline should be a subheading under History section
*Introduction should answer these questions: What is it characterised by? How does it appear on individuals with this condition? What causes it? etc. It will be good to include a picture/ cartoon of an individual with cleft palate and lip.
*Duplication of references should be avoided.
*Some of the references are not formatted correctly.

--Z3389806 12:21, 27 September 2011 (EST)

===Lab 10 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.'''
::Another environmental teratogen that can lead to hearing loss is congenital cytomegalovirus infection.<ref><pubmed>16209862</pubmed></ref>

'''2. Identify 3 factors that contribute to poor neonatal drainage of the middle ear.'''
::The 3 factors are:
::*inflammation (and hence swelling) in the middle ear
::*damage of the tensor palate muscle
::*the (almost) horizontal running of the Eustachian tube

'''3. Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.'''
::A genetic abnormality that affects hearing development is paragangliomas.[http://www.ncbi.nlm.nih.gov/omim/168000 OMIM - Paragangliomas]
|}
--Z3389806 22:24, 6 October 2011 (EST)

===Lab 11 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.'''
::*''Septum primum'' formation from the roof of the atrium separates the right from the left atrium.
::*Perforations of the septum primum gives rise to the ''foramen secundum'' which allows blood flow from right to the left atrium.
::*''Septum secundum'' then forms to the right of the septum primum and incomplete partition of the septum primum gives rise to ''foramen ovale''.

'''2. Identify the cardiac defects that arise through abnormal development of the outflow tract.'''
::The 3 factors are:
::*Transposition of the Great Vessels
|}
--Z3389806 13:04, 13 October 2011 (EST)

==Attendance==

--[[User:Z3389806|Z3389806]] 18:01, 29 July 2011 (EST)

--[[User:Z3389806|Z3389806]] 12:55, 4 August 2011 (EST)

--Z3389806 11:41, 11 August 2011 (EST)

--Z3389806 11:07, 18 August 2011 (EST)

--Z3389806 11:12, 25 August 2011 (EST)

--Z3389806 11:11, 1 September 2011 (EST)

--Z3389806 11:13, 15 September 2011 (EST)

--Z3389806 11:09, 22 September 2011 (EST)

--Z3389806 11:11, 29 September 2011 (EST)

--Z3389806 11:19, 6 October 2011 (EST)

--Z3389806 11:19, 13 October 2011 (EST)

==References==
<references/>

User:Z3389806

2011-10-13T00:19:59Z

Z3389806: /* Attendance */

{{2011Student}}

==Lab Assessments==

===Lab 1 Assessment===

{| style="border: solid 1px #a0a0ff"
|- style="background:#eeeeff"
|'''1. Identify the origin of ''in vitro'' fertilisation and the 2010 Nobel Prize winner associated with this technique.'''
::[[Wikipedia: In vitro fertilisation|''In vitro'' fertilisation]] (IVF) technique was conceptualized by [[Wikipedia: Robert G. Edwards|Sir Robert Geoffrey Edwards]] when he first managed to fertilise a human egg successfully in the laboratory in 1968. This led to the birth of the first baby conceived through IVF, [[WIkipedia: Louise Brown|Louise Brown]], on 25th July 1978. Sir Robert Geoffrey Edwards is also the [[Wikipedia: Nobel Prize in Physiology or Medicine|2010 Nobel Prize]] winner associated with ''in vitro'' fertilisation.

'''2. Identify a recent paper on fertilisation and describe its key findings.'''
::A recent paper on fertilisation is titled “Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during ''in vitro'' fertilisation treatment”<ref>Chen H, Wang W, Mo Y, Ma Y, Ouyang N, Li R, Mai M, He Y, Bodombossou-Djobo MM, Yang D.
'''Women with high telomerase activity in luteinised granulosa cells have a higher pregnancy rate during in vitro fertilisation treatment.''' J Assist Reprod Genet.: 2011 PMID:21717175 [http://www.ncbi.nlm.nih.gov/pubmed/21717175]</ref> by Hong Chen et al. It was reported in the paper that telomerase activity (TA) in the luteinized granulosa cells is positively correlated with clinical pregnancy rate. Clinical pregnancy rate increases with level of TA. This would mean that the success rate of the IVF treatment (resulting in pregnancy) can be predicted by measuring the levels of TA in the granulosa cells.

'''3. Identify 2 congenital anomalies.'''
::The two congenital anomalies are [[wikipedia: Spina bifida|spina bifida]], in which the embryonic neural tube is only partially closed, and [[wikipedia: hydrocephalus|hydrocephalus]], in which there is an unusual accumulation of fluid in the brain.
|}

--[[User:S8600021|Mark Hill]] 00:44, 30 July 2011 (EST) Good wiki coding. Though I am not a fan of Wikipedia linking, should seek scientific references where possible, nobel prize link is better.

===Lab 2 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.'''
::The ZP protein that spermatozoa binds is the zona pelucida glycoprotein 3 (ZP3), also known as the sperm receptor.[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7784]
::Once fertilisation occurs, the oocyte releases enzymes which will alter the terminal carbohydrate residues of ZP3. ZP3 loses the ability to bind sperms, preventing polyspermy.<ref><pubmed>9369183</pubmed></ref>

'''2. Identify a review and a research article related to your group topic.'''
::''Review'': Bassuk AG, Kibar Z. '''Genetic basis of neural tube defects.''' Semin Pediatr Neurol. 2009 Sep;16(3):101-10<ref><pubmed>19778707</pubmed></ref>
::''Research'': De Marco P, Merello E, Cama A, Kibar Z, Capra V.''' Human neural tube defects: Genetic causes and prevention.''' Biofactors. 2011 Jun 14. <ref><pubmed>21674647</pubmed></ref>
|}
--[[User:Z3389806|Nur Sharalyn Abdullah]] 14:20, 10 August 2011 (EST)

===Lab 3 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What is the maternal dietary requirement for late neural development? '''
::The maternal dietary requirement for late neural development is iodine. Iodine is essential in the production of thyroid hormones which play a role in brain development.<ref><pubmed>15107513</pubmed></ref>
::Lack in iodine intake can result in cretinism. The recommended iodine intake during pregnancy is 200-250 micrograms per day.<ref><pubmed>19088150</pubmed></ref>

2. '''Upload a picture relating to your group project.'''

'''Melatonin levels in Huntington's disease patients and controls'''

[[File:Melatonin levels in HD patients and controls.jpg|border]]

The diurnal melatonin rise was significantly delayed in HD patients by about 01:30 h (p = 0.048). The black bar on the abscissa indicates the dark period (23:00–7:30 h).
|}
--Nur Sharalyn Abdullah 12:47, 16 August 2011 (EST)

===Lab 4 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. The allantois, identified in the placental cord, is continuous with what anatomical structure?'''
::The allantois, which originates from the hindgut, is continuous with the bladder.

'''2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.'''
::*Ductus arteriosus: located between pulmonary artery and aortic arch
::*Ductus venosus: located between umbilical vein and inferior vena cava
::*Foramen ovale: located between left atrium and right atrium

'''3. Identify the group project sub-section that you will be researching.'''
::*History
::*Treatment
::*Epidemiology
|}
--Nur Sharalyn Abdullah 21:47, 20 August 2011 (EST)

===Lab 5 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Which side (L/R) is most common for diaphragmatic hernia and why?'''
::The left side is the most common for diaphragmatic hernia. It is thought that this is due to the earlier closure of the right pleuroperitoneal opening.<ref>Moore, K.L. & Persuad, T.V.N. (2008). The Developing Human: clinically oriented embryology (8th ed.). Philadelphia: Saunders, p. 153</ref>
|}
--Z3389806 19:10, 31 August 2011 (EST)

===Lab 6 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. What week of development do the palatal shelves fuse?'''
:: The fusion of palatal shelves fuse during week 9 of embryonic development.

'''2. What animal model helped elucidate the neural crest origin and migration of cells?'''
:: The animal model which helped elucidate neural crest origin and migration of cells is the quail-chick chimeras.<ref><pubmed>3058162</pubmed></ref>

'''3. What abnormality results from neural crest not migrating into the cardiac outflow tract?'''
:: Tetralogy of Fallot will be resulted.<ref><pubmed>3568286</pubmed></ref><ref><pubmed>3791607</pubmed></ref>
|}
--Z3389806 22:52, 13 September 2011 (EST)

===Lab 7 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?'''
:: (a) No, satellite cells are not necessary for muscle hypertrophy.
:: (b) Yes, satellite cells are generally involved in hypertrophy.

'''2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?'''
:: Chronic low frequency stimulation subjects the fast muscles to activity of low frequency and thereby, changing the pattern of motor activity imposed upon them. This alters the contractile characteristics of the fast muscles, making it to contract more slowly. This corresponds to the fast to slow fibre type shift.<ref><pubmed>4736724</pubmed></ref>

'''3. Write a comment about the online page on [[Trisomy 21|Trisomy 21]] based upon the group assessment criteria.'''
* ''The frequency of trisomy 21 in the population is approximately 1 in 650 to 1,000 live births, in Australia between 1991-97 there were 2,358 Trisomy 21 (Down) infants.'': it would be better to put this statement under the heading "Prevalence".
* It would be clearer to put the data under "Prevalence" in the form of a table.
* The caption for the table on detection rate of various procedures, "Table data from United Kingdom" is too vague and not clear.
* Choice of headings/sub-headings can be improved. For example, the headings, "Heart Defects" & "Limb Defects" can be sub-headings under "Associated Congenital Abnormalities".
* The sequence of the headings can also be improved. For example, the heading "Recent Findings" should probably be one of the last few headings and should not be just after the introduction as it gives a disjointed feel to the page.
* Reference No. 20 was not formatted properly.
|}
--Z3389806 16:00, 18 September 2011 (EST)

===Lab 8 Assessment===

====Comments on Group Project 1====
'''Strengths:'''
*The alphabetisation of the glossary helps readers to search for terms more easily. I really like this bit.
*The link of some of the words under Etiology to Glossary is really good. The reader can directly find out the meaning of a particular word without scrolling down much.
*All the characteristics and diseases are supported by scientific articles.
*The summaries given for each of the articles under Research gives the reader a gist of each article. It gives the reader a rough idea of where research for Turner Syndrome is heading towards.
*Overall: It has a good flow to the page with headings and sub-headings appropriately placed.
'''Weaknesses:'''
*The wikipage needs to be vetted. There are quite a few grammatical and punctuation errors.
*The placements of some images are disrupting the format of the page e.g the image of “22+23=45”.
*There are duplication in referencing. It will be good to combine the references to only one reference number per article to avoid duplication
*Some of the images did not include copyright statements which allow wiki users to reuse the images e.g. the karyotype image & image on abnormalities.
*Some of the references are just website links. This will need to be corrected.
*History of Turner Syndrome is not available. How was the syndrome first discovered? When was it discovered?
'''Specific corrections:'''
*The second sentence of introduction “It is caused by…survive to term” is a bit too long. Breaking it into two sentences might be better.
*“During normal fetal development, each ovary contain as many as 7 million oocytes”. The word “contain” should be “contains”.
*“The oocytes gradually reduced to 400,000 during menarche and during menopause fewer than 10,000 remains.” Insert the word “are” after “oocytes”.
*Standardise the term “Turner Syndrome”. Either all should be “Turner Syndrome” or “Turner syndrome”
*“…which is complete by the time the infant, is aged 2.” The word “complete” should be “completed”.
*“Genetically menopause” I’m not sure what this means. Is it supposed to be “Genetically-induced menopause”?
*“For example short stature is caused by a deletion of the Xp chromosome and the deletion of Xq causes gonadal dysfunction”. There should be a comma after the word “example”.
*The image on abnormalities associated with Turner Syndrome might be more suitable to be placed under clinical manifestations.

====Comments on Group Project 2====
'''Strengths:'''
*Good placement of sub-headings and headings.
*I like how the introduction gives an overview of the syndrome.
*All images have copyright statements.
'''Weaknesses:'''
*The epidemiology and etiology sections seem like really wordy, overwhelming to read. It is paragraphed but maybe the paragraphs could be more distinct.
*It would be good to link the words that is defined the glossary to the glossary.
*Some of the references are not formatted properly.
'''Specific corrections:'''
*It would be good if introduction immediately started with what is DiGeorge Syndrome instead of leading up with the definition/characteristic of congenital disorder. This definition can be shifted to the glossary
*Just curious, it will be interesting to hear how different the first sound of a DiGeorge baby differs from a normal one.
*”Dianostic Tests” is spelt incorrectly.
*Instead of the sub-heading “Based on symptoms”, it could be “Symptomatic diagnosis”.
*What is “clinodactyly” in the description of the image under “based on symptoms”?
*The link under images for BAC subheading could go under external links section?
*Maybe the table under “Tetralogy of Fallot...in DiGeorge Syndrome” could be vertical instead of horizontal? It will look neater.

====Comments on Group Project 3====
'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

====Comments on Group Project 5====
'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it can be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

====Comments on Group Project 6====
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

====Comments on Group Project 7====
'''Strengths:'''
*The history section was very well done. The block of text above the timeline provided just enough information and captured my interest. The timeline provided adequate summary of the major milestones in research of Angelman Syndrome.
*The glossary section seems decent.
*The student images are really good, especially the mechanism illustrations.
'''Weaknesses:'''
*Lack of use of subheadings. More subheadings can be used to break some of the sections up. It would not look so overwhelming then.
*Format of the overall page is not the best as it can be.
*There is some duplication in references.
'''Specific corrections:'''
*Just curious, why are males more predisposed to early developmental delay?
*It would be good to make the format of the stats under epidemiology consistent. Either fraction or ratio (I prefer ratio :D).
*Maybe for some of the tables, it will look better with an outline border so it is easier to see when the text in the table ends and when text in paragraphs starts.
*Use more subheadings e.g. Under Signs & Symptoms, the subheadings would be “Behavioural Characteristics”, “Communication Skills”, “Clinical & External Characteristics”, etc.
*Section under genetic counselling should come with an explanation or a paragraph of text. It will be good to elaborate further than just a table.

====Comments on Group Project 8====
'''Strengths:'''
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.
*The referencing is well-done with correct formatting and there seemed to be no duplication.
*The external links section is good.
'''Weaknesses:'''
*There are some inconsistencies in formatting.
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.
'''Specific corrections:'''
*Maybe include “frataxin” in the glossary?
*Reference 38 is missing.
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?

====Comments on Group Project 9====
'''Strengths:'''
*Good use of subheadings. It gives the page a structured feel to it.
*For most part of the references, it is good with the initiative to prevent duplication of references.
* I really like the “Specialised Facilities and Supportive Associations” section. Parents who just found out about their child’s condition would probably want to know more and seek help and this would be good for them.
'''Weaknesses:'''
*The history section looks really overwhelming.
*The glossary section is poorly done, with missing definitions for some words. There are other words that should be included in the glossary but was not.
*The image of the typical facial feature of an individual with WS looks similar to the one shown during lecture by Dr Palmer. It would be good to acknowledge what the image drawn was based on.
'''Specific corrections:'''
*It will be good to include an image in either the introduction or history section. At least it will be able to grab some attention.
*Reference 23 is missing its source.
*It will be good to elaborate more on some of the research studies being done to give the readers a feel of the direction in which the research for Williams Syn is gearing towards.

====Comments on Group Project 10====
'''Strengths:'''
*The flow of the page is smooth with appropriate placement of the various headings.
*Clinical manifestation section looks really decent without appearing too verbose but yet sufficient information is given.
*The last image has correct referencing and the copyright statement is also included.
'''Weaknesses:'''
*Some of the references are not formatted properly. There are also a couple of duplications under References.
*Glossary is not complete.
*The formatting for the overall page is not as consistent as it can be.
'''Specific corrections:'''
*Maybe it would be better to have a heading for the genetic condition just on its own and not put it with the introduction heading.
* Maybe future treatments can come under a new heading “future research”?
*It will be good to elaborate more on current treatments.
*Diagnosis can be more detailed.
*Include a timeline under history to summarise that section.
*The copyright statement that allows wikiusers to use the student image after 6 months is not included.

====Comments on Group Project 11====
'''Strengths:'''
*Good use of tables especially under Diagnosis.
*Some of the images are quite good especially on the correcting process (surgery) for cleft palate.
'''Weaknesses:'''
*Placement of headings is not quite appropriate. It gives the page a disjointed feel to it.
*There is a lack of use of subheadings.
*The introduction did not give an overview of the condition.
'''Specific corrections:'''
*Timeline should be a subheading under History section
*Introduction should answer these questions: What is it characterised by? How does it appear on individuals with this condition? What causes it? etc. It will be good to include a picture/ cartoon of an individual with cleft palate and lip.
*Duplication of references should be avoided.
*Some of the references are not formatted correctly.

--Z3389806 12:21, 27 September 2011 (EST)

===Lab 10 Assessment===

{| style="border: solid 1px #a0a0ff; width:100%"
|- style="background:#eeeeff"
|'''1. Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.'''
::Another environmental teratogen that can lead to hearing loss is congenital cytomegalovirus infection.<ref><pubmed>16209862</pubmed></ref>

'''2. Identify 3 factors that contribute to poor neonatal drainage of the middle ear.'''
::The 3 factors are:
::*inflammation (and hence swelling) in the middle ear
::*damage of the tensor palate muscle
::*the (almost) horizontal running of the Eustachian tube

'''3. Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.'''
::A genetic abnormality that affects hearing development is paragangliomas.[http://www.ncbi.nlm.nih.gov/omim/168000 OMIM - Paragangliomas]
|}
--Z3389806 22:24, 6 October 2011 (EST)

==Attendance==

--[[User:Z3389806|Z3389806]] 18:01, 29 July 2011 (EST)

--[[User:Z3389806|Z3389806]] 12:55, 4 August 2011 (EST)

--Z3389806 11:41, 11 August 2011 (EST)

--Z3389806 11:07, 18 August 2011 (EST)

--Z3389806 11:12, 25 August 2011 (EST)

--Z3389806 11:11, 1 September 2011 (EST)

--Z3389806 11:13, 15 September 2011 (EST)

--Z3389806 11:09, 22 September 2011 (EST)

--Z3389806 11:11, 29 September 2011 (EST)

--Z3389806 11:19, 6 October 2011 (EST)

--Z3389806 11:19, 13 October 2011 (EST)

==References==
<references/>

2011 Group Project 4

2011-10-12T23:21:23Z

Z3389806: /* Genetic testing and prenatal diagnosis */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an [[#Autosomal dominant|autosomal-dominant]] disorder caused by a faulty gene on the 4th autosomal chromosome (hence it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females. <ref><pubmed>21983719</pubmed></ref>

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene on fourth chromosome]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 [[#Exon|exons]] and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, [[#Dendrite|dendrites]] and nerve terminals and is also associated with cellular organelles such as golgi apparatus, [[#Endoplasmic reticulum|endoplasmic reticulum]] and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the [[#Striatum|striatum]] (integral part of basal ganglia). <ref name="PMID15459747"/>

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in [[#Dendrite|dendrites]], signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in [[#Endocytosis|endocytosis]], [[#Neuronal|neuronal]] transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from [[#Apoptosis|apoptotic]] stress, hence having pro-survival role in neural tissue.

* A recent study has shown that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause [[#Neurodegeneration|neurodegeneration]]. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Comparison between healthy huntingtin gene & huntingtin gene in Huntington's disease]]

Huntington Disease - caused by a mutation on the 1st [[#Exon|exon]] of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="PMID15459747"/>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the [[#Neurodegeneration|neurodegeneration]] and serious loss of cognitive abilities has not yet been fully understood.
There are key pathological mechanisms that has been used to explain the pathways by which a mutation [[File:Regions of the brain significant in Huntington's disease.jpg|right|thumb|245px|Regions of the brain significant in Huntington's disease]] in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the [[#Striatum|striatum]] forming the basal ganglia region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also less significantly located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the [[#Striatum|striatum]] known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of [[#Gamma-aminobutyric acid (GABA)| gamma-aminobutyric acid (GABA)]], which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The [[#Striatum|striatum]] is the main target for [[#Glutamatergic|glutamatergic]] output from the afferant neurons of thalamus and the cortex, making striatal cells highly sensitive to [[#Glutamate|glutamate]]. Even though striatal cells depend on [[#Glutamate|glutamate]] for function and survival, [[#Glutamate|glutamate]] in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an [[#Excitotoxin|excitotoxin]]. [[#Neurodegeneration|Neurodegeneration]] and excitotoxicity is therefore inducible by directly injecting [[#Glutamate|glutamate]] into the [[#Striatum|striatum]]. Hence the accumulation of long polyglutamine chains in the [[#Striatum|striatum]] of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb its key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as [[#Chorea|chorea]].
[[File:Key cellular pathogenic mechanisms in Huntington's disease.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. The misshapen proteins are labeled by antibodies and targeted by [[#Proteasome|proteasomes]] in the cytoplasm for degradation.<ref name="MM"/> However [[#Proteasome|proteasome]] efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the [[#Protease|proteases]] become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref> Toxicity can also arise when the polyglutamine domain of mutant HTT attracts and binds to other cytoplasmic and nuclear structures that contain polyglutamine. By forming aggregates with these structures, they are able to inhibit their physiological function within the neural cells and cause further cellular dysfunction and induce [[#Apoptosis|apoptosis]]. The implication of [[#Proteasome|proteasome]] in HD is further consolidated when [[#Proteasome|proteasome]] inhibitors are administered in animal models of HD, that have lead to more rapid and increasing number of aggregates.

Proteosomal enzymes are capable of breaking down polyglutamine flanking sequences but not the polyglutamine tract itself. Mutant HTT protein is cleaved by a different number of [[#Protease|proteases]] such as caspases and calcium-dependent [[#Protease|proteases]] such as calpain. The proteolytic activity of these enzymes leads to the formation of shorter polyglutamine peptides that are even more toxic and are capable of inducing neuronal death. <ref><pubmed>12223539</pubmed></ref> <ref name="MM"/>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and [[#Neurotrophic factor|neurotrophic factor]]. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIP1, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and [[#Apoptosis|apoptotic]] cell death by impairing [[#Proteasome|proteasome]] activity and interfering with calcium signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the [[#Endoplasmic reticulum|endoplasmic reticulum]] and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and [[#Apoptosis|apoptosis]]-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="PMID15459747"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neurotophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neurotrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. [[#Chorionic villus sampling|Chorionic villus sampling]] can be carried out between the 10th and 12th week of pregnancy whereas [[#Amniocentesis|amniocentesis]] is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Related Links==

* [[Molecular Development]] - this page gives an explanation of the dominant inheritance nature of HD.
* [[Prenatal Diagnosis]] - this page relates to the ethics and consequences of prenatal testing for Huntington's disease (HD).
* [[Amniocentesis]] - More information about this procedure of prenatal testing for HD can be found here.
* [[Chorionic villus sampling]] - More information about this procedure of prenatal testing for HD can be found here.
* [[Computed Tomography]] - More information about this procedure of prenatal testing for HD can be found here.

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Amniocentesis"></div>'''Amniocentesis:''' A medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections by taking a sample of the amniotic fluid. The fluid is then analysed to observe for any abmornalities.

<div id="Antibody"></div>'''Antibody:''' Any of a large number of proteins of high molecular weight that are produced normally after stimulation by an antigen.

<div id="Apoptosis"></div>'''Apoptosis:'''Programmed cell death. Natural process by which the organism discards unwanted or damaged cells.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Chorionic villus sampling"></div>'''Chorionic villus sampling:''' A form of prenatal diagnosis to determine chromosomal orgenetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dendrite"></div>'''Dendrite:''' Projective protoplasmic processes that carry out impulses toward the main organisation of a nerve cell.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Endocytosis"></div>'''Endocytosis:''' Cellular absorption of external substances by the process of phagocytosis or pinocytosis.

<div id="Endoplasmic reticulum"></div>'''Endoplasmic reticulum:''' Cellular organelle consisting of vesicular and cytoplasmic membranes that are involved in cellular transport.

<div id="Excitotoxin"></div>'''Excitotoxin:''' class of substances that damage neurons.

<div id="Exon"></div>'''Exon:''' Sequence of amino acids in DNA that codes the information required for cellular protein production.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Glutamate"></div>'''Glutamate:''' A salt of glutamic acid that is involved in neurological signal transmission pathways as a neurotransmitter.

<div id="Glutamatergic"></div>'''Glutamatergic:''' Relative to the function of glutamate as a neurotransmitter or its involvement in metabolic pathways.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Neurodogeneration"></div>'''Neurodegeneration:''' Selective degeneration of neurons.

<div id="Neurotrophic factor"></div>'''Standard definition given to a group of molecules that are involved in neuronal survival and protection.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Protease"></div>'''Protease:''' Enzymes that catalyse the proteolytic breakdown of proteins to smaller proteins or it’s component amino acids.

<div id="Proteasome"></div>'''Proteasome:''' A group of large proteins located in eukaryotic cells and archae which are involved in protein degradation.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length [[#Polymorphisms|polymorphisms]] (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

Talk:2011 Group Project 4

2011-10-12T04:50:47Z

Z3389806: /* Post-Peer review discussion */

[[2011_Group_Project_4|'''Group 4''']]: [[User:z3389806]] | [[User:z3290270]] | [[User:z3290379]] | [[User:z3290558]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_4_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_4_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

== Post-Peer review discussion ==

I've fixed the reference, thanks for the heads-up, Maeda!. I've added the "Related Links" section so I think we are done! Yay! See you girls (:

--[[User:Z3389806|Nur Sharalyn Abdullah]] 15:50, 12 October 2011 (EST)

Took me while but I linked all the words in my section to the glossary. :)
--[[User:Z3290270|Maeda Sadeghpour]] 19:34, 10 October 2011 (EST)

Good job girls- page is looking good! Sharalyn, thanks for fixing the references and glossary. See you all on thursday

--[[User:Z3290379|Elizabeth Blanchard]] 14:44, 10 October 2011 (EST)

Thanks for that Nur, one problem, reference 1 and 63 are citing the same reference. Would you be able to fix that? :)
--[[User:Z3290270|Maeda Sadeghpour]] 07:00, 10 October 2011 (EST)

Hey girls, I've done the linkage for the glossary. So if you wanna add new words to the glossary, refer to the words that are already linked for the format kay? If you aren't able to do it, do tell me and i will fix it up. Have a great weekend! :)
--Nur Sharalyn Abdullah 12:14, 9 October 2011 (EST)

Yup, I've fixed the references all up (:
--Nur Sharalyn Abdullah 13:15, 7 October 2011 (EST)

Hey guys, good job on the intro image I really like it. Also, Nur are you still okay with fixing the references? :)
--[[User:Z3290270|Maeda Sadeghpour]] 00:20, 2 October 2011 (EST)

Hey guys, I made our facebook page public because Mark said he needs to be able to access the page to show that we have had substantial discussion amongst the group.
--[[User:Z3290270|Maeda Sadeghpour]] 11:19, 6 October 2011 (EST)

Also, Mark said we can delete the comments he made on the page from previous weeks so that's gone.

--[[User:Z3290270|Maeda Sadeghpour]] 11:20, 6 October 2011 (EST)

==Peer Review==

Group 4:
Truly amazing work on this page. The balance between the images and text is phenomenal. It seems quite simple but easy to read well referenced.
I like how you used tables to illustrate the epidemiology
Nicely drawn images in Genetics Section.
I really don’t see many things wrong with the page… It is well done.. the tables and images all speak up for the quality of the page. However, pay closer attention to the references because some of them are repeated or empty when you look at the list.
Great work.
--[[User:Z3284061|z3284061]] 11:55, 29 September 2011 (EST)

'''Group 4'''

* Overall the project is good
* An image could be good in the introduction
* History and Timeline are good
* In the History section it might be useful to have the years in bold
* Well researched
* Image for "Role in Transciption inhibition" needs to be fixed
* Good table in treatment
* Image in Pathogenesis needs copyright info
* Good use of text/tables/images
--[[User:Z3292953|z3292953]] 11:10, 29 September 2011 (EST)

'''''Huntington’s Disease (Group 4) Peer Review:'''''

Introduction: Good content. Possibly include a picture to get the reader interested from the beginning.

History: Great section! Many references which shows you have done your research. Possibly make the dates bold so that they stand out more. Good use of quote. Image needs to be referenced properly and lacks a student template.

Epidemiology: Extensive! Great use of tables and explanation of the tables! Well done.

Genetics: Great detail in this section. Images are well drawn and relevant to the information. Remember to include a student template in these images.

Molecular Mechanisms and Pathogenesis: Great use of subheadings to organize the text. Image is good, just try to format the reference better and once again, include the student template.

Clinical Manifestations: Image is slightly too small as a thumbnail. Good information, however, I think this section would benefit with a table to help better organize the information.

Diagnostic Tests: Very extensive section. Good use of images, however maybe their placement needs to be more thought out. Also, delete the subheading for the video as this is irrelevant. Great use of video- stimulates the viewer!

Treatment: Table is very extensive and well done. This section is impressive! Images need to have a student template and correct referencing.

Current/ Future Research: Good information in this section. Image on right needs a label at the bottom.

Glossary: Heading needs to be to the left – it is slightly distorted by the image above it.
Extensive glossary.

References: Well done, a lot of research has been done.

Overall, impressive page! --[[User:Z3290808|z3290808]] 10:43, 29 September 2011 (EST)

Huntingtons – Group 4

* This page looks very good and highly detailed. Some of the images do not have correct referencing information and could also contain a little more of a description.
* Excellent use of referencing. This seems highly detailed and looks like a lot of work has been done to get the page to this standard.
* Some formatting issues such as the image in future research and in diagnostic tests headings.
* Video of Huntington’s patient doesn’t need such a big heading, ruins the flow of the page in my opinion.
* Timeline could give a bit more information, and the importance of these events explained better.
* Overall was very good work of a high standard
--[[User:Z3288196|Z3288196]] 10:41, 29 September 2011 (EST)

Group 4:

Glossary and reference take up half the page because the glossary has terms which should probably be explained in the text instead of being an item in the glossary. The references section should also be checked, for example 56, 57,60, 69 all reference Zuccato, C, 2009. There is an excessive amount of references. Not every sentence needs to be referenced.

Title “video of Huntington’s disease patient” should probably go as a subheading not a heading coz then all of the information that should be refering to diagnostic test becomes a subheading of the video. But its a good idea to have the links to videos for extra information.

Apart from that, good assignment. Good use of pictures and written text. And tables.

z3332178 =]

Peer review:

*intro is a bit wordy e.g polyglutamate
*history: indent the quotes, maybe italcis too. timeline can be bolded to make it more readable.
*epidemiology: could have verbose words simplified and explained (the ones that are not in the glossary)
*genetics could have a picture about where the gene is located abnd also be simplified into tables.
*the picture in pathogenesis could have alot less writing or have it simplified, spaced and bolded.
*clinical manifestations is well written and succinct
*picture in diagnosis could be explained better so we can see the link to HD
*expand glossary and recheck the references
--[[User:Z3291423|Jasjit Walia]] 10:14, 29 September 2011 (EST)

'''Group 4 peer review'''

History: I love the idea of the quote. Is 'On Chorea' a book, article or report? Clarifying this would be nice.

Epidemiology: I like how you have elaborate on table one. I found the paragraph on Warby et al paper hard to understand. I think it may become easier to understand if you linked terminologies (like HTT and Halotypes) to the glossary, even if a particular terminology has been linked before in other sections because some readers might be just reading your section.

Clinical manifestations: It was an interesting read. :) But one suggestion ( this is what I got suggested for my section and I thought it was a good idea) is to enlarge the image so that the writing can be seen clearly. I understand that you may think that readers can click on it and see the enlarged picture but some readers may not be bothered and would prefer being able to read it on the main page. Plus, you have unlimited space and with a large image the webpage may look more interesting.

Treatment: In the clinical manifestation, the symptoms are divided into three classes: motor, cognitive and behaviour. It may be more consistant if you reorganise the classes of medication so that it falls into the three classes described in clinical manifestation. I know, this may sound like a huge task, if so, why don't you just ask the clinical manifestation person to change their classes to two, motor and psychiatric.

--[[User:Z3289301|z3289301]] 09:44, 29 September 2011 (EST)

'''Group 4 Peer Assessment'''
*Good introduction: concise and easy to understand. It might be a good idea to hyperlink some words in this section with the glossary.
*History and time line; well written and researched. I really like how you inserted one the original quotes in the text. I suggest you putting the timeline into a table so it looks better.
*Epidemiology; Good use of tables to summarize the figures/numbers. The placement of the tables between paragraphs also break up the text nicely.
*I strongly suggest hyperlinking words to the glossary. Makes the page more user friendly.
*Small typo in "Hungtingtin" title in the genetics section, but that's just a minor fix up. The section was well written. Good us of student drawn images to explain the concepts. I like how the genetics was sub-sectioned into the normal and diseased parts, makes it easier to understand.
*Other sections were also well done. Maybe include a table in the 'clinical manifestations' section. Also I'm not sure if this is beyond the scope of the course but have they been able to link the five specific features of this disease to specific genetic abnormalities or pathways that happens due to this disease? What causes these features? (This is just out of my curiosity).
*Maybe it would look neater if the "imaging" heading was also placed on the most left hand side of the page so it aligns with other headings such as 'neuropathy'. It seems a bit messy atm. Same goes for genetic testing and prenatal diagnosis.
*Excellent table in the treatment section. Is there a specific reason only the actions of 'Tetrabenazine' was explained below the table? if so, what are the reasons?
*Overall, good job :)
--[[User:Z3291622|z3291622]] 09:19, 29 September 2011 (EST)

'''Group 4 Peer evaluation'''

*The introduction is very informative and actually introduced most of the subheadings that will be discussed in the page. The downfall of this introduction is the failure to introduce all of the sections of and proof-reading this section it is fine.
*The history of the disease is very well-done. The quick description or beginning of the history combined with the timeline is utilised well. Only improvement that would make it better is making the dates stand out by putting it I bold or something.
*I can find no fault in the epidemiology. It is the best one I have seen so far. You have described the demography of the disease and the statistics of other mutations. The tables were used appropriately as well, and the fact that it was described straight after the table is perfect.
*I like the genetics section of the page. It made sense and easy to understand. The diagrams are all relevant to the page section. Only criticism I can say is the description of the gene could probably be organised in a much simpler or better fashion, like a table, rather than just one whole sentence. Also I don’t know if it is typo or if that’s how you actually spell it, but I would just like to mention “Huntingtin gene”.
*The pathogenesis section is very informative of the disease. Unfortunately it is very disjointed. One idea was introduced after the other and they did not really connect properly. I think as the reader I am looking for some sort of direction that leads Huntington’s, like a step by step thing.
*I am assuming that the clinical manifestation is not yet finished, so I won’t say anything else other than change the positioning of the image to the other side because it breaks the page and it does not aid in getting the information across to your readers.
*The diagnostic test is a bit of a disappointment. I’m pretty sure that since it is a genetic disease there is some form of genetic testing that doctors can use to diagnose the onset of the disease, unless the etiology is still under debate and not sure of, and from what I have read from your page so far it is pretty definite that mutation in a particular gene is already implicated in the disease. So I think this section could probably do a lot more research and work.
*The video… section of your page is pointless, why isn’t this in the diagnostic section?? I think synthesizing both section is needed, as this section alone is pointless.
*The really like the table in the treatment section it is a a very good summary. If you could add the actual effect of each drugs to the patient, it would make this table better than what it actually is. The tetrabenzaine part is a bit out of place. If you are elaborating on the entire active chemical ingredients, I believe this is a good idea.
*I like the current and future research section of the page, as it informs the reader that the page is current and well informed about the recent endeavors on the disease. The only let down is that there is not a single research on finding a cure for the disease or looking for other treatments, which I think is one of the most popular topic on this disease. If you could add this in this section it would make this area much better. You could even add it in the treatment section.
*Not really a big fan of the glossary, but it is good idea anyway.
--[[User:Z3290841|z3290841]] 10:23, 29 September 2011 (EST)

Group 4

*Very clear introduction, seems well researched and easy to understand
*History – good structure, my only suggestion is to put the timeline into a table and to highlight or bold the years mentioned, it’d look sweet as then.
*I like the tables in epidemiology, same colour structure could be used for the timeline under history maybe?
*Genetics – quite possibly the best heading on this page, I’m sure other people have mentioned this but ‘Huntington Gene’ the sub-heading is spelt wrong. Great incorporation of the student drawn image, this heading is very clear and easy to follow.
*Image under ‘Molecular Mechanisms & Pathogenesis’ is a bit big in my opinion, maybe consider reformatting it so the text is not broken up so suddenly.
*Image under ‘Clinical Manifestations’ could be better placed on the right hand side of the page so that there is continuity on the page, same with the other images under ‘Video of Huntington's disease patient’ and ‘Treatment’ and ‘Current/Future Research’
*Overall a well detailed page that is easy to understand and clear in its aims.

--[[User:Z3331469|z3331469]] 06:59, 29 September 2011 (EST)

'''Group 4 Peer Review'''

• Great sub-heading structure, and the overall flow of the page is neat. Although, it would appear more orderly if all images were on
the right hand side of the page, in alignment with the text (it looks messy otherwise).

• The introduction is very clear and to the point, I think a picture which portrays the abnormality would look good here.

• History is done really well, I loved the quote and the picture of George Huntington. The only thing in this section would be to make
the dates bold or possibly even use a table.

• Nice use of tables in epidemiology, they make the information easy to read and easily accessible.

• Well described genetics component and nice incorporation of the student drawn image. I’m not sure if there’s a need to break down
Huntington (misspelt as ‘Huntingtin’ in the heading) gene into more headings.

• Molecular mechanisms and pathogenesis is done well. I actually think the image is a good size, as its side-by-side to the text and clearly explains what most of the text is about.

• I think a table would be helpful in clinical manifestations. Also, the image would look better larger and on the right hand side of the page.

• Treatment section was a little overwhelming. Too much detail in the table, possibly?

• Good glossary and a vast range of references, good work thus far!

--[[User:Z3289829|z3289829]] 02:42, 29 September 2011 (EST)

'''Peer Review'''
* Introduction does well in that it briefly addresses each of the facets of the topic that follow.
* Relevance of each historical point in the timeline is not adequately explained.
* Use of the table to show epidemiology is very nicely set up.
* Epidemiology is very much at the level required, delving into specific research details.
* You misspelled "Huntington" in "Huntingtin Gene". Really?
* Image error in the Molecular Mechanisms section. Remaining picture is very comprehensive though.
* Could potentially use more references in the Molecular Mechanisms section; otherwise decently referenced.
* The Diagnostic tests aren't actually mentioned, only their significance is outlined.
* "Neuropathology" section is not properly titled - it seems to be a subset of the Video section (which, incidentally, can probably be moved within Clinical Manifestations)
* Medication table is very nicely set out.
* Picture in Current/Future research (mouse/person/etc) seems irrelevant, and is not actually explained.
* Glossary is thorough
--[[User:Z3290689|z3290689]] 00:46, 29 September 2011 (EST)

'''Peer Review for Group 4'''

*Introduction is informative but not catchy. You need the reader to feel eager to read on the rest of the page.
*I like the way the history has a portrait and how there is a blue box around the quote. Maybe In the timeline you should bold the dates so it looks better on the page.
*Information found in the epidemiology is great, and the use of tables is very good. Just wanted to let yous know that whenever I read HD I always remember High Definition, a little distraction to my reading. Just wanted to make that point.
*Information in the HTT & normal functions section seems a bit disjointed and doesn’t seem to flow well.
*The HTT and Huntington’s disease section showed be reformatted so it is one nice flowing informative paragraph.
*Image found in the molecular mechanisms and pathogenesis section doesn’t show. Please fix it or remove the thumb altogether. However included information in this section is informative
*In clinical manifestations, it would be really good if you could describe how the clinical manifestations are brought about at a neurological level.
*It’s not necessary to have a large subheading for’ Video of Huntington's disease patient’
*Diagnostics has lots of info so formatting it so it’s spread out will be good.
*The image of Amniocentesis seems not to have the copyright clearance for it to be modified. Please fix it.
*Table in the treatments section is cool and massive, try to make it a bit smaller?
*I believe if the tetrabenzine information should come first then the massive medications table it would make the treatments part look and flow better.
*Current and future research section has information that very informative and portrays a good view on the current research arena for HD. However I don’t understand the relevance of having the brain scans in this section. Maybe have another section as a glossary which you could use for all other miscellaneous pictures.
*Some parts of the referencing include multiple referencing, just fix that up it will make it much better
*Overall, page is really well constructed, put a lot of work in and I’m impressed. Good word to picture ratio thus makes the page to be wanted to be read. Good work people of group 4.

--[[User:Z3291317|Z3291317]] 23:50, 28 September 2011 (EST)

'''Group 4'''

Introduction: Introduction is alright but could be more detailed.

History: This section is good but the timeline would be better with more information/ more detailed explanation of the points already there.

Epidemiology: This section seems too concerned with the occurrence of the HD. I think this section could use some more general
epidemiological information as well.

Genetics: This section is explained clearly and done quite well. The pictures need to be bigger though.

Pathogenesis: This section is good. The image could be a tiny bit bigger and would be better if it had a caption explaining the different parts of the diagram.

Clinical manifestations: This section could be longer/more detailed. You could explain some of the symptoms. Eg.what is chorea? Also, the picture is good but needs to be much bigger.

Diagnosis: This section doesn’t seem to actually explain how HD is diagnosed. Where is the diagnosis? Also, the picture is good but needs a more detailed caption.

Treatment: This table is not very nice to read and seems a bit complicated. I think it would work better simplified and put into paragraphs.

Future research: Good pictures and text. I think the images need more explaining. Eg. where is the caudate located in the brain. Maybe arrows could show this.
--[[User:Z3291324|z3291324]] 23:21, 28 September 2011 (EST)

Group 4

Hey, this is a nicely structured page with interesting content that is presented well. There is a nice balance of text and image

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: good, to the point
#* History: Nice section, perhaps bold the years?
#* Epidemiology: I really liked this section, both visually and content wise. The table is easy to read and I liked your explanations for the HD prevalence, well done
#* Genetics: Perhaps you could have the 'CAG (cytosine-adenine-glutamine)' in the introduction when you first refer to it? Referencing is required in i'HTT and normal functions'. I really liked your subheadings, made it very easy to understand and follow
#* Pathogenesis: Image is too big, good subheadings, I suggest that if you write in purple to highlight some words, maybe you could do that for the whole page?
#* Clinical: liked the motor impairment explanations, how about explaining the cognitive and behaviour impairments as well? (it'll be worth it!)
#* Diagnosis: Nice content, but it just feels a bit too crowded, maybe rearrange the images and decrease image size
#* Treatment: Very nice section with nice images and good format!
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Good balance of images and text, though some rearrangement of images would make this page look better. Very good use of subheadings to make the content more easy to digest
#Content is correctly cited and referenced.
#* overall referencing was well done
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.
* good range of tables, images and self drawn images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* Nice range of references used
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* just minor changes such as resizing some of the images, making the sections consistent in format

--[[User:Z3291643|z3291643]] 22:32, 28 September 2011 (EST)

'''Group 4:'''

•Formatting of the page seems well done, I like the inclusion of the quote in the history section, maybe put the timeline into a table as this would make it more visually appealing

•The file Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg, does not have the correct copyright information for the student drawn images

•I like the inclusion of the video, but am not sure about the subheading choice for this section. Does the video need its own separate heading?

•Good balance of text and images

•A couple of the references seem to be missing some of the information, but you have a large number of references so it looks like a lot of research has gone into this, good work so far.

--[[User:Z3332183|z3332183]] 21:26, 28 September 2011 (EST)

'''Group 4: Peer Assessment'''
* Your page has a good balance of text, images and tables
* I like that your introduction is brief and to the point
* You history section is the best one have seen so far, it looks good and it easy to read
* The image in the pathogenesis has no copyright information
* In clinical manifestations are quite important I think and your section seems a little weak in comparison to the rest
* Treatment: I'm sure the table was a lot of work but it is quite complex ad all the drug names make me a bid dizzy. May be you can shorten it to the most relevant?
*Overall the page has a good content and it's fun to read. The diagrams and drawings are great --z3279511 17:09, 28 September 2011 (EST)

'''GROUP 4: Huntington's Disease'''
*Intro has good summary of the disease, however the first paragraph is a little too technical, could you maybe simplify it a little so you don't lose the reader right at the start (reference 5 is missing though)
*History is succinct and summarised well, i like the quote included, could you have gone a little further with the timeline? (maybe include some of the more recent developments), maybe the timeline could be better formatted in a table
*Good info from a variety of sources in epidemiology, good use of tables, I like how prevalence has been compared and how the table is explained (one little thing: could you maybe find more statistics for Australia?)
*Inheritance image needs student template added and maybe made a little bigger so detail can be seen
*Genetics section is informative but could use an image of the gene maybe
*Molecular Mechanisms & Pathogenesis section is well researched and good summary is provided. I like how key words have been highlighted. images need fixing (more descriptive legend is needed for the first image and what happened to the second image?
*I don't think you need to explain what the disease is again in the clinical manifestation segment (don't want to sound repetitive), image in this section isn't very clear, I feel that this section is a tad incomplete-maybe some expansion is needed e.g. classes 2 and 3 could be expanded on more
*I feel that diagnosis section could go further up? This section is very informative, but could be summarised a little more Some of the images in this section need better explaining, good balance of text and images in this section
*good use of table in treatment section, however more info could be provided as to how these drugs help the disorder
*Current/Future Research is very up to date, images here again need more description

Overall:
*it is evident that this project has been extensively researched
*good use of subheadings and headings
*maybe include the acronyms in the glossary and it would be good if glossary words were linked to text
*make sure all images include the student template required and legends of some images need to be expanded (more info on what the image is about)
*fix repetitive sentences
*good balance of images and text, good use of tables

--[[User:Z3331556|z3331556]] 15:27, 28 September 2011 (EST)

'''Peer Assessment Group 4'''

*Second sentence of intro is WAY too detailed for the intro, it means very little as the disease has not yet been explained to us and is too technical – OR, keep it but explain it in a more general way.
*What do you mean by familially or sporadical development? Define what you mean by this (intro)
*Timeline – events need to be explained. E.g. Venezuela Project – what is this? Why is it significant? (this is needed for most of the history entries)
*HTT and normal functions – can you explain what some of the processes are? E.g. dynactin complex, clathrin-mediated endocytosis are?
*Calcium signalling in pathogenesis – maybe explain why the calcium signalling pathway is important?
*The video file – make sure you write a little para about it. It has a new headings – shouldn’t it be a subheading?
*The paragraph of ‘Imaging’ in diagnostic tests needs to be pushed so its under the pics from neuropathology
*Tetrabenazine – I think have an intro sentence about it to highlight that this is the most commonly used one, as you only discuss it in depth (as a drug treatment) – unless you are going to add in explanations of other drugs?
*In Current/future research, refer to the pics on the RHS if they are relevant, otherwise I think they need to go somewhere else
*Overall comment: its good, lots of research, but even as someone who has a background in bio, we still don’t know everything about everything, so I think as you go, explain some of the more complicated processes so you can really understand what is going on.

--[[User:Z3332824|z3332824]] 11:48, 28 September 2011 (EST)

Group 4: Huntington’s Disease

'''Group 4 Peer Review'''
* Good introduction, history seems adequate - although the timeline stops at 2002? Is there anything after this?
* Nice table for epidemiology; although some terms require explaining
* Excellent student-drawn diagrams and genetics section with a good balance between the text, bullet points and images. One image has been removed so be sure that that is re-uploaded!
* Video section: Formatting is a bit of a pain to read when the left hand margin keeps shifting with the images being placed here. Fix this please so that it is easier to track the page with our eyes.
* Treatment section is overwhelming, whilst some might have said that it looks great (and it really does), to suddenly be hit with such a huge table is exhausting. Perhaps shorten this section by mentioning that there is only treatment available for the symptoms, list them, and then link to an image containing the table in its entirety.
* Current/Future research section seems a bit short.
* Overall, it looks like an excellent project that has had a lot of thought put into it. Well done guys :)
--[[User:Z3288827|Leonard Tiong]] 10:25, 28 September 2011 (EST)

Initial thoughts, was wow! Clearly immense time and effort was put into this! Loved the structure of the headings and sub-headings.
*Introduction: Top notch, just needs an image to complete it.
*History: Nice use of the quote box, this section was done very well, except BOLD the years. Personally, I would have liked it more if the timeline itself was in a coloured table, no biggie.
*Epidemiology: Add “(Australia)” After Tasmania? Or just listing countries would be better? Overall, nicely done.
*Genetics: “Inheritance” part feels a little too short. Preferred if the image had black text over a white background. Everything else was great!
*Molecular Mechanisms & Pathogenesis: The space between the purple words and commas could be removed. The purple colour, made me think they were hyperlinks, maybe chose either to bold or colour the words, as having both is a bit much.
*Clinical Manifestations: The features would look better in a table, in my opinion. I like the image, very nice indeed! Good summary.
*Diagnostic Tests: Done well, though compared to the rest of the webpage, it looks very insignificant. I suggest adding more information!
*Video: Fix the formatting please!
*Treatment: Nice table, informative. The “Tetrabenzine” section, the text needs some formatting, sentences are cut off to the next line for some reason, to be honest Medications and Therapies seem to be most important part, so they should maybe be expanded on?
*Glossary: Looks good, just a few full stops missing!
--[[User:Z3332327|Lisa Xiao]] 01:24, 28 September 2011 (EST)

'''Group 4'''

*Very good introduction

*History: looks very nice, but the layout of the quote disrupts the page. I think it would be better to use bold letters, good idea though.

*Epidemiology: nice section, useful tables

*Genetics: good detailed content and drawings

*Pathogenesis: do not bold words in only one section, it disrupts the whole picture, good use of sub- headings.

*Clinical manifestations: good summary of the symptoms in the drawing, the classes and the five specific features would look better in a table, otherwise good section

*Diagnostic tests: the video subheading needs to be fixed, really irritating. Very detailed, I would put all images to the same side

*Treadment: mechanism of tetrabenazine inhibition image could have been done with more effort

*Research: very nice clear section
--[[User:Z3387190|Z3387190]] 21:27, 27 September 2011 (EST)

'''group peer assessment'''
*Introduction is well structured though image of the Huntington gene protein would be more beneficial to where I’m looking relating to genetics
*Genetics could expand more on the inheritance and the Huntington gene
*Role in transcription sub heading image removed
*Diagnostic test image needs to placed in correct section and the video should be placed at the end of the section, placement of the video cause confusion of the other diagnosis tests
*Treatment should have an introduction which introduces the drug used to manage diseases and therapies, better layout where most commonly used drug form management and therapies following the table to show alternative treatment.
*Current/future research should have some future research and images placed have no description which research project image belongs to
*References contain mistakes with repetitions and blanks also some done incorrectly such as reference “3” where not properly inputted on the wiki page
*Glossary was not linked to the web page as well while reading was lost without referring to a dictionary due to no indications definition is in the glossary
z3332250 23:46, 26 September 2011 (EST)

Group 4 Peer Review

*Punchy introduction-well done
*Timeline under history was excellent
*Seemed very scientific and wordy at times-a lot of detail is unnecessary; “less is more”
*Great balance of text and images-very readable
*Page flowed well in a logical manner
*Diagnosis section is very well done however there seems to be too much content/focus relative to the rest of the page. Perhaps add some more to other sections or make this section more concise?
*An extensive glossary and reference list-thorough research
*I learnt a lot from this page so well done!
*Overall, an impressive page. A few more things to tweak to make it excellent.
--[[User:Z3308965|Fleur McGregor]] 19:13, 26 September 2011 (EST)

'''Group 4 Critique'''

#• Introduction was quite good
#• History was good. I liked the timeline
#• Tables in the epidemiology were good
#• The genetics was clearly explained
#• Pathogenesis was really good. I quite liked it
#• Clinical manifestations is good
#• Diagnostic tests could be more detailed
#• Overall, quite a well written project. Well done. Maybe add a little more about the medications.

--[[User:Z3289991|Robert Klein]] 18:47, 24 September 2011 (EST)

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

Group 4
* On first looking at the project it looks like there is a good text/image ratio. However an image in the introduction would work well
* The content of the introduction is very clear and introduces the reader to the topic well
* I really like the history section. The story makes me a little excited about the condition in a way. I am left feeling keen to know more and there is an extensive list of discoveries. There needs to be more after 2002 though. I find it difficult to believe that nothing has been found in the last 9 years.
* The epidemiology table is a nice way of showing the data. But maybe you should put the Australian states in bold and at the top- also maybe include all of the states or Australia as a whole, not just NSW and TAS
* There is a file in the pathogenesis that is not accessible- either get the file up or remove the link
* The image in the pathogenesis has no copyright information
* A couple of grammar problems in the pathogenesis that could be fixed up- full stops mid sentence for example
* The clinical manifestations sections outlines the types of classes of manifestations but it is difficult to actually access the information on what the manifestations are. It would work well in a table with a little more detail on what the patient experiences
* The video is put as a new subheading within diagnosis. It needs to be made into the smaller subheading because I thought diagnosis section was over but it continues underneath
* The diagnosis section is in great detail, somewhat more detail than other sections. This is very interesting and shows that this team member worked hard on their section.
* Good work on the project, just a little editing and formatting to make it a finished product!

'''Group 4'''
* Nice structure of headings and subheadings, it breaks up the text and makes it a readable page. Extremely interesting topic!
* I found the history very interesting and enjoyed the quote from Huntington.
* maybe bold the dates in the timeline, just to make the page easy to follow. Or maybe a table could be appropriate.
* I liked the structure of the epidemiology section and the tabulated prevalences! good work!
* Molecular Mechanisms & Pathogenesis: unsure as to why some sentences were bolded.
* Differential Diagnosis: very interesting I liked that you added this in.
* Treatments table very succinct easy to understand and follow! Great!
* Good to see that most of your references were grouped. only a few that were doubled.
* Maybe have a continuos colour scheme for the page and type of table used.
* Good use of tables and I like that you explained what they were about.
* Make sure all acronyms and scientific language is in the glossary
* good student illustrations
* overall great ratio of text and pictures!

'''Group 4 Assessment'''
*This might be a bit nit-picky, but for the references given throughout the wiki, there isn’t any consistency. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*The information within the introduction seems to be substantial. Only suggestion would be to add a picture to add to the overall look.
*In the history section, it was a good idea to have the single quote stand out in a colored box to itself. First time I’ve seen this. Looks professional. I question though, if all the events within the timeline are absolutely necessary…
*Epidemiology- Both tables are well organized and look extremely professional. Good information within this section, although it might be a good idea to reference a few more not-so-common terms in the glossary, such as SNP’s and others which may not be common knowledge for all.
*The Genetics section is well formatted with what I believe is the vital information needed in this section. Only complaint is the first picture (Inheritance Pattern…) doesn’t have the copyright information claiming that it is okay to use this image.
*The “Key cellular pathogenic mechanisms in HD” image likewise does not have the copyright information to verify its legal usage.
*Molecular Mechanisms and Pathogenesis section- Very well formatted and aesthetically appeasing. Why are some of the words in purple though? Are they meant to be defined the glossary, or just key points? “The Mutant Huntington gene…” file is also not on the page… Where is it?
*Diagnostic Tests  Research – I have no complaints. These sections look immaculate.
*In the glossary, try having a bullet list and also having the words within the wiki page to link to its definition in the glossary.
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
*Overall, good content within the page and very appealing visually. Just minor editing needs to be done I think. Good job!
--[[User:Z3391078|Z3391078]] 14:31, 27 September 2011 (EST)

'''Peer Assessment: Group Project 4'''
*The introduction and history sections are concise and well formatted.
*A few of the points in the timeline would be improved by containing a bit more information such as 'Mendel's work' and 'The Venezuala project'
*The tables used in the epidemiology section are clear and highly informative.
*The abbreviation HTT is used throughout the epidemiology section before it is stated what it means in the genetics section. This should be changed.
*The picture related to transcription factors needs to be fixed so that it can be displayed.
*The section entitled 'Video of Huntington's disease patient' should have a more appropriate heading to encompass the rest of the written information in that section.
*Under the information in some of the images you have uploaded, you still need to add <nowiki>{{Template:2011 Student Image}}</nowiki>.
*Some of the references are duplicated. They can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
*Overall the project is highly informative, well written and formatted.
--[[User:Z3217345|z3217345]] 21:34, 27 September 2011 (EST)

Group 3:
* The introduction is very lengthy, some parts feel as though they would be more appropriate in other sections. The image here fits nicely with the text but it could benefit from a more descriptive legend and needs to include “{{Template:2011 Student Image}}”.
* In the history, you begin to use the short hand “KS” without an initially stating that this is the abbreviation for “Klinefelters syndrome (KS)”. The dates that are mentioned are very detailed although it ends in 1970, were there any other breakthroughs since then? A picture of Klinefelter would be a nice touch here.
* Epidemiology requires some proof reading as there are a couple of little mistakes and the images would have more of an impact if they were slightly larger.
* I like how you have linked figure 1 to the non-disjunction sub-heading under aetiology. The image in this section could benefit from a coloured legend, ie. Instead of saying “Blue circles are male cells”, in a box include an actual blue circle = male cells along with the other descriptions. It also needs to be properly cited.
* There is too much repetition between pathogenesis and aetiology, maybe discussion between these two students is needed to minimise repetition. Good hand drawn images but you need to include the student template as mentioned previously.
* Signs and symptoms would look better in a coloured table and with more images. I don’t think it is necessary to repeat the image comparing age and intellect here.
* Diagnosis; nice use of another form of media – a video. The abbreviation of KS in this section needs to be established first by placing KS after the first time you mention Klinefelters syndrome.
* Management is very concise and thorough
* Other similar defects; nice touch, it could look more appealing with the use of colour and larger images though.
* Current research is formatted nicely and flows well

'''Group 4: '''
* The introduction provides a great overview but remember it needs to be easy to read, even for those who have never heard of Huntington’s disease. If you explain scientific and medical terms (such as neurodegenerative and CAG trinucleotide tract) more generally/broadly, it will solve this problem.
* History: great use of a quote and image. The timeline would look better and make it easier to read if the dates were bolded or if it were in a table. The explanations could be elaborated more such as “1900: Mendel’s work was rediscovered”. Image needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>.
* Epidemiology: Although you’ve stated that Venezuela and North Ireland have notably high prevalence of this disease, you haven’t stated the actual prevalence of Venezuela. You also need to re-read this section as there are a couple of mistakes eg “There <font color=red>seem</font> to be an increased prevalence of Huntington's disease...” and this sentence doesn’t make sense “Two of the most well-known populations in which high prevalence of HD was notably in the state of Zulia, Venezuela and Northern Ireland”. What are HTTP haplotypes?, overall I found the explanation of the paper by Warby et al hard to understand, maybe another attempt of explaining this paper is needed by spelling out the haplotypes even more so. In saying this, the tables are formatted very nicely.
* Genetics: Nice student drawn images but just make sure you include the student template as mentioned above. The “Huntingtin Gene” section would benefit from an image of the specific regions on the chromosome as it is hard to follow with just text.
* Molecular mechanisms and pathogenesis: a lot to take on but is made easier to read through the use of good sub-headings and highlighted words and large image. Make sure you include the student template here as well and there is an image missing in this section though.
* Clinical manifestations: You have mentioned 3 classes of symptoms but have only gone into detail about one of them; motor movement impairment. What happened to cognitive and behavioural explanations? Nice student drawn image, I like how it is oriented to the left to change it up a bit.
* Diagnostic test: The table could be formatted with more colour to make it more aesthetically pleasing. I personally don’t understand including an image of another disease, i would stick to images specifically relating to HD.
* Under neuropathogy there is a little typo “The neuropathological hallmark of Huntington’s disease is now <font color=red>know</font> to be the gradual loss of spiny GABAergic...”, there could be more so i would advise to check this section again.
*Under genetic testing there is also another little typo “However it wasn’t <font colour=red>until the 1993</font> when...”
*Treatment and future research: very well researched and I really liked the use of the table and images here, it provides great balance and flow.

--z3290815 19:05, 28 September 2011 (EST)

'''Group 4: '''

*The page had a nice format that was appealing to read.
*The structuring of the images between and beside the text was perfect because it was not too big and not too small. It was easy to view and nice to see.
*The table for the treatment heading was nice but the last column is hard to read because the information was listed in a horizontal fashion maybe changing it and putting it into dot point form would be good.
*The student drawn image was clear!
*Fixing the formatting/structure of the glossary heading is needed
*Double referencing can be seen
*Sub heading for the video would be nice to see. The idea of including a video is quite nice.

--[[User:Z3330313|z3330313]] 19:57, 28 September 2011 (EST)

'''Peer Review'''

* Organised well
* Subheadings in the epidemiology section not in the centre of table
* images in the current/future research section is disorganised
* a lot of referencing was done and maybe not necessary
* choice of pictures were good examples

--[[User:Z3060621|z3060621]] 21:14, 28 September 2011 (EST)

'''Group 4'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
Main sections are there, Not sure if 'video of huntington's patient' should be a big heading - maybe put it in an 'external links' section?

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Content is well done and headings/sub-headings are organised well.

'''*Content is correctly cited and referenced.'''
Fix up doubling of references. File:Mutant Huntingtin gene and its effects on transcription.jpg is missing. No references in therapies?

'''*The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.'''
Student image well done and explanation works well.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Comprehensive research, but maybe more information in glossary as the wiki uses quite a lot of technical language.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Any thing else on diagnosis? As mentioned by Mark, since this is a disease that presents complications after birth, more information should be added. Perhaps include some information on diagnostic tests? The imaging section in neuropathy could be added to diagnostic tests if diagnosis is possible by examining neurological changes?

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Development of wiki page has followed above guidelines, but some minor adjustments can be made.

--z3329495 21:15, 28 September 2011 (EST)

*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.
*'''History''': Looks good.
*'''Epidemiology''': Nice detail.
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.
*'''Clinical Manifestations''': Good.
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.
*'''Glossary''': Looks good, but some more terms still need explaining.
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.

==Discussion==

Hey girls, Found a photo for the introduction. Let me know what you think/feel free to change it if you wish :)

--[[User:Z3290379|Elizabeth Blanchard]] 17:10, 1 October 2011 (EST)

Hey Liz, I posted on the fb page regarding the genetics and pathogenesis part. The student drawn image I'm okay with doing yes. So far I was thinking about doing a picture showing the autosomal dominant nature of the gene. Basically a "tree diagram" of what happens when one parent is affected and the offspring has a 50% chance of inheriting HD.
But I'm okay at drawing so if someone else has something better they'd like me to draw I'm okay with it. :)
Girls please check fb, bit of a crisis.
:)

--[[User:Z3290270|Maeda Sadeghpour]] 06:00, 14 September 2011 (EST)

hey girls, i think we really need to start hurrying things along with our project. Maedeh, i know you said that peer reviews arnt getting marked, but we need to have our project FINISHED by then because after that we are only making finishing touches based on teh peer reviews. Also, are you still doing the student drawn image? Ta

--[[User:Z3290379|Elizabeth Blanchard]] 12:41, 13 September 2011 (EST)

Genetics + Pathogenesis

Yea I think so, it would make it more relative. If anyone comes across any studies just post the link here or on fb. :)

--[[User:Z3290270|z3290270]] 23:36, 24 August 2011 (EST)

Hmm, are epidemiological studies on HD? If there is, we should add. It will make our webpage more comprehensive.
And I don't mind doing that section.

--Nur Sharalyn Abdullah 20:24, 23 August 2011 (EST)

Girls, do you think we need an 'Epidemiology' heading??

--[[User:Z3290379|Elizabeth Blanchard]] 17:25, 23 August 2011 (EST)

Introduction + Clinical Manifestations.

--[[User:Z3290558|Lisa Lee]] 14:42, 23 August 2011 (EST)

Current + Future Research & Diagnostic Tests.

--[[User:Z3290379|Elizabeth Blanchard]] 09:30, 22 August 2011 (EST)

Sharalyn: History & treatment

--Nur Sharalyn Abdullah 20:15, 20 August 2011 (EST)

'''White blood cell populations from Huntington's Disease patients'''

[[File:White_blood_HD.gif]]

--[[User:Z3290558|z3290558]] 23:46, 17 August 2011 (EST)

===Establishment of HD hybrid cell line===

[[File:Establishment of HD hybrid cell line.jpg]]

(A) First polar body of mature rhesus macaque oocyte was removed by gentle squeezing through a slit of zona pellucida (A-a). Staining of 1st polar body DNA (arrowhead) and oocyte DNA (arrow) (A-b). HD monkey skin cell was placed under the zona pellucida (black arrow) (A-c). Reconstructed oocyte with HD monkey skin cell (A-d; yellow arrow) was placed between two electrodes for electrofusion (A-d). (B) Day 12 hatching blastocyst derived from HD monkey hybrid embryo (B-a; arrow indicated ICM). HD monkey hybrid blastocyst outgrowth at six days after attached onto feeder cells (B-b). High magnification of selected region (inset) of the ICM outgrowth (arrowhead). HD monkey hybrid cell line (TrES1) at passage 10 (B-c). (C) G-banding analysis of TrES1. Cytogenetic analysis of TrES1 demonstrated tetraploid chromosome (84; XXXY). (D) Expression of ES-cell specific markers: Alkaline phosphatase, Oct4, SSEA4 and TRA-1-60.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833146/?tool=pmcentrez

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

--[[User:Z3290270|Maeda Sadeghpour]] 21:30, 17 August 2011 (EST)

'''Large stem cell-derived neurospheres were generated from 33-week old HD hippocampus, but not WT hippocampus.'''

[[File:Stem cells neurospheres drived from Huntingtons Disease hippocampus.png]]

--[[User:Z3290379|Elizabeth Blanchard]] 15:06, 16 August 2011 (EST)

'''Melatonin levels in Huntington's disease patients and controls'''

[[File:Melatonin levels in HD patients and controls.jpg]]

The diurnal melatonin rise was significantly delayed in HD patients by about 01:30 h (p = 0.048). The black bar on the abscissa indicates the dark period (23:00–7:30 h).

--Nur Sharalyn Abdullah 12:21, 16 August 2011 (EST)

We decided on Huntington's Disease, I believe Nur spoke to you at the end of the class. :)

--[[User:Z3290270|Maeda Sadeghpour]] 16:44, 13 August 2011 (EST)

--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.

Group 4 Topic: Neural Tube Defect

Research Article:

Conway S.J., Gosnell M., Rogers R., Simmons O., Snider P., Young R. (2011), Notochordal and foregut abnormalities correlate with elevated neural crest apoptosis in Patch embryos. Birth Defects Research Part A: Clinical and Molecular Teratology. doi: 10.1002/bdra.20802. Epub 2011 May 6.

http://www.ncbi.nlm.nih.gov/pubmed/21557455

Review Article:

Abdel-Hamed Z., Johnson C.A., Logan C.V. (2011), Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects. Molecular Neurobiology

http://www.ncbi.nlm.nih.gov/pubmed/21110233

--[[User:Z3290558|z3290558]] 02:07, 11 August 2011 (EST)

'''Neural Tube Defects'''

[[Review:]] Padmanabhan, R. (2006). Etiology, pathogenesis and prevention of neural tube defects. ''Congenital Anomalies'', 46(2), 55-67.

[[Research:]] Joó, J. G., Beke, A., Papp, C., Tóth-Pál, E., Csaba, A., Szigeti, Z., Papp, Z. (2007). Neural tube defects in the sample of genetic counselling. ''Prenatal Diagnosis'', 27(10), 912-21.

--[[User:Z3290270|z3290270]] 02:34, 11 August 2011 (EST)

''Review'': Bassuk AG, Kibar Z. '''Genetic basis of neural tube defects.''' Semin Pediatr Neurol. 2009 Sep;16(3):101-10 [http://www.ncbi.nlm.nih.gov/pubmed/19778707]

''Research'': De Marco P, Merello E, Cama A, Kibar Z, Capra V.''' Human neural tube defects: Genetic causes and prevention.''' Biofactors. 2011 Jun 14.[http://www.ncbi.nlm.nih.gov/pubmed/21674647]

--[[User:Z3389806|Nur Sharalyn Abdullah]] 14:24, 10 August 2011 (EST)

We are doing on neural tube defects!

--[[User:Z3389806|Nur Sharalyn Abdullah]] 13:47, 10 August 2011 (EST)

Neural Tube Defects

Article: <ref><pubmed>19120526</pubmed></ref>
Review: <ref><pubmed>18182339</pubmed></ref>

===References===
<references/>

--[[User:Z3290379|Elizabeth Blanchard]] 22:25, 9 August 2011 (EST)

Hi girls (: I actually managed to find some genetics-related articles on neural tube defects. It has something to do with folate and folate-related genes from what I have read so far. So how about it? Shall our website be based on neural tube defects? (:

--[[User:Z3389806|Nur Sharalyn Abdullah]] 08:12, 9 August 2011 (EST)

Hey girls,

So I've done a bit of research on a few of them.
One of the things we need to keep in mind is that it has to relate to the '''learning outcomes''', which I think is the embryological process, and how the genetic disorder relates to it or how its affected by it? (I tried looking it up but couldnt find it).

Here's a list of the topics I've been looking into:

[[Turner Syndrome:]] commonly known to have one missing sex chromosome, (or both) - LOTS of info on this. (only thing is, because its such a broad topic, we might have articles that contradict each other, or might not have that many embryology related new articles...?)

[[Klinefelter's Syndrome:]] the gigantic disease with the extra chromosome (XXY). there's a decent amount of info on this, but not as much as Turner.

[[Neural Tube defects:]] problems happening in the first month of baby formation because of the folate deficiency in the mother. But i'm not too sure where the genetics come into this..

Which topics have you guys been looking at? Let us know! cos we need to have some articles in '''[[2-3days time!]]''' :)

Ye it's better to research an area instead of just one disease then, because that will give us more to talk about... especially the genetic components which Mark commented on. So I was thinking Neural Tube Defects instead. That will give us Anencephaly, Encephaloceles, Hydranencephaly, Iniencephaly and Spina bifida. ?--[[User:Z3290270|Maeda Sadeghpour]] 01:09, 8 August 2011 (EST)

You need to think about what the genetic component will be for the disease you select. --[[User:S8600021|Mark Hill]] 23:51, 7 August 2011 (EST)

I don't think that having 4 categories will be a problem. I actually think that it will be good to have extra stuff to talk about. Have a look at the other pages from previous years, they are very elaborated so I think it's actually a good thing to have alot of things to talk about. But anyway lets decide on something so that we can post up our articles

--[[User:Z3290379|Elizabeth Blanchard]] 22:00, 7 August 2011 (EST)

Hey! I get what you mean, Maeda. Doing 4 categories can be quite heavy. Hmm, but I was thinking, since this is going to be a wikipage and the elaboration for the 'original' wikipage for spina bifida is not very deep for the 4 categories, maybe we could leverage on this weakness and make ours more detailed? :) But if you guys think it is too much, I don't mind doing the other suggestions too! Anyway, this is just a preliminary decision. It depends on the topics that other groups have chosen too. Would it be possible for us to finalise the topic by tomorrow?

--[[User:Z3389806|Nur Sharalyn Abdullah]] 17:18, 7 August 2011 (EST)

Hello people. I was basically trying to see which diseases had the most current information available online, and cystic fibrosis seems to be very well known. Spina Bifida is very interesting as well, my only concern with it is the 4 categories it's divided into, which I thought might make it a bit more work. What do you guys think? :)

--[[User:Z3290270|Maeda Sadeghpour]] 00:25, 6 August 2011 (EST)

Hey, girls! I'm thinking of spina bifida and hydrocephalus. Cheers!

--[[User:Z3389806|Nur Sharalyn Abdullah]] 20:26, 5 August 2011 (EST)

hey guys, had a quick look and Spina bifida and Turner's Syndrome both seem to have a decent amount of information on them

--[[User:Z3290379|Elizabeth Blanchard]] 14:26, 5 August 2011 (EST)

==Peer Assessments==
* Interesting but good use of a quote
* The introductory paragraph for the “history” section could probably be cut down or eliminated altogether
* Great inclusion of statistics in regards to epidemiology
* Student images were excellent, well drawn and were engaging
* Pathogenesis section could have been placed in a table just to change up the formatting
* The video inclusion was good and relevant
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
--[[User:Z3332629|z3332629]] 15:24, 22 September 2011 (EST)

File:George Huntington.jpg

2011-10-12T04:39:52Z

Z3389806: /* George Huntington */

==George Huntington==
Portrait of George Huntington, done in 1872.

Image link: http://upload.wikimedia.org/wikipedia/commons/7/7f/George_Huntington_%28c._1872%29.jpg <ref>George Huntington (c.1872) '''Wikimedia Commons'''[http://commons.wikimedia.org/wiki/File:George_Huntington_(c._1872).jpg]</ref>

Author: Unknown

===References===

<references/>

Copyright: This media file is in the public domain in the United States. This applies to U.S. works where the copyright has expired, often because its first publication occurred prior to January 1, 1923.

{{Template:2011 Student Image}}.

2011 Group Project 4

2011-10-12T04:28:11Z

Z3389806: /* Related Links */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an [[#Autosomal dominant|autosomal-dominant]] disorder caused by a faulty gene on the 4th autosomal chromosome (hence it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 [[#Exon|exons]] and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, [[#Dendrite|dendrites]] and nerve terminals and is also associated with cellular organelles such as golgi apparatus, [[#Endoplasmic reticulum|endoplasmic reticulum]] and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia). <ref name="PMID15459747"/>

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in [[#Dendrite|dendrites]], signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in [[#Endocytosis|endocytosis]], [[#Neuronal|neuronal]] transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from [[#Apoptosis|apoptotic]] stress, hence having pro-survival role in neural tissue.

* A recent study has showb that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause [[#Neurodegeneration|neurodegeneration]]. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Comparison between healthy huntingtin gene and huntingtin gene in Huntington's disease]]

Huntington Disease - caused by a mutation on the 1st [[#Exon|exon]] of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="PMID15459747"/>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the [[#Neurodegeneration|neurodegeneration]] and serious loss of cognitive abilities has not yet been fully understood.
There are key pathological mechanisms that has been used to explain the pathways by which a mutation [[File:Regions of the brain.jpg|right|thumb|245px|Regions of the brain]] in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also less significantly located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of [[#Gamma-aminobutyric acid (GABA)| gamma-aminobutyric acid (GABA)]], which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for [[#Glutamatergic|glutamatergic]] output from the afferant neurons of thalamus and the cortex, making striatal cells highly sensitive to [[#Glutamate|glutamate]]. Even though striatal cells depend on [[#Glutamate|glutamate]] for function and survival, [[#Glutamate|glutamate]] in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an [[#Excitotoxin|excitotoxin]]. [[#Neurodegeneration|Neurodegeneration]] and excitotoxicity is therefore inducible by directly injecting [[#Glutamate|glutamate]] into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb its key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.
[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. The misshapen proteins are labeled by antibodies and targeted by [[#Proteasome|proteasomes]] in the cytoplasm for degradation.<ref name="MM"/> However [[#Proteasome|proteasome]] efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the [[#Protease|proteases]] become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref> Toxicity can also arise when the polyglutamine domain of mutant HTT attracts and binds to other cytoplasmic and nuclear structures that contain polyglutamine. By forming aggregates with these structures, they are able to inhibit their physiological function within the neural cells and cause further cellular dysfunction and induce [[#Apoptosis|apoptosis]]. The implication of [[#Proteasome|proteasome]] in HD is further consolidated when [[#Proteasome|proteasome]] inhibitors are administered in animal models of HD, that have lead to more rapid and increasing number of aggregates.

Proteosomal enzymes are capable of breaking down polyglutamine flanking sequences but not the polyglutamine tract itself. Mutant HTT protein is cleaved by a different number of [[#Protease|proteases]] such as caspases and calcium-dependent [[#Protease|proteases]] such as calpain. The proteolytic activity of these enzymes leads to the formation of shorter polyglutamine peptides that are even more toxic and are capable of inducing neuronal death. <ref><pubmed>12223539</pubmed></ref> <ref name="MM"/>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and [[#Neurotrophic factor|neurotrophic factor]]. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIP1, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and [[#Apoptosis|apoptotic]] cell death by impairing [[#Proteasome|proteasome]] activity and interfering with calcium signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the [[#Endoplasmic reticulum|endoplasmic reticulum]] and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and [[#Apoptosis|apoptosis]]-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="PMID15459747"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neurotophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neurotrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. [[#Chorionic villus sampling|Chorionic villus sampling]] can be carried out between the 10th and 12th week of pregnancy whereas [[#Amniocentesis|amniocentesis]] is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Related Links==

* [[Molecular Development]] - this page gives an explanation of the dominant inheritance nature of HD.
* [[Prenatal Diagnosis]] - this page relates to the ethics and consequences of prenatal testing for Huntington's disease (HD).
* [[Amniocentesis]] - More information about this procedure of prenatal testing for HD can be found here.
* [[Chorionic villus sampling]] - More information about this procedure of prenatal testing for HD can be found here.
* [[Computed Tomography]] - More information about this procedure of prenatal testing for HD can be found here.

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Amniocentesis"></div>'''Amniocentesis:''' A medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections by taking a sample of the amniotic fluid. The fluid is then analysed to observe for any abmornalities.

<div id="Antibody"></div>'''Antibody:''' Any of a large number of proteins of high molecular weight that are produced normally after stimulation by an antigen.

<div id="Apoptosis"></div>'''Apoptosis:'''The programmed death of some of an organism's cells as part of its natural growth and development. Also called programmed cell death.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Chorionic villus sampling"></div>'''Chorionic villus sampling:''' A form of prenatal diagnosis to determine chromosomal orgenetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dendrite"></div>'''Dendrite:''' any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Endocytosis"></div>'''Endocytosis:''' Incorporation of substances into a cell by phagocytosis or pinocytosis.

<div id="Endoplasmic reticulum"></div>'''Endoplasmic reticulum:''' Any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Excitotoxin"></div>'''Excitotoxin:''' class of substances that damage neurons.

<div id="Exon"></div>'''Exon:''' A polynucleotide sequence in a nucleic acid that codes information for protein synthesis and that is copied and spliced together with other such sequences to form messenger RNA.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Glutamate"></div>'''Glutamate:''' A salt of glutamic acid.

<div id="Glutamatergic"></div>'''Glutamatergic:''' Pertaining to the action of glutamate or to neural or metabolic pathways in which it functions as a transmitter.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Neurodogeneration"></div>'''Neurodegeneration:''' Selective degeneration of neurons.

<div id="Neurotrophic factor"></div>'''Neurotrophic factor:''' A generic term for any of a family of substances with roles in maintenance and survival of neurons.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Protease"></div>'''Protease:''' Any of various enzymes, including the endopeptidases and exopeptidases, that catalyse the hydrolytic breakdown of proteins into peptides or amino acids.

<div id="Proteasome"></div>'''Proteasome:''' A protein degradation "machine" within the cell that can digest a variety of proteins into short polypeptides and amino acids.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length [[#Polymorphisms|polymorphisms]] (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-12T04:15:21Z

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{{2011ProjectsMH}}

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=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an [[#Autosomal dominant|autosomal-dominant]] disorder caused by a faulty gene on the 4th autosomal chromosome (hence it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 [[#Exon|exons]] and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, [[#Dendrite|dendrites]] and nerve terminals and is also associated with cellular organelles such as golgi apparatus, [[#Endoplasmic reticulum|endoplasmic reticulum]] and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia). <ref name="PMID15459747"/>

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in [[#Dendrite|dendrites]], signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in [[#Endocytosis|endocytosis]], [[#Neuronal|neuronal]] transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from [[#Apoptosis|apoptotic]] stress, hence having pro-survival role in neural tissue.

* A recent study has showb that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause [[#Neurodegeneration|neurodegeneration]]. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Comparison between healthy huntingtin gene and huntingtin gene in Huntington's disease]]

Huntington Disease - caused by a mutation on the 1st [[#Exon|exon]] of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="PMID15459747"/>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the [[#Neurodegeneration|neurodegeneration]] and serious loss of cognitive abilities has not yet been fully understood.
There are key pathological mechanisms that has been used to explain the pathways by which a mutation [[File:Regions of the brain.jpg|right|thumb|245px|Regions of the brain]] in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also less significantly located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of [[#Gamma-aminobutyric acid (GABA)| gamma-aminobutyric acid (GABA)]], which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for [[#Glutamatergic|glutamatergic]] output from the afferant neurons of thalamus and the cortex, making striatal cells highly sensitive to [[#Glutamate|glutamate]]. Even though striatal cells depend on [[#Glutamate|glutamate]] for function and survival, [[#Glutamate|glutamate]] in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an [[#Excitotoxin|excitotoxin]]. [[#Neurodegeneration|Neurodegeneration]] and excitotoxicity is therefore inducible by directly injecting [[#Glutamate|glutamate]] into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb its key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.
[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. The misshapen proteins are labeled by antibodies and targeted by [[#Proteasome|proteasomes]] in the cytoplasm for degradation.<ref name="MM"/> However [[#Proteasome|proteasome]] efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the [[#Protease|proteases]] become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref> Toxicity can also arise when the polyglutamine domain of mutant HTT attracts and binds to other cytoplasmic and nuclear structures that contain polyglutamine. By forming aggregates with these structures, they are able to inhibit their physiological function within the neural cells and cause further cellular dysfunction and induce [[#Apoptosis|apoptosis]]. The implication of [[#Proteasome|proteasome]] in HD is further consolidated when [[#Proteasome|proteasome]] inhibitors are administered in animal models of HD, that have lead to more rapid and increasing number of aggregates.

Proteosomal enzymes are capable of breaking down polyglutamine flanking sequences but not the polyglutamine tract itself. Mutant HTT protein is cleaved by a different number of [[#Protease|proteases]] such as caspases and calcium-dependent [[#Protease|proteases]] such as calpain. The proteolytic activity of these enzymes leads to the formation of shorter polyglutamine peptides that are even more toxic and are capable of inducing neuronal death. <ref><pubmed>12223539</pubmed></ref> <ref name="MM"/>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and [[#Neurotrophic factor|neurotrophic factor]]. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIP1, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and [[#Apoptosis|apoptotic]] cell death by impairing [[#Proteasome|proteasome]] activity and interfering with calcium signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the [[#Endoplasmic reticulum|endoplasmic reticulum]] and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and [[#Apoptosis|apoptosis]]-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="PMID15459747"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neurotophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neurotrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. [[#Chorionic villus sampling|Chorionic villus sampling]] can be carried out between the 10th and 12th week of pregnancy whereas [[#Amniocentesis|amniocentesis]] is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Related Links==

* [[Prenatal Diagnosis]] - this page relates to the ethics and consequences of prenatal testing for Huntington's disease (HD).
* [[Molecular Development]] - this page gives an explanation of the dominant inheritance nature of HD.

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Amniocentesis"></div>'''Amniocentesis:''' A medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections by taking a sample of the amniotic fluid. The fluid is then analysed to observe for any abmornalities.

<div id="Antibody"></div>'''Antibody:''' Any of a large number of proteins of high molecular weight that are produced normally after stimulation by an antigen.

<div id="Apoptosis"></div>'''Apoptosis:'''The programmed death of some of an organism's cells as part of its natural growth and development. Also called programmed cell death.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Chorionic villus sampling"></div>'''Chorionic villus sampling:''' A form of prenatal diagnosis to determine chromosomal orgenetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dendrite"></div>'''Dendrite:''' any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Endocytosis"></div>'''Endocytosis:''' Incorporation of substances into a cell by phagocytosis or pinocytosis.

<div id="Endoplasmic reticulum"></div>'''Endoplasmic reticulum:''' Any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Excitotoxin"></div>'''Excitotoxin:''' class of substances that damage neurons.

<div id="Exon"></div>'''Exon:''' A polynucleotide sequence in a nucleic acid that codes information for protein synthesis and that is copied and spliced together with other such sequences to form messenger RNA.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Glutamate"></div>'''Glutamate:''' A salt of glutamic acid.

<div id="Glutamatergic"></div>'''Glutamatergic:''' Pertaining to the action of glutamate or to neural or metabolic pathways in which it functions as a transmitter.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Neurodogeneration"></div>'''Neurodegeneration:''' Selective degeneration of neurons.

<div id="Neurotrophic factor"></div>'''Neurotrophic factor:''' A generic term for any of a family of substances with roles in maintenance and survival of neurons.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Protease"></div>'''Protease:''' Any of various enzymes, including the endopeptidases and exopeptidases, that catalyse the hydrolytic breakdown of proteins into peptides or amino acids.

<div id="Proteasome"></div>'''Proteasome:''' A protein degradation "machine" within the cell that can digest a variety of proteins into short polypeptides and amino acids.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length [[#Polymorphisms|polymorphisms]] (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

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{{2011Projects}}

2011 Group Project 4

2011-10-12T04:05:47Z

Z3389806: /* Current/Future Research */

{{2011ProjectsMH}}

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=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an [[#Autosomal dominant|autosomal-dominant]] disorder caused by a faulty gene on the 4th autosomal chromosome (hence it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 [[#Exon|exons]] and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, [[#Dendrite|dendrites]] and nerve terminals and is also associated with cellular organelles such as golgi apparatus, [[#Endoplasmic reticulum|endoplasmic reticulum]] and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia). <ref name="PMID15459747"/>

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in [[#Dendrite|dendrites]], signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in [[#Endocytosis|endocytosis]], [[#Neuronal|neuronal]] transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from [[#Apoptosis|apoptotic]] stress, hence having pro-survival role in neural tissue.

* A recent study has showb that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause [[#Neurodegeneration|neurodegeneration]]. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Comparison between healthy huntingtin gene and huntingtin gene in Huntington's disease]]

Huntington Disease - caused by a mutation on the 1st [[#Exon|exon]] of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="PMID15459747"/>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the [[#Neurodegeneration|neurodegeneration]] and serious loss of cognitive abilities has not yet been fully understood.
There are key pathological mechanisms that has been used to explain the pathways by which a mutation [[File:Regions of the brain.jpg|right|thumb|245px|Regions of the brain]] in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also less significantly located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of [[#Gamma-aminobutyric acid (GABA)| gamma-aminobutyric acid (GABA)]], which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for [[#Glutamatergic|glutamatergic]] output from the afferant neurons of thalamus and the cortex, making striatal cells highly sensitive to [[#Glutamate|glutamate]]. Even though striatal cells depend on [[#Glutamate|glutamate]] for function and survival, [[#Glutamate|glutamate]] in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an [[#Excitotoxin|excitotoxin]]. [[#Neurodegeneration|Neurodegeneration]] and excitotoxicity is therefore inducible by directly injecting [[#Glutamate|glutamate]] into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb its key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.
[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. The misshapen proteins are labeled by antibodies and targeted by [[#Proteasome|proteasomes]] in the cytoplasm for degradation.<ref name="MM"/> However [[#Proteasome|proteasome]] efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the [[#Protease|proteases]] become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref> Toxicity can also arise when the polyglutamine domain of mutant HTT attracts and binds to other cytoplasmic and nuclear structures that contain polyglutamine. By forming aggregates with these structures, they are able to inhibit their physiological function within the neural cells and cause further cellular dysfunction and induce [[#Apoptosis|apoptosis]]. The implication of [[#Proteasome|proteasome]] in HD is further consolidated when [[#Proteasome|proteasome]] inhibitors are administered in animal models of HD, that have lead to more rapid and increasing number of aggregates.

Proteosomal enzymes are capable of breaking down polyglutamine flanking sequences but not the polyglutamine tract itself. Mutant HTT protein is cleaved by a different number of [[#Protease|proteases]] such as caspases and calcium-dependent [[#Protease|proteases]] such as calpain. The proteolytic activity of these enzymes leads to the formation of shorter polyglutamine peptides that are even more toxic and are capable of inducing neuronal death. <ref><pubmed>12223539</pubmed></ref> <ref name="MM"/>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and [[#Neurotrophic factor|neurotrophic factor]]. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIP1, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and [[#Apoptosis|apoptotic]] cell death by impairing [[#Proteasome|proteasome]] activity and interfering with calcium signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the [[#Endoplasmic reticulum|endoplasmic reticulum]] and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and [[#Apoptosis|apoptosis]]-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="PMID15459747"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neurotophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neurotrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. [[#Chorionic villus sampling|Chorionic villus sampling]] can be carried out between the 10th and 12th week of pregnancy whereas [[#Amniocentesis|amniocentesis]] is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Related Links==

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Amniocentesis"></div>'''Amniocentesis:''' A medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections by taking a sample of the amniotic fluid. The fluid is then analysed to observe for any abmornalities.

<div id="Antibody"></div>'''Antibody:''' Any of a large number of proteins of high molecular weight that are produced normally after stimulation by an antigen.

<div id="Apoptosis"></div>'''Apoptosis:'''The programmed death of some of an organism's cells as part of its natural growth and development. Also called programmed cell death.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Chorionic villus sampling"></div>'''Chorionic villus sampling:''' A form of prenatal diagnosis to determine chromosomal orgenetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dendrite"></div>'''Dendrite:''' any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Endocytosis"></div>'''Endocytosis:''' Incorporation of substances into a cell by phagocytosis or pinocytosis.

<div id="Endoplasmic reticulum"></div>'''Endoplasmic reticulum:''' Any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Excitotoxin"></div>'''Excitotoxin:''' class of substances that damage neurons.

<div id="Exon"></div>'''Exon:''' A polynucleotide sequence in a nucleic acid that codes information for protein synthesis and that is copied and spliced together with other such sequences to form messenger RNA.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Glutamate"></div>'''Glutamate:''' A salt of glutamic acid.

<div id="Glutamatergic"></div>'''Glutamatergic:''' Pertaining to the action of glutamate or to neural or metabolic pathways in which it functions as a transmitter.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Neurodogeneration"></div>'''Neurodegeneration:''' Selective degeneration of neurons.

<div id="Neurotrophic factor"></div>'''Neurotrophic factor:''' A generic term for any of a family of substances with roles in maintenance and survival of neurons.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Protease"></div>'''Protease:''' Any of various enzymes, including the endopeptidases and exopeptidases, that catalyse the hydrolytic breakdown of proteins into peptides or amino acids.

<div id="Proteasome"></div>'''Proteasome:''' A protein degradation "machine" within the cell that can digest a variety of proteins into short polypeptides and amino acids.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length [[#Polymorphisms|polymorphisms]] (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-12T04:02:13Z

Z3389806: /* Current/Future Research */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an [[#Autosomal dominant|autosomal-dominant]] disorder caused by a faulty gene on the 4th autosomal chromosome (hence it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 [[#Exon|exons]] and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, [[#Dendrite|dendrites]] and nerve terminals and is also associated with cellular organelles such as golgi apparatus, [[#Endoplasmic reticulum|endoplasmic reticulum]] and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia). <ref name="PMID15459747"/>

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in [[#Dendrite|dendrites]], signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in [[#Endocytosis|endocytosis]], [[#Neuronal|neuronal]] transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from [[#Apoptosis|apoptotic]] stress, hence having pro-survival role in neural tissue.

* A recent study has showb that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause [[#Neurodegeneration|neurodegeneration]]. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Comparison between healthy huntingtin gene and huntingtin gene in Huntington's disease]]

Huntington Disease - caused by a mutation on the 1st [[#Exon|exon]] of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="PMID15459747"/>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the [[#Neurodegeneration|neurodegeneration]] and serious loss of cognitive abilities has not yet been fully understood.
There are key pathological mechanisms that has been used to explain the pathways by which a mutation [[File:Regions of the brain.jpg|right|thumb|245px|Regions of the brain]] in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also less significantly located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of [[#Gamma-aminobutyric acid (GABA)| gamma-aminobutyric acid (GABA)]], which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for [[#Glutamatergic|glutamatergic]] output from the afferant neurons of thalamus and the cortex, making striatal cells highly sensitive to [[#Glutamate|glutamate]]. Even though striatal cells depend on [[#Glutamate|glutamate]] for function and survival, [[#Glutamate|glutamate]] in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an [[#Excitotoxin|excitotoxin]]. [[#Neurodegeneration|Neurodegeneration]] and excitotoxicity is therefore inducible by directly injecting [[#Glutamate|glutamate]] into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb its key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.
[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. The misshapen proteins are labeled by antibodies and targeted by [[#Proteasome|proteasomes]] in the cytoplasm for degradation.<ref name="MM"/> However [[#Proteasome|proteasome]] efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the [[#Protease|proteases]] become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref> Toxicity can also arise when the polyglutamine domain of mutant HTT attracts and binds to other cytoplasmic and nuclear structures that contain polyglutamine. By forming aggregates with these structures, they are able to inhibit their physiological function within the neural cells and cause further cellular dysfunction and induce [[#Apoptosis|apoptosis]]. The implication of [[#Proteasome|proteasome]] in HD is further consolidated when [[#Proteasome|proteasome]] inhibitors are administered in animal models of HD, that have lead to more rapid and increasing number of aggregates.

Proteosomal enzymes are capable of breaking down polyglutamine flanking sequences but not the polyglutamine tract itself. Mutant HTT protein is cleaved by a different number of [[#Protease|proteases]] such as caspases and calcium-dependent [[#Protease|proteases]] such as calpain. The proteolytic activity of these enzymes leads to the formation of shorter polyglutamine peptides that are even more toxic and are capable of inducing neuronal death. <ref><pubmed>12223539</pubmed></ref> <ref name="MM"/>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and [[#Neurotrophic factor|neurotrophic factor]]. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIP1, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and [[#Apoptosis|apoptotic]] cell death by impairing [[#Proteasome|proteasome]] activity and interfering with calcium signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the [[#Endoplasmic reticulum|endoplasmic reticulum]] and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and [[#Apoptosis|apoptosis]]-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="PMID15459747"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neurotophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neurotrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. [[#Chorionic villus sampling|Chorionic villus sampling]] can be carried out between the 10th and 12th week of pregnancy whereas [[#Amniocentesis|amniocentesis]] is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Related Links==

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Amniocentesis"></div>'''Amniocentesis:''' A medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections by taking a sample of the amniotic fluid. The fluid is then analysed to observe for any abmornalities.

<div id="Antibody"></div>'''Antibody:''' Any of a large number of proteins of high molecular weight that are produced normally after stimulation by an antigen.

<div id="Apoptosis"></div>'''Apoptosis:'''The programmed death of some of an organism's cells as part of its natural growth and development. Also called programmed cell death.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Chorionic villus sampling"></div>'''Chorionic villus sampling:''' A form of prenatal diagnosis to determine chromosomal orgenetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dendrite"></div>'''Dendrite:''' any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Endocytosis"></div>'''Endocytosis:''' Incorporation of substances into a cell by phagocytosis or pinocytosis.

<div id="Endoplasmic reticulum"></div>'''Endoplasmic reticulum:''' Any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Excitotoxin"></div>'''Excitotoxin:''' class of substances that damage neurons.

<div id="Exon"></div>'''Exon:''' A polynucleotide sequence in a nucleic acid that codes information for protein synthesis and that is copied and spliced together with other such sequences to form messenger RNA.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Glutamate"></div>'''Glutamate:''' A salt of glutamic acid.

<div id="Glutamatergic"></div>'''Glutamatergic:''' Pertaining to the action of glutamate or to neural or metabolic pathways in which it functions as a transmitter.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Neurodogeneration"></div>'''Neurodegeneration:''' Selective degeneration of neurons.

<div id="Neurotrophic factor"></div>'''Neurotrophic factor:''' A generic term for any of a family of substances with roles in maintenance and survival of neurons.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Protease"></div>'''Protease:''' Any of various enzymes, including the endopeptidases and exopeptidases, that catalyse the hydrolytic breakdown of proteins into peptides or amino acids.

<div id="Proteasome"></div>'''Proteasome:''' A protein degradation "machine" within the cell that can digest a variety of proteins into short polypeptides and amino acids.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length [[#Polymorphisms|polymorphisms]] (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-12T03:38:34Z

Z3389806: /* Role in transcription inhibition */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an [[#Autosomal dominant|autosomal-dominant]] disorder caused by a faulty gene on the 4th autosomal chromosome (hence it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 [[#Exon|exons]] and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, [[#Dendrite|dendrites]] and nerve terminals and is also associated with cellular organelles such as golgi apparatus, [[#Endoplasmic reticulum|endoplasmic reticulum]] and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia). <ref name="PMID15459747"/>

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in [[#Dendrite|dendrites]], signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in [[#Endocytosis|endocytosis]], [[#Neuronal|neuronal]] transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from [[#Apoptosis|apoptotic]] stress, hence having pro-survival role in neural tissue.

* A recent study has showb that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause [[#Neurodegeneration|neurodegeneration]]. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Comparison between healthy huntingtin gene and huntingtin gene in Huntington's disease]]

Huntington Disease - caused by a mutation on the 1st [[#Exon|exon]] of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="PMID15459747"/>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the [[#Neurodegeneration|neurodegeneration]] and serious loss of cognitive abilities has not yet been fully understood.
There are key pathological mechanisms that has been used to explain the pathways by which a mutation [[File:Regions of the brain.jpg|right|thumb|245px|Regions of the brain]] in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also less significantly located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of [[#Gamma-aminobutyric acid (GABA)| gamma-aminobutyric acid (GABA)]], which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for [[#Glutamatergic|glutamatergic]] output from the afferant neurons of thalamus and the cortex, making striatal cells highly sensitive to [[#Glutamate|glutamate]]. Even though striatal cells depend on [[#Glutamate|glutamate]] for function and survival, [[#Glutamate|glutamate]] in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an [[#Excitotoxin|excitotoxin]]. [[#Neurodegeneration|Neurodegeneration]] and excitotoxicity is therefore inducible by directly injecting [[#Glutamate|glutamate]] into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb its key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.
[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. The misshapen proteins are labeled by antibodies and targeted by [[#Proteasome|proteasomes]] in the cytoplasm for degradation.<ref name="MM"/> However [[#Proteasome|proteasome]] efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the [[#Protease|proteases]] become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref> Toxicity can also arise when the polyglutamine domain of mutant HTT attracts and binds to other cytoplasmic and nuclear structures that contain polyglutamine. By forming aggregates with these structures, they are able to inhibit their physiological function within the neural cells and cause further cellular dysfunction and induce [[#Apoptosis|apoptosis]]. The implication of [[#Proteasome|proteasome]] in HD is further consolidated when [[#Proteasome|proteasome]] inhibitors are administered in animal models of HD, that have lead to more rapid and increasing number of aggregates.

Proteosomal enzymes are capable of breaking down polyglutamine flanking sequences but not the polyglutamine tract itself. Mutant HTT protein is cleaved by a different number of [[#Protease|proteases]] such as caspases and calcium-dependent [[#Protease|proteases]] such as calpain. The proteolytic activity of these enzymes leads to the formation of shorter polyglutamine peptides that are even more toxic and are capable of inducing neuronal death. <ref><pubmed>12223539</pubmed></ref> <ref name="MM"/>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and [[#Neurotrophic factor|neurotrophic factor]]. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIP1, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and [[#Apoptosis|apoptotic]] cell death by impairing [[#Proteasome|proteasome]] activity and interfering with calcium signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the [[#Endoplasmic reticulum|endoplasmic reticulum]] and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and [[#Apoptosis|apoptosis]]-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="PMID15459747"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neurotophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neurotrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. [[#Chorionic villus sampling|Chorionic villus sampling]] can be carried out between the 10th and 12th week of pregnancy whereas [[#Amniocentesis|amniocentesis]] is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Amniocentesis"></div>'''Amniocentesis:''' A medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections by taking a sample of the amniotic fluid. The fluid is then analysed to observe for any abmornalities.

<div id="Antibody"></div>'''Antibody:''' Any of a large number of proteins of high molecular weight that are produced normally after stimulation by an antigen.

<div id="Apoptosis"></div>'''Apoptosis:'''The programmed death of some of an organism's cells as part of its natural growth and development. Also called programmed cell death.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Chorionic villus sampling"></div>'''Chorionic villus sampling:''' A form of prenatal diagnosis to determine chromosomal orgenetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dendrite"></div>'''Dendrite:''' any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Endocytosis"></div>'''Endocytosis:''' Incorporation of substances into a cell by phagocytosis or pinocytosis.

<div id="Endoplasmic reticulum"></div>'''Endoplasmic reticulum:''' Any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Excitotoxin"></div>'''Excitotoxin:''' class of substances that damage neurons.

<div id="Exon"></div>'''Exon:''' A polynucleotide sequence in a nucleic acid that codes information for protein synthesis and that is copied and spliced together with other such sequences to form messenger RNA.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Glutamate"></div>'''Glutamate:''' A salt of glutamic acid.

<div id="Glutamatergic"></div>'''Glutamatergic:''' Pertaining to the action of glutamate or to neural or metabolic pathways in which it functions as a transmitter.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Neurodogeneration"></div>'''Neurodegeneration:''' Selective degeneration of neurons.

<div id="Neurotrophic factor"></div>'''Neurotrophic factor:''' A generic term for any of a family of substances with roles in maintenance and survival of neurons.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Protease"></div>'''Protease:''' Any of various enzymes, including the endopeptidases and exopeptidases, that catalyse the hydrolytic breakdown of proteins into peptides or amino acids.

<div id="Proteasome"></div>'''Proteasome:''' A protein degradation "machine" within the cell that can digest a variety of proteins into short polypeptides and amino acids.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length [[#Polymorphisms|polymorphisms]] (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-12T03:35:17Z

Z3389806: /* Huntingtin Gene */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an [[#Autosomal dominant|autosomal-dominant]] disorder caused by a faulty gene on the 4th autosomal chromosome (hence it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 [[#Exon|exons]] and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, [[#Dendrite|dendrites]] and nerve terminals and is also associated with cellular organelles such as golgi apparatus, [[#Endoplasmic reticulum|endoplasmic reticulum]] and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia). <ref name="PMID15459747"/>

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in [[#Dendrite|dendrites]], signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in [[#Endocytosis|endocytosis]], [[#Neuronal|neuronal]] transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from [[#Apoptosis|apoptotic]] stress, hence having pro-survival role in neural tissue.

* A recent study has showb that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause [[#Neurodegeneration|neurodegeneration]]. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Comparison between healthy huntingtin gene and huntingtin gene in Huntington's disease]]

Huntington Disease - caused by a mutation on the 1st [[#Exon|exon]] of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="PMID15459747"/>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the [[#Neurodegeneration|neurodegeneration]] and serious loss of cognitive abilities has not yet been fully understood.
There are key pathological mechanisms that has been used to explain the pathways by which a mutation [[File:Regions of the brain.jpg|right|thumb|245px|Regions of the brain]] in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also less significantly located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of [[#Gamma-aminobutyric acid (GABA)| gamma-aminobutyric acid (GABA)]], which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for [[#Glutamatergic|glutamatergic]] output from the afferant neurons of thalamus and the cortex, making striatal cells highly sensitive to [[#Glutamate|glutamate]]. Even though striatal cells depend on [[#Glutamate|glutamate]] for function and survival, [[#Glutamate|glutamate]] in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an [[#Excitotoxin|excitotoxin]]. [[#Neurodegeneration|Neurodegeneration]] and excitotoxicity is therefore inducible by directly injecting [[#Glutamate|glutamate]] into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb its key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.
[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. The misshapen proteins are labeled by antibodies and targeted by [[#Proteasome|proteasomes]] in the cytoplasm for degradation.<ref name="MM"/> However [[#Proteasome|proteasome]] efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the [[#Protease|proteases]] become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref> Toxicity can also arise when the polyglutamine domain of mutant HTT attracts and binds to other cytoplasmic and nuclear structures that contain polyglutamine. By forming aggregates with these structures, they are able to inhibit their physiological function within the neural cells and cause further cellular dysfunction and induce [[#Apoptosis|apoptosis]]. The implication of [[#Proteasome|proteasome]] in HD is further consolidated when [[#Proteasome|proteasome]] inhibitors are administered in animal models of HD, that have lead to more rapid and increasing number of aggregates.

Proteosomal enzymes are capable of breaking down polyglutamine flanking sequences but not the polyglutamine tract itself. Mutant HTT protein is cleaved by a different number of [[#Protease|proteases]] such as caspases and calcium-dependent [[#Protease|proteases]] such as calpain. The proteolytic activity of these enzymes leads to the formation of shorter polyglutamine peptides that are even more toxic and are capable of inducing neuronal death. <ref><pubmed>12223539</pubmed></ref> <ref name="MM"/>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and [[#Neurotrophic factor|neurotrophic factor]]. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIP1, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and [[#Apoptosis|apoptotic]] cell death by impairing [[#Proteasome|proteasome]] activity and interfering with calcium signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the [[#Endoplasmic reticulum|endoplasmic reticulum]] and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and [[#Apoptosis|apoptosis]]-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neurotophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neurotrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. [[#Chorionic villus sampling|Chorionic villus sampling]] can be carried out between the 10th and 12th week of pregnancy whereas [[#Amniocentesis|amniocentesis]] is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Amniocentesis"></div>'''Amniocentesis:''' A medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections by taking a sample of the amniotic fluid. The fluid is then analysed to observe for any abmornalities.

<div id="Antibody"></div>'''Antibody:''' Any of a large number of proteins of high molecular weight that are produced normally after stimulation by an antigen.

<div id="Apoptosis"></div>'''Apoptosis:'''The programmed death of some of an organism's cells as part of its natural growth and development. Also called programmed cell death.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Chorionic villus sampling"></div>'''Chorionic villus sampling:''' A form of prenatal diagnosis to determine chromosomal orgenetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dendrite"></div>'''Dendrite:''' any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Endocytosis"></div>'''Endocytosis:''' Incorporation of substances into a cell by phagocytosis or pinocytosis.

<div id="Endoplasmic reticulum"></div>'''Endoplasmic reticulum:''' Any of the usually branching protoplasmic processes that conduct impulses toward the body of a nerve cell.

<div id="Excitotoxin"></div>'''Excitotoxin:''' class of substances that damage neurons.

<div id="Exon"></div>'''Exon:''' A polynucleotide sequence in a nucleic acid that codes information for protein synthesis and that is copied and spliced together with other such sequences to form messenger RNA.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Glutamate"></div>'''Glutamate:''' A salt of glutamic acid.

<div id="Glutamatergic"></div>'''Glutamatergic:''' Pertaining to the action of glutamate or to neural or metabolic pathways in which it functions as a transmitter.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Neurodogeneration"></div>'''Neurodegeneration:''' Selective degeneration of neurons.

<div id="Neurotrophic factor"></div>'''Neurotrophic factor:''' A generic term for any of a family of substances with roles in maintenance and survival of neurons.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Protease"></div>'''Protease:''' Any of various enzymes, including the endopeptidases and exopeptidases, that catalyse the hydrolytic breakdown of proteins into peptides or amino acids.

<div id="Proteasome"></div>'''Proteasome:''' A protein degradation "machine" within the cell that can digest a variety of proteins into short polypeptides and amino acids.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length [[#Polymorphisms|polymorphisms]] (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

Talk:2011 Group Project 4

2011-10-09T01:14:42Z

Z3389806:

[[2011_Group_Project_4|'''Group 4''']]: [[User:z3389806]] | [[User:z3290270]] | [[User:z3290379]] | [[User:z3290558]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_4_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_4_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

== Post-Peer review discussion ==

Hey girls, I've done the linkage for the glossary. So if you wanna add new words to the glossary, refer to the words that are already linked for the format kay? If you aren't able to do it, do tell me and i will fix it up. Have a great weekend! :)
--Nur Sharalyn Abdullah 12:14, 9 October 2011 (EST)

Yup, I've fixed the references all up (:
--Nur Sharalyn Abdullah 13:15, 7 October 2011 (EST)

Hey guys, good job on the intro image I really like it. Also, Nur are you still okay with fixing the references? :)
--[[User:Z3290270|Maeda Sadeghpour]] 00:20, 2 October 2011 (EST)

Hey guys, I made our facebook page public because Mark said he needs to be able to access the page to show that we have had substantial discussion amongst the group.
--[[User:Z3290270|Maeda Sadeghpour]] 11:19, 6 October 2011 (EST)

Also, Mark said we can delete the comments he made on the page from previous weeks so that's gone.

--[[User:Z3290270|Maeda Sadeghpour]] 11:20, 6 October 2011 (EST)

==Peer Review==

Group 4:
Truly amazing work on this page. The balance between the images and text is phenomenal. It seems quite simple but easy to read well referenced.
I like how you used tables to illustrate the epidemiology
Nicely drawn images in Genetics Section.
I really don’t see many things wrong with the page… It is well done.. the tables and images all speak up for the quality of the page. However, pay closer attention to the references because some of them are repeated or empty when you look at the list.
Great work.
--[[User:Z3284061|z3284061]] 11:55, 29 September 2011 (EST)

'''Group 4'''

* Overall the project is good
* An image could be good in the introduction
* History and Timeline are good
* In the History section it might be useful to have the years in bold
* Well researched
* Image for "Role in Transciption inhibition" needs to be fixed
* Good table in treatment
* Image in Pathogenesis needs copyright info
* Good use of text/tables/images
--[[User:Z3292953|z3292953]] 11:10, 29 September 2011 (EST)

'''''Huntington’s Disease (Group 4) Peer Review:'''''

Introduction: Good content. Possibly include a picture to get the reader interested from the beginning.

History: Great section! Many references which shows you have done your research. Possibly make the dates bold so that they stand out more. Good use of quote. Image needs to be referenced properly and lacks a student template.

Epidemiology: Extensive! Great use of tables and explanation of the tables! Well done.

Genetics: Great detail in this section. Images are well drawn and relevant to the information. Remember to include a student template in these images.

Molecular Mechanisms and Pathogenesis: Great use of subheadings to organize the text. Image is good, just try to format the reference better and once again, include the student template.

Clinical Manifestations: Image is slightly too small as a thumbnail. Good information, however, I think this section would benefit with a table to help better organize the information.

Diagnostic Tests: Very extensive section. Good use of images, however maybe their placement needs to be more thought out. Also, delete the subheading for the video as this is irrelevant. Great use of video- stimulates the viewer!

Treatment: Table is very extensive and well done. This section is impressive! Images need to have a student template and correct referencing.

Current/ Future Research: Good information in this section. Image on right needs a label at the bottom.

Glossary: Heading needs to be to the left – it is slightly distorted by the image above it.
Extensive glossary.

References: Well done, a lot of research has been done.

Overall, impressive page! --[[User:Z3290808|z3290808]] 10:43, 29 September 2011 (EST)

Huntingtons – Group 4

* This page looks very good and highly detailed. Some of the images do not have correct referencing information and could also contain a little more of a description.
* Excellent use of referencing. This seems highly detailed and looks like a lot of work has been done to get the page to this standard.
* Some formatting issues such as the image in future research and in diagnostic tests headings.
* Video of Huntington’s patient doesn’t need such a big heading, ruins the flow of the page in my opinion.
* Timeline could give a bit more information, and the importance of these events explained better.
* Overall was very good work of a high standard
--[[User:Z3288196|Z3288196]] 10:41, 29 September 2011 (EST)

Group 4:

Glossary and reference take up half the page because the glossary has terms which should probably be explained in the text instead of being an item in the glossary. The references section should also be checked, for example 56, 57,60, 69 all reference Zuccato, C, 2009. There is an excessive amount of references. Not every sentence needs to be referenced.

Title “video of Huntington’s disease patient” should probably go as a subheading not a heading coz then all of the information that should be refering to diagnostic test becomes a subheading of the video. But its a good idea to have the links to videos for extra information.

Apart from that, good assignment. Good use of pictures and written text. And tables.

z3332178 =]

Peer review:

*intro is a bit wordy e.g polyglutamate
*history: indent the quotes, maybe italcis too. timeline can be bolded to make it more readable.
*epidemiology: could have verbose words simplified and explained (the ones that are not in the glossary)
*genetics could have a picture about where the gene is located abnd also be simplified into tables.
*the picture in pathogenesis could have alot less writing or have it simplified, spaced and bolded.
*clinical manifestations is well written and succinct
*picture in diagnosis could be explained better so we can see the link to HD
*expand glossary and recheck the references
--[[User:Z3291423|Jasjit Walia]] 10:14, 29 September 2011 (EST)

'''Group 4 peer review'''

History: I love the idea of the quote. Is 'On Chorea' a book, article or report? Clarifying this would be nice.

Epidemiology: I like how you have elaborate on table one. I found the paragraph on Warby et al paper hard to understand. I think it may become easier to understand if you linked terminologies (like HTT and Halotypes) to the glossary, even if a particular terminology has been linked before in other sections because some readers might be just reading your section.

Clinical manifestations: It was an interesting read. :) But one suggestion ( this is what I got suggested for my section and I thought it was a good idea) is to enlarge the image so that the writing can be seen clearly. I understand that you may think that readers can click on it and see the enlarged picture but some readers may not be bothered and would prefer being able to read it on the main page. Plus, you have unlimited space and with a large image the webpage may look more interesting.

Treatment: In the clinical manifestation, the symptoms are divided into three classes: motor, cognitive and behaviour. It may be more consistant if you reorganise the classes of medication so that it falls into the three classes described in clinical manifestation. I know, this may sound like a huge task, if so, why don't you just ask the clinical manifestation person to change their classes to two, motor and psychiatric.

--[[User:Z3289301|z3289301]] 09:44, 29 September 2011 (EST)

'''Group 4 Peer Assessment'''
*Good introduction: concise and easy to understand. It might be a good idea to hyperlink some words in this section with the glossary.
*History and time line; well written and researched. I really like how you inserted one the original quotes in the text. I suggest you putting the timeline into a table so it looks better.
*Epidemiology; Good use of tables to summarize the figures/numbers. The placement of the tables between paragraphs also break up the text nicely.
*I strongly suggest hyperlinking words to the glossary. Makes the page more user friendly.
*Small typo in "Hungtingtin" title in the genetics section, but that's just a minor fix up. The section was well written. Good us of student drawn images to explain the concepts. I like how the genetics was sub-sectioned into the normal and diseased parts, makes it easier to understand.
*Other sections were also well done. Maybe include a table in the 'clinical manifestations' section. Also I'm not sure if this is beyond the scope of the course but have they been able to link the five specific features of this disease to specific genetic abnormalities or pathways that happens due to this disease? What causes these features? (This is just out of my curiosity).
*Maybe it would look neater if the "imaging" heading was also placed on the most left hand side of the page so it aligns with other headings such as 'neuropathy'. It seems a bit messy atm. Same goes for genetic testing and prenatal diagnosis.
*Excellent table in the treatment section. Is there a specific reason only the actions of 'Tetrabenazine' was explained below the table? if so, what are the reasons?
*Overall, good job :)
--[[User:Z3291622|z3291622]] 09:19, 29 September 2011 (EST)

'''Group 4 Peer evaluation'''

*The introduction is very informative and actually introduced most of the subheadings that will be discussed in the page. The downfall of this introduction is the failure to introduce all of the sections of and proof-reading this section it is fine.
*The history of the disease is very well-done. The quick description or beginning of the history combined with the timeline is utilised well. Only improvement that would make it better is making the dates stand out by putting it I bold or something.
*I can find no fault in the epidemiology. It is the best one I have seen so far. You have described the demography of the disease and the statistics of other mutations. The tables were used appropriately as well, and the fact that it was described straight after the table is perfect.
*I like the genetics section of the page. It made sense and easy to understand. The diagrams are all relevant to the page section. Only criticism I can say is the description of the gene could probably be organised in a much simpler or better fashion, like a table, rather than just one whole sentence. Also I don’t know if it is typo or if that’s how you actually spell it, but I would just like to mention “Huntingtin gene”.
*The pathogenesis section is very informative of the disease. Unfortunately it is very disjointed. One idea was introduced after the other and they did not really connect properly. I think as the reader I am looking for some sort of direction that leads Huntington’s, like a step by step thing.
*I am assuming that the clinical manifestation is not yet finished, so I won’t say anything else other than change the positioning of the image to the other side because it breaks the page and it does not aid in getting the information across to your readers.
*The diagnostic test is a bit of a disappointment. I’m pretty sure that since it is a genetic disease there is some form of genetic testing that doctors can use to diagnose the onset of the disease, unless the etiology is still under debate and not sure of, and from what I have read from your page so far it is pretty definite that mutation in a particular gene is already implicated in the disease. So I think this section could probably do a lot more research and work.
*The video… section of your page is pointless, why isn’t this in the diagnostic section?? I think synthesizing both section is needed, as this section alone is pointless.
*The really like the table in the treatment section it is a a very good summary. If you could add the actual effect of each drugs to the patient, it would make this table better than what it actually is. The tetrabenzaine part is a bit out of place. If you are elaborating on the entire active chemical ingredients, I believe this is a good idea.
*I like the current and future research section of the page, as it informs the reader that the page is current and well informed about the recent endeavors on the disease. The only let down is that there is not a single research on finding a cure for the disease or looking for other treatments, which I think is one of the most popular topic on this disease. If you could add this in this section it would make this area much better. You could even add it in the treatment section.
*Not really a big fan of the glossary, but it is good idea anyway.
--[[User:Z3290841|z3290841]] 10:23, 29 September 2011 (EST)

Group 4

*Very clear introduction, seems well researched and easy to understand
*History – good structure, my only suggestion is to put the timeline into a table and to highlight or bold the years mentioned, it’d look sweet as then.
*I like the tables in epidemiology, same colour structure could be used for the timeline under history maybe?
*Genetics – quite possibly the best heading on this page, I’m sure other people have mentioned this but ‘Huntington Gene’ the sub-heading is spelt wrong. Great incorporation of the student drawn image, this heading is very clear and easy to follow.
*Image under ‘Molecular Mechanisms & Pathogenesis’ is a bit big in my opinion, maybe consider reformatting it so the text is not broken up so suddenly.
*Image under ‘Clinical Manifestations’ could be better placed on the right hand side of the page so that there is continuity on the page, same with the other images under ‘Video of Huntington's disease patient’ and ‘Treatment’ and ‘Current/Future Research’
*Overall a well detailed page that is easy to understand and clear in its aims.

--[[User:Z3331469|z3331469]] 06:59, 29 September 2011 (EST)

'''Group 4 Peer Review'''

• Great sub-heading structure, and the overall flow of the page is neat. Although, it would appear more orderly if all images were on
the right hand side of the page, in alignment with the text (it looks messy otherwise).

• The introduction is very clear and to the point, I think a picture which portrays the abnormality would look good here.

• History is done really well, I loved the quote and the picture of George Huntington. The only thing in this section would be to make
the dates bold or possibly even use a table.

• Nice use of tables in epidemiology, they make the information easy to read and easily accessible.

• Well described genetics component and nice incorporation of the student drawn image. I’m not sure if there’s a need to break down
Huntington (misspelt as ‘Huntingtin’ in the heading) gene into more headings.

• Molecular mechanisms and pathogenesis is done well. I actually think the image is a good size, as its side-by-side to the text and clearly explains what most of the text is about.

• I think a table would be helpful in clinical manifestations. Also, the image would look better larger and on the right hand side of the page.

• Treatment section was a little overwhelming. Too much detail in the table, possibly?

• Good glossary and a vast range of references, good work thus far!

--[[User:Z3289829|z3289829]] 02:42, 29 September 2011 (EST)

'''Peer Review'''
* Introduction does well in that it briefly addresses each of the facets of the topic that follow.
* Relevance of each historical point in the timeline is not adequately explained.
* Use of the table to show epidemiology is very nicely set up.
* Epidemiology is very much at the level required, delving into specific research details.
* You misspelled "Huntington" in "Huntingtin Gene". Really?
* Image error in the Molecular Mechanisms section. Remaining picture is very comprehensive though.
* Could potentially use more references in the Molecular Mechanisms section; otherwise decently referenced.
* The Diagnostic tests aren't actually mentioned, only their significance is outlined.
* "Neuropathology" section is not properly titled - it seems to be a subset of the Video section (which, incidentally, can probably be moved within Clinical Manifestations)
* Medication table is very nicely set out.
* Picture in Current/Future research (mouse/person/etc) seems irrelevant, and is not actually explained.
* Glossary is thorough
--[[User:Z3290689|z3290689]] 00:46, 29 September 2011 (EST)

'''Peer Review for Group 4'''

*Introduction is informative but not catchy. You need the reader to feel eager to read on the rest of the page.
*I like the way the history has a portrait and how there is a blue box around the quote. Maybe In the timeline you should bold the dates so it looks better on the page.
*Information found in the epidemiology is great, and the use of tables is very good. Just wanted to let yous know that whenever I read HD I always remember High Definition, a little distraction to my reading. Just wanted to make that point.
*Information in the HTT & normal functions section seems a bit disjointed and doesn’t seem to flow well.
*The HTT and Huntington’s disease section showed be reformatted so it is one nice flowing informative paragraph.
*Image found in the molecular mechanisms and pathogenesis section doesn’t show. Please fix it or remove the thumb altogether. However included information in this section is informative
*In clinical manifestations, it would be really good if you could describe how the clinical manifestations are brought about at a neurological level.
*It’s not necessary to have a large subheading for’ Video of Huntington's disease patient’
*Diagnostics has lots of info so formatting it so it’s spread out will be good.
*The image of Amniocentesis seems not to have the copyright clearance for it to be modified. Please fix it.
*Table in the treatments section is cool and massive, try to make it a bit smaller?
*I believe if the tetrabenzine information should come first then the massive medications table it would make the treatments part look and flow better.
*Current and future research section has information that very informative and portrays a good view on the current research arena for HD. However I don’t understand the relevance of having the brain scans in this section. Maybe have another section as a glossary which you could use for all other miscellaneous pictures.
*Some parts of the referencing include multiple referencing, just fix that up it will make it much better
*Overall, page is really well constructed, put a lot of work in and I’m impressed. Good word to picture ratio thus makes the page to be wanted to be read. Good work people of group 4.

--[[User:Z3291317|Z3291317]] 23:50, 28 September 2011 (EST)

'''Group 4'''

Introduction: Introduction is alright but could be more detailed.

History: This section is good but the timeline would be better with more information/ more detailed explanation of the points already there.

Epidemiology: This section seems too concerned with the occurrence of the HD. I think this section could use some more general
epidemiological information as well.

Genetics: This section is explained clearly and done quite well. The pictures need to be bigger though.

Pathogenesis: This section is good. The image could be a tiny bit bigger and would be better if it had a caption explaining the different parts of the diagram.

Clinical manifestations: This section could be longer/more detailed. You could explain some of the symptoms. Eg.what is chorea? Also, the picture is good but needs to be much bigger.

Diagnosis: This section doesn’t seem to actually explain how HD is diagnosed. Where is the diagnosis? Also, the picture is good but needs a more detailed caption.

Treatment: This table is not very nice to read and seems a bit complicated. I think it would work better simplified and put into paragraphs.

Future research: Good pictures and text. I think the images need more explaining. Eg. where is the caudate located in the brain. Maybe arrows could show this.
--[[User:Z3291324|z3291324]] 23:21, 28 September 2011 (EST)

Group 4

Hey, this is a nicely structured page with interesting content that is presented well. There is a nice balance of text and image

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: good, to the point
#* History: Nice section, perhaps bold the years?
#* Epidemiology: I really liked this section, both visually and content wise. The table is easy to read and I liked your explanations for the HD prevalence, well done
#* Genetics: Perhaps you could have the 'CAG (cytosine-adenine-glutamine)' in the introduction when you first refer to it? Referencing is required in i'HTT and normal functions'. I really liked your subheadings, made it very easy to understand and follow
#* Pathogenesis: Image is too big, good subheadings, I suggest that if you write in purple to highlight some words, maybe you could do that for the whole page?
#* Clinical: liked the motor impairment explanations, how about explaining the cognitive and behaviour impairments as well? (it'll be worth it!)
#* Diagnosis: Nice content, but it just feels a bit too crowded, maybe rearrange the images and decrease image size
#* Treatment: Very nice section with nice images and good format!
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Good balance of images and text, though some rearrangement of images would make this page look better. Very good use of subheadings to make the content more easy to digest
#Content is correctly cited and referenced.
#* overall referencing was well done
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.
* good range of tables, images and self drawn images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* Nice range of references used
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* just minor changes such as resizing some of the images, making the sections consistent in format

--[[User:Z3291643|z3291643]] 22:32, 28 September 2011 (EST)

'''Group 4:'''

•Formatting of the page seems well done, I like the inclusion of the quote in the history section, maybe put the timeline into a table as this would make it more visually appealing

•The file Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg, does not have the correct copyright information for the student drawn images

•I like the inclusion of the video, but am not sure about the subheading choice for this section. Does the video need its own separate heading?

•Good balance of text and images

•A couple of the references seem to be missing some of the information, but you have a large number of references so it looks like a lot of research has gone into this, good work so far.

--[[User:Z3332183|z3332183]] 21:26, 28 September 2011 (EST)

'''Group 4: Peer Assessment'''
* Your page has a good balance of text, images and tables
* I like that your introduction is brief and to the point
* You history section is the best one have seen so far, it looks good and it easy to read
* The image in the pathogenesis has no copyright information
* In clinical manifestations are quite important I think and your section seems a little weak in comparison to the rest
* Treatment: I'm sure the table was a lot of work but it is quite complex ad all the drug names make me a bid dizzy. May be you can shorten it to the most relevant?
*Overall the page has a good content and it's fun to read. The diagrams and drawings are great --z3279511 17:09, 28 September 2011 (EST)

'''GROUP 4: Huntington's Disease'''
*Intro has good summary of the disease, however the first paragraph is a little too technical, could you maybe simplify it a little so you don't lose the reader right at the start (reference 5 is missing though)
*History is succinct and summarised well, i like the quote included, could you have gone a little further with the timeline? (maybe include some of the more recent developments), maybe the timeline could be better formatted in a table
*Good info from a variety of sources in epidemiology, good use of tables, I like how prevalence has been compared and how the table is explained (one little thing: could you maybe find more statistics for Australia?)
*Inheritance image needs student template added and maybe made a little bigger so detail can be seen
*Genetics section is informative but could use an image of the gene maybe
*Molecular Mechanisms & Pathogenesis section is well researched and good summary is provided. I like how key words have been highlighted. images need fixing (more descriptive legend is needed for the first image and what happened to the second image?
*I don't think you need to explain what the disease is again in the clinical manifestation segment (don't want to sound repetitive), image in this section isn't very clear, I feel that this section is a tad incomplete-maybe some expansion is needed e.g. classes 2 and 3 could be expanded on more
*I feel that diagnosis section could go further up? This section is very informative, but could be summarised a little more Some of the images in this section need better explaining, good balance of text and images in this section
*good use of table in treatment section, however more info could be provided as to how these drugs help the disorder
*Current/Future Research is very up to date, images here again need more description

Overall:
*it is evident that this project has been extensively researched
*good use of subheadings and headings
*maybe include the acronyms in the glossary and it would be good if glossary words were linked to text
*make sure all images include the student template required and legends of some images need to be expanded (more info on what the image is about)
*fix repetitive sentences
*good balance of images and text, good use of tables

--[[User:Z3331556|z3331556]] 15:27, 28 September 2011 (EST)

'''Peer Assessment Group 4'''

*Second sentence of intro is WAY too detailed for the intro, it means very little as the disease has not yet been explained to us and is too technical – OR, keep it but explain it in a more general way.
*What do you mean by familially or sporadical development? Define what you mean by this (intro)
*Timeline – events need to be explained. E.g. Venezuela Project – what is this? Why is it significant? (this is needed for most of the history entries)
*HTT and normal functions – can you explain what some of the processes are? E.g. dynactin complex, clathrin-mediated endocytosis are?
*Calcium signalling in pathogenesis – maybe explain why the calcium signalling pathway is important?
*The video file – make sure you write a little para about it. It has a new headings – shouldn’t it be a subheading?
*The paragraph of ‘Imaging’ in diagnostic tests needs to be pushed so its under the pics from neuropathology
*Tetrabenazine – I think have an intro sentence about it to highlight that this is the most commonly used one, as you only discuss it in depth (as a drug treatment) – unless you are going to add in explanations of other drugs?
*In Current/future research, refer to the pics on the RHS if they are relevant, otherwise I think they need to go somewhere else
*Overall comment: its good, lots of research, but even as someone who has a background in bio, we still don’t know everything about everything, so I think as you go, explain some of the more complicated processes so you can really understand what is going on.

--[[User:Z3332824|z3332824]] 11:48, 28 September 2011 (EST)

Group 4: Huntington’s Disease

'''Group 4 Peer Review'''
* Good introduction, history seems adequate - although the timeline stops at 2002? Is there anything after this?
* Nice table for epidemiology; although some terms require explaining
* Excellent student-drawn diagrams and genetics section with a good balance between the text, bullet points and images. One image has been removed so be sure that that is re-uploaded!
* Video section: Formatting is a bit of a pain to read when the left hand margin keeps shifting with the images being placed here. Fix this please so that it is easier to track the page with our eyes.
* Treatment section is overwhelming, whilst some might have said that it looks great (and it really does), to suddenly be hit with such a huge table is exhausting. Perhaps shorten this section by mentioning that there is only treatment available for the symptoms, list them, and then link to an image containing the table in its entirety.
* Current/Future research section seems a bit short.
* Overall, it looks like an excellent project that has had a lot of thought put into it. Well done guys :)
--[[User:Z3288827|Leonard Tiong]] 10:25, 28 September 2011 (EST)

Initial thoughts, was wow! Clearly immense time and effort was put into this! Loved the structure of the headings and sub-headings.
*Introduction: Top notch, just needs an image to complete it.
*History: Nice use of the quote box, this section was done very well, except BOLD the years. Personally, I would have liked it more if the timeline itself was in a coloured table, no biggie.
*Epidemiology: Add “(Australia)” After Tasmania? Or just listing countries would be better? Overall, nicely done.
*Genetics: “Inheritance” part feels a little too short. Preferred if the image had black text over a white background. Everything else was great!
*Molecular Mechanisms & Pathogenesis: The space between the purple words and commas could be removed. The purple colour, made me think they were hyperlinks, maybe chose either to bold or colour the words, as having both is a bit much.
*Clinical Manifestations: The features would look better in a table, in my opinion. I like the image, very nice indeed! Good summary.
*Diagnostic Tests: Done well, though compared to the rest of the webpage, it looks very insignificant. I suggest adding more information!
*Video: Fix the formatting please!
*Treatment: Nice table, informative. The “Tetrabenzine” section, the text needs some formatting, sentences are cut off to the next line for some reason, to be honest Medications and Therapies seem to be most important part, so they should maybe be expanded on?
*Glossary: Looks good, just a few full stops missing!
--[[User:Z3332327|Lisa Xiao]] 01:24, 28 September 2011 (EST)

'''Group 4'''

*Very good introduction

*History: looks very nice, but the layout of the quote disrupts the page. I think it would be better to use bold letters, good idea though.

*Epidemiology: nice section, useful tables

*Genetics: good detailed content and drawings

*Pathogenesis: do not bold words in only one section, it disrupts the whole picture, good use of sub- headings.

*Clinical manifestations: good summary of the symptoms in the drawing, the classes and the five specific features would look better in a table, otherwise good section

*Diagnostic tests: the video subheading needs to be fixed, really irritating. Very detailed, I would put all images to the same side

*Treadment: mechanism of tetrabenazine inhibition image could have been done with more effort

*Research: very nice clear section
--[[User:Z3387190|Z3387190]] 21:27, 27 September 2011 (EST)

'''group peer assessment'''
*Introduction is well structured though image of the Huntington gene protein would be more beneficial to where I’m looking relating to genetics
*Genetics could expand more on the inheritance and the Huntington gene
*Role in transcription sub heading image removed
*Diagnostic test image needs to placed in correct section and the video should be placed at the end of the section, placement of the video cause confusion of the other diagnosis tests
*Treatment should have an introduction which introduces the drug used to manage diseases and therapies, better layout where most commonly used drug form management and therapies following the table to show alternative treatment.
*Current/future research should have some future research and images placed have no description which research project image belongs to
*References contain mistakes with repetitions and blanks also some done incorrectly such as reference “3” where not properly inputted on the wiki page
*Glossary was not linked to the web page as well while reading was lost without referring to a dictionary due to no indications definition is in the glossary
z3332250 23:46, 26 September 2011 (EST)

Group 4 Peer Review

*Punchy introduction-well done
*Timeline under history was excellent
*Seemed very scientific and wordy at times-a lot of detail is unnecessary; “less is more”
*Great balance of text and images-very readable
*Page flowed well in a logical manner
*Diagnosis section is very well done however there seems to be too much content/focus relative to the rest of the page. Perhaps add some more to other sections or make this section more concise?
*An extensive glossary and reference list-thorough research
*I learnt a lot from this page so well done!
*Overall, an impressive page. A few more things to tweak to make it excellent.
--[[User:Z3308965|Fleur McGregor]] 19:13, 26 September 2011 (EST)

'''Group 4 Critique'''

#• Introduction was quite good
#• History was good. I liked the timeline
#• Tables in the epidemiology were good
#• The genetics was clearly explained
#• Pathogenesis was really good. I quite liked it
#• Clinical manifestations is good
#• Diagnostic tests could be more detailed
#• Overall, quite a well written project. Well done. Maybe add a little more about the medications.

--[[User:Z3289991|Robert Klein]] 18:47, 24 September 2011 (EST)

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

Group 4
* On first looking at the project it looks like there is a good text/image ratio. However an image in the introduction would work well
* The content of the introduction is very clear and introduces the reader to the topic well
* I really like the history section. The story makes me a little excited about the condition in a way. I am left feeling keen to know more and there is an extensive list of discoveries. There needs to be more after 2002 though. I find it difficult to believe that nothing has been found in the last 9 years.
* The epidemiology table is a nice way of showing the data. But maybe you should put the Australian states in bold and at the top- also maybe include all of the states or Australia as a whole, not just NSW and TAS
* There is a file in the pathogenesis that is not accessible- either get the file up or remove the link
* The image in the pathogenesis has no copyright information
* A couple of grammar problems in the pathogenesis that could be fixed up- full stops mid sentence for example
* The clinical manifestations sections outlines the types of classes of manifestations but it is difficult to actually access the information on what the manifestations are. It would work well in a table with a little more detail on what the patient experiences
* The video is put as a new subheading within diagnosis. It needs to be made into the smaller subheading because I thought diagnosis section was over but it continues underneath
* The diagnosis section is in great detail, somewhat more detail than other sections. This is very interesting and shows that this team member worked hard on their section.
* Good work on the project, just a little editing and formatting to make it a finished product!

'''Group 4'''
* Nice structure of headings and subheadings, it breaks up the text and makes it a readable page. Extremely interesting topic!
* I found the history very interesting and enjoyed the quote from Huntington.
* maybe bold the dates in the timeline, just to make the page easy to follow. Or maybe a table could be appropriate.
* I liked the structure of the epidemiology section and the tabulated prevalences! good work!
* Molecular Mechanisms & Pathogenesis: unsure as to why some sentences were bolded.
* Differential Diagnosis: very interesting I liked that you added this in.
* Treatments table very succinct easy to understand and follow! Great!
* Good to see that most of your references were grouped. only a few that were doubled.
* Maybe have a continuos colour scheme for the page and type of table used.
* Good use of tables and I like that you explained what they were about.
* Make sure all acronyms and scientific language is in the glossary
* good student illustrations
* overall great ratio of text and pictures!

'''Group 4 Assessment'''
*This might be a bit nit-picky, but for the references given throughout the wiki, there isn’t any consistency. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*The information within the introduction seems to be substantial. Only suggestion would be to add a picture to add to the overall look.
*In the history section, it was a good idea to have the single quote stand out in a colored box to itself. First time I’ve seen this. Looks professional. I question though, if all the events within the timeline are absolutely necessary…
*Epidemiology- Both tables are well organized and look extremely professional. Good information within this section, although it might be a good idea to reference a few more not-so-common terms in the glossary, such as SNP’s and others which may not be common knowledge for all.
*The Genetics section is well formatted with what I believe is the vital information needed in this section. Only complaint is the first picture (Inheritance Pattern…) doesn’t have the copyright information claiming that it is okay to use this image.
*The “Key cellular pathogenic mechanisms in HD” image likewise does not have the copyright information to verify its legal usage.
*Molecular Mechanisms and Pathogenesis section- Very well formatted and aesthetically appeasing. Why are some of the words in purple though? Are they meant to be defined the glossary, or just key points? “The Mutant Huntington gene…” file is also not on the page… Where is it?
*Diagnostic Tests  Research – I have no complaints. These sections look immaculate.
*In the glossary, try having a bullet list and also having the words within the wiki page to link to its definition in the glossary.
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
*Overall, good content within the page and very appealing visually. Just minor editing needs to be done I think. Good job!
--[[User:Z3391078|Z3391078]] 14:31, 27 September 2011 (EST)

'''Peer Assessment: Group Project 4'''
*The introduction and history sections are concise and well formatted.
*A few of the points in the timeline would be improved by containing a bit more information such as 'Mendel's work' and 'The Venezuala project'
*The tables used in the epidemiology section are clear and highly informative.
*The abbreviation HTT is used throughout the epidemiology section before it is stated what it means in the genetics section. This should be changed.
*The picture related to transcription factors needs to be fixed so that it can be displayed.
*The section entitled 'Video of Huntington's disease patient' should have a more appropriate heading to encompass the rest of the written information in that section.
*Under the information in some of the images you have uploaded, you still need to add <nowiki>{{Template:2011 Student Image}}</nowiki>.
*Some of the references are duplicated. They can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
*Overall the project is highly informative, well written and formatted.
--[[User:Z3217345|z3217345]] 21:34, 27 September 2011 (EST)

Group 3:
* The introduction is very lengthy, some parts feel as though they would be more appropriate in other sections. The image here fits nicely with the text but it could benefit from a more descriptive legend and needs to include “{{Template:2011 Student Image}}”.
* In the history, you begin to use the short hand “KS” without an initially stating that this is the abbreviation for “Klinefelters syndrome (KS)”. The dates that are mentioned are very detailed although it ends in 1970, were there any other breakthroughs since then? A picture of Klinefelter would be a nice touch here.
* Epidemiology requires some proof reading as there are a couple of little mistakes and the images would have more of an impact if they were slightly larger.
* I like how you have linked figure 1 to the non-disjunction sub-heading under aetiology. The image in this section could benefit from a coloured legend, ie. Instead of saying “Blue circles are male cells”, in a box include an actual blue circle = male cells along with the other descriptions. It also needs to be properly cited.
* There is too much repetition between pathogenesis and aetiology, maybe discussion between these two students is needed to minimise repetition. Good hand drawn images but you need to include the student template as mentioned previously.
* Signs and symptoms would look better in a coloured table and with more images. I don’t think it is necessary to repeat the image comparing age and intellect here.
* Diagnosis; nice use of another form of media – a video. The abbreviation of KS in this section needs to be established first by placing KS after the first time you mention Klinefelters syndrome.
* Management is very concise and thorough
* Other similar defects; nice touch, it could look more appealing with the use of colour and larger images though.
* Current research is formatted nicely and flows well

'''Group 4: '''
* The introduction provides a great overview but remember it needs to be easy to read, even for those who have never heard of Huntington’s disease. If you explain scientific and medical terms (such as neurodegenerative and CAG trinucleotide tract) more generally/broadly, it will solve this problem.
* History: great use of a quote and image. The timeline would look better and make it easier to read if the dates were bolded or if it were in a table. The explanations could be elaborated more such as “1900: Mendel’s work was rediscovered”. Image needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>.
* Epidemiology: Although you’ve stated that Venezuela and North Ireland have notably high prevalence of this disease, you haven’t stated the actual prevalence of Venezuela. You also need to re-read this section as there are a couple of mistakes eg “There <font color=red>seem</font> to be an increased prevalence of Huntington's disease...” and this sentence doesn’t make sense “Two of the most well-known populations in which high prevalence of HD was notably in the state of Zulia, Venezuela and Northern Ireland”. What are HTTP haplotypes?, overall I found the explanation of the paper by Warby et al hard to understand, maybe another attempt of explaining this paper is needed by spelling out the haplotypes even more so. In saying this, the tables are formatted very nicely.
* Genetics: Nice student drawn images but just make sure you include the student template as mentioned above. The “Huntingtin Gene” section would benefit from an image of the specific regions on the chromosome as it is hard to follow with just text.
* Molecular mechanisms and pathogenesis: a lot to take on but is made easier to read through the use of good sub-headings and highlighted words and large image. Make sure you include the student template here as well and there is an image missing in this section though.
* Clinical manifestations: You have mentioned 3 classes of symptoms but have only gone into detail about one of them; motor movement impairment. What happened to cognitive and behavioural explanations? Nice student drawn image, I like how it is oriented to the left to change it up a bit.
* Diagnostic test: The table could be formatted with more colour to make it more aesthetically pleasing. I personally don’t understand including an image of another disease, i would stick to images specifically relating to HD.
* Under neuropathogy there is a little typo “The neuropathological hallmark of Huntington’s disease is now <font color=red>know</font> to be the gradual loss of spiny GABAergic...”, there could be more so i would advise to check this section again.
*Under genetic testing there is also another little typo “However it wasn’t <font colour=red>until the 1993</font> when...”
*Treatment and future research: very well researched and I really liked the use of the table and images here, it provides great balance and flow.

--z3290815 19:05, 28 September 2011 (EST)

'''Group 4: '''

*The page had a nice format that was appealing to read.
*The structuring of the images between and beside the text was perfect because it was not too big and not too small. It was easy to view and nice to see.
*The table for the treatment heading was nice but the last column is hard to read because the information was listed in a horizontal fashion maybe changing it and putting it into dot point form would be good.
*The student drawn image was clear!
*Fixing the formatting/structure of the glossary heading is needed
*Double referencing can be seen
*Sub heading for the video would be nice to see. The idea of including a video is quite nice.

--[[User:Z3330313|z3330313]] 19:57, 28 September 2011 (EST)

'''Peer Review'''

* Organised well
* Subheadings in the epidemiology section not in the centre of table
* images in the current/future research section is disorganised
* a lot of referencing was done and maybe not necessary
* choice of pictures were good examples

--[[User:Z3060621|z3060621]] 21:14, 28 September 2011 (EST)

'''Group 4'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
Main sections are there, Not sure if 'video of huntington's patient' should be a big heading - maybe put it in an 'external links' section?

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Content is well done and headings/sub-headings are organised well.

'''*Content is correctly cited and referenced.'''
Fix up doubling of references. File:Mutant Huntingtin gene and its effects on transcription.jpg is missing. No references in therapies?

'''*The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.'''
Student image well done and explanation works well.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Comprehensive research, but maybe more information in glossary as the wiki uses quite a lot of technical language.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Any thing else on diagnosis? As mentioned by Mark, since this is a disease that presents complications after birth, more information should be added. Perhaps include some information on diagnostic tests? The imaging section in neuropathy could be added to diagnostic tests if diagnosis is possible by examining neurological changes?

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Development of wiki page has followed above guidelines, but some minor adjustments can be made.

--z3329495 21:15, 28 September 2011 (EST)

*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.
*'''History''': Looks good.
*'''Epidemiology''': Nice detail.
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.
*'''Clinical Manifestations''': Good.
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.
*'''Glossary''': Looks good, but some more terms still need explaining.
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.

==Discussion==

Hey girls, Found a photo for the introduction. Let me know what you think/feel free to change it if you wish :)

--[[User:Z3290379|Elizabeth Blanchard]] 17:10, 1 October 2011 (EST)

Hey Liz, I posted on the fb page regarding the genetics and pathogenesis part. The student drawn image I'm okay with doing yes. So far I was thinking about doing a picture showing the autosomal dominant nature of the gene. Basically a "tree diagram" of what happens when one parent is affected and the offspring has a 50% chance of inheriting HD.
But I'm okay at drawing so if someone else has something better they'd like me to draw I'm okay with it. :)
Girls please check fb, bit of a crisis.
:)

--[[User:Z3290270|Maeda Sadeghpour]] 06:00, 14 September 2011 (EST)

hey girls, i think we really need to start hurrying things along with our project. Maedeh, i know you said that peer reviews arnt getting marked, but we need to have our project FINISHED by then because after that we are only making finishing touches based on teh peer reviews. Also, are you still doing the student drawn image? Ta

--[[User:Z3290379|Elizabeth Blanchard]] 12:41, 13 September 2011 (EST)

Genetics + Pathogenesis

Yea I think so, it would make it more relative. If anyone comes across any studies just post the link here or on fb. :)

--[[User:Z3290270|z3290270]] 23:36, 24 August 2011 (EST)

Hmm, are epidemiological studies on HD? If there is, we should add. It will make our webpage more comprehensive.
And I don't mind doing that section.

--Nur Sharalyn Abdullah 20:24, 23 August 2011 (EST)

Girls, do you think we need an 'Epidemiology' heading??

--[[User:Z3290379|Elizabeth Blanchard]] 17:25, 23 August 2011 (EST)

Introduction + Clinical Manifestations.

--[[User:Z3290558|Lisa Lee]] 14:42, 23 August 2011 (EST)

Current + Future Research & Diagnostic Tests.

--[[User:Z3290379|Elizabeth Blanchard]] 09:30, 22 August 2011 (EST)

Sharalyn: History & treatment

--Nur Sharalyn Abdullah 20:15, 20 August 2011 (EST)

'''White blood cell populations from Huntington's Disease patients'''

[[File:White_blood_HD.gif]]

--[[User:Z3290558|z3290558]] 23:46, 17 August 2011 (EST)

===Establishment of HD hybrid cell line===

[[File:Establishment of HD hybrid cell line.jpg]]

(A) First polar body of mature rhesus macaque oocyte was removed by gentle squeezing through a slit of zona pellucida (A-a). Staining of 1st polar body DNA (arrowhead) and oocyte DNA (arrow) (A-b). HD monkey skin cell was placed under the zona pellucida (black arrow) (A-c). Reconstructed oocyte with HD monkey skin cell (A-d; yellow arrow) was placed between two electrodes for electrofusion (A-d). (B) Day 12 hatching blastocyst derived from HD monkey hybrid embryo (B-a; arrow indicated ICM). HD monkey hybrid blastocyst outgrowth at six days after attached onto feeder cells (B-b). High magnification of selected region (inset) of the ICM outgrowth (arrowhead). HD monkey hybrid cell line (TrES1) at passage 10 (B-c). (C) G-banding analysis of TrES1. Cytogenetic analysis of TrES1 demonstrated tetraploid chromosome (84; XXXY). (D) Expression of ES-cell specific markers: Alkaline phosphatase, Oct4, SSEA4 and TRA-1-60.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833146/?tool=pmcentrez

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

--[[User:Z3290270|Maeda Sadeghpour]] 21:30, 17 August 2011 (EST)

'''Large stem cell-derived neurospheres were generated from 33-week old HD hippocampus, but not WT hippocampus.'''

[[File:Stem cells neurospheres drived from Huntingtons Disease hippocampus.png]]

--[[User:Z3290379|Elizabeth Blanchard]] 15:06, 16 August 2011 (EST)

'''Melatonin levels in Huntington's disease patients and controls'''

[[File:Melatonin levels in HD patients and controls.jpg]]

The diurnal melatonin rise was significantly delayed in HD patients by about 01:30 h (p = 0.048). The black bar on the abscissa indicates the dark period (23:00–7:30 h).

--Nur Sharalyn Abdullah 12:21, 16 August 2011 (EST)

We decided on Huntington's Disease, I believe Nur spoke to you at the end of the class. :)

--[[User:Z3290270|Maeda Sadeghpour]] 16:44, 13 August 2011 (EST)

--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.

Group 4 Topic: Neural Tube Defect

Research Article:

Conway S.J., Gosnell M., Rogers R., Simmons O., Snider P., Young R. (2011), Notochordal and foregut abnormalities correlate with elevated neural crest apoptosis in Patch embryos. Birth Defects Research Part A: Clinical and Molecular Teratology. doi: 10.1002/bdra.20802. Epub 2011 May 6.

http://www.ncbi.nlm.nih.gov/pubmed/21557455

Review Article:

Abdel-Hamed Z., Johnson C.A., Logan C.V. (2011), Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects. Molecular Neurobiology

http://www.ncbi.nlm.nih.gov/pubmed/21110233

--[[User:Z3290558|z3290558]] 02:07, 11 August 2011 (EST)

'''Neural Tube Defects'''

[[Review:]] Padmanabhan, R. (2006). Etiology, pathogenesis and prevention of neural tube defects. ''Congenital Anomalies'', 46(2), 55-67.

[[Research:]] Joó, J. G., Beke, A., Papp, C., Tóth-Pál, E., Csaba, A., Szigeti, Z., Papp, Z. (2007). Neural tube defects in the sample of genetic counselling. ''Prenatal Diagnosis'', 27(10), 912-21.

--[[User:Z3290270|z3290270]] 02:34, 11 August 2011 (EST)

''Review'': Bassuk AG, Kibar Z. '''Genetic basis of neural tube defects.''' Semin Pediatr Neurol. 2009 Sep;16(3):101-10 [http://www.ncbi.nlm.nih.gov/pubmed/19778707]

''Research'': De Marco P, Merello E, Cama A, Kibar Z, Capra V.''' Human neural tube defects: Genetic causes and prevention.''' Biofactors. 2011 Jun 14.[http://www.ncbi.nlm.nih.gov/pubmed/21674647]

--[[User:Z3389806|Nur Sharalyn Abdullah]] 14:24, 10 August 2011 (EST)

We are doing on neural tube defects!

--[[User:Z3389806|Nur Sharalyn Abdullah]] 13:47, 10 August 2011 (EST)

Neural Tube Defects

Article: <ref><pubmed>19120526</pubmed></ref>
Review: <ref><pubmed>18182339</pubmed></ref>

===References===
<references/>

--[[User:Z3290379|Elizabeth Blanchard]] 22:25, 9 August 2011 (EST)

Hi girls (: I actually managed to find some genetics-related articles on neural tube defects. It has something to do with folate and folate-related genes from what I have read so far. So how about it? Shall our website be based on neural tube defects? (:

--[[User:Z3389806|Nur Sharalyn Abdullah]] 08:12, 9 August 2011 (EST)

Hey girls,

So I've done a bit of research on a few of them.
One of the things we need to keep in mind is that it has to relate to the '''learning outcomes''', which I think is the embryological process, and how the genetic disorder relates to it or how its affected by it? (I tried looking it up but couldnt find it).

Here's a list of the topics I've been looking into:

[[Turner Syndrome:]] commonly known to have one missing sex chromosome, (or both) - LOTS of info on this. (only thing is, because its such a broad topic, we might have articles that contradict each other, or might not have that many embryology related new articles...?)

[[Klinefelter's Syndrome:]] the gigantic disease with the extra chromosome (XXY). there's a decent amount of info on this, but not as much as Turner.

[[Neural Tube defects:]] problems happening in the first month of baby formation because of the folate deficiency in the mother. But i'm not too sure where the genetics come into this..

Which topics have you guys been looking at? Let us know! cos we need to have some articles in '''[[2-3days time!]]''' :)

Ye it's better to research an area instead of just one disease then, because that will give us more to talk about... especially the genetic components which Mark commented on. So I was thinking Neural Tube Defects instead. That will give us Anencephaly, Encephaloceles, Hydranencephaly, Iniencephaly and Spina bifida. ?--[[User:Z3290270|Maeda Sadeghpour]] 01:09, 8 August 2011 (EST)

You need to think about what the genetic component will be for the disease you select. --[[User:S8600021|Mark Hill]] 23:51, 7 August 2011 (EST)

I don't think that having 4 categories will be a problem. I actually think that it will be good to have extra stuff to talk about. Have a look at the other pages from previous years, they are very elaborated so I think it's actually a good thing to have alot of things to talk about. But anyway lets decide on something so that we can post up our articles

--[[User:Z3290379|Elizabeth Blanchard]] 22:00, 7 August 2011 (EST)

Hey! I get what you mean, Maeda. Doing 4 categories can be quite heavy. Hmm, but I was thinking, since this is going to be a wikipage and the elaboration for the 'original' wikipage for spina bifida is not very deep for the 4 categories, maybe we could leverage on this weakness and make ours more detailed? :) But if you guys think it is too much, I don't mind doing the other suggestions too! Anyway, this is just a preliminary decision. It depends on the topics that other groups have chosen too. Would it be possible for us to finalise the topic by tomorrow?

--[[User:Z3389806|Nur Sharalyn Abdullah]] 17:18, 7 August 2011 (EST)

Hello people. I was basically trying to see which diseases had the most current information available online, and cystic fibrosis seems to be very well known. Spina Bifida is very interesting as well, my only concern with it is the 4 categories it's divided into, which I thought might make it a bit more work. What do you guys think? :)

--[[User:Z3290270|Maeda Sadeghpour]] 00:25, 6 August 2011 (EST)

Hey, girls! I'm thinking of spina bifida and hydrocephalus. Cheers!

--[[User:Z3389806|Nur Sharalyn Abdullah]] 20:26, 5 August 2011 (EST)

hey guys, had a quick look and Spina bifida and Turner's Syndrome both seem to have a decent amount of information on them

--[[User:Z3290379|Elizabeth Blanchard]] 14:26, 5 August 2011 (EST)

==Peer Assessments==
* Interesting but good use of a quote
* The introductory paragraph for the “history” section could probably be cut down or eliminated altogether
* Great inclusion of statistics in regards to epidemiology
* Student images were excellent, well drawn and were engaging
* Pathogenesis section could have been placed in a table just to change up the formatting
* The video inclusion was good and relevant
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
--[[User:Z3332629|z3332629]] 15:24, 22 September 2011 (EST)

2011 Group Project 4

2011-10-09T01:11:18Z

Z3389806: /* Genetic testing and prenatal diagnosis */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, [[#Neuronal|neuronal]] transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. [[#Chorionic villus sampling|Chorionic villus sampling]] can be carried out between the 10th and 12th week of pregnancy whereas [[#Amniocentesis|amniocentesis]] is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Amniocentesis"></div>'''Amniocentesis:''' A medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections by taking a sample of the amniotic fluid. The fluid is then analysed to observe for any abmornalities.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Chorionic villus sampling"></div>'''Chorionic villus sampling:''' A form of prenatal diagnosis to determine chromosomal orgenetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length [[#Polymorphisms|polymorphisms]] (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-09T01:07:57Z

Z3389806: /* Glossary */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, [[#Neuronal|neuronal]] transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Amniocentesis"></div>'''Amniocentesis:''' A medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections by taking a sample of the amniotic fluid. The fluid is then analysed to observe for any abmornalities.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Chorionic villus sampling"></div>'''Chorionic villus sampling:''' A form of prenatal diagnosis to determine chromosomal orgenetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length [[#Polymorphisms|polymorphisms]] (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-09T01:00:45Z

Z3389806: /* Huntingtin Gene */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, [[#Neuronal|neuronal]] transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

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{{2011Projects}}

2011 Group Project 4

2011-10-09T00:58:16Z

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{{2011ProjectsMH}}

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=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of [[#Transcription factor|transcription factors]] and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-09T00:55:50Z

Z3389806: /* Clinical Manifestations */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a [[#Hyperkinetic disorder|hyperkinetic disorder]] which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. [[#Motor impersistence|Motor impersistence]] is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-09T00:45:16Z

Z3389806: /* Epidemiology */

{{2011ProjectsMH}}

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=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene [[#Haplotype|haplotypes]] contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-09T00:41:14Z

Z3389806: /* Huntingtin Gene */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss [[#Cognitive|cognitive]] abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-09T00:36:12Z

Z3389806: /* Neuropathology */

{{2011ProjectsMH}}

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=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss cognitive abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the [[#Atrophy|atrophy]] of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-09T00:33:21Z

Z3389806: /* Treatment */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss cognitive abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the atrophy of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the [[#Vesicular monoamine transporters (VMAT)|vesicular monoamine transporters (VMAT)]].

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, akathisia <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, [[#Nystagmus|nystagmus]] <ref><pubmed>12552061</pubmed></ref>, [[#Teratogenicity|teratogenicity]] <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-09T00:28:00Z

Z3389806: /* Glossary */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss cognitive abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the atrophy of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the vesicular monoamine transporters (VMAT).

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, restless legs syndrome (RLS) <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, nystagmus <ref><pubmed>12552061</pubmed></ref>, teratogenicity <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A [[#Catecholamines|catecholamine]], which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-09T00:22:27Z

Z3389806: /* Diagnostic Tests */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss cognitive abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is [[#Asymptomatic|asymptomatic]], by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe [[#Neuropathological|neuropathological]] changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the atrophy of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of [[#Computed tomography (CT)|computed tomography (CT)]] scans, [[#Magnetic Resonance Images (MRI)|magnetic resonance images (MRIs)]], [[#Single-photon emission computed tomography (SPECT)|single-photon emission computed tomography (SPECT)]] as well as [[#Positron Emission Tomography (PET)|positron emission tomography (PET)]].<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, [[#Visuospatial|visuospatial]] skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using [[#Linkage Analysis|linkage analysis]]. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the vesicular monoamine transporters (VMAT).

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, restless legs syndrome (RLS) <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, nystagmus <ref><pubmed>12552061</pubmed></ref>, teratogenicity <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Coagulopathies"></div>'''Coagulopathies:''' A disease or condition affecting the blood's ability to coagulate.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hemorrhagic pancreatitis"></div>'''Hemorrhagic pancreatitis:''' Inflammation of the pancreas accompanied by the formation of necrotic areas on the surface of the pancreas and in the omentum and, frequently, also accompanied by hemorrhages into the substance of the gland.

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hypotension"></div>'''Hypotension:''' Low blood pressure.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A catecholamine, which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Rhinitis"></div>'''Rhinitis:''' Irritation and inflammation of some internal areas of the nose, resulting in ‘stuffy nose’.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic[1] imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

<div id="Xerostomia"></div>'''Xerostomia:''' Dry mouth resulting from reduced or absent saliva flow.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-09T00:10:33Z

Z3389806: /* Other drugs */

{{2011ProjectsMH}}

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=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss cognitive abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is asymptomatic, by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe neuropathological changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the atrophy of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of '''computed tomography (CT) scans''', '''magnetic resonance images (MRIs)''', '''single-photon emission computed tomography (SPECT)''' as well as '''positron emission tomography (PET)'''.<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, visuospatial skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using '''linkage analysis'''. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the vesicular monoamine transporters (VMAT).

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances [[#Gamma-aminobutyric acid (GABA)|gamma-aminobutyric acid (GABA)]]-mediated neurotransmission, which decreases the excitability of neurons and inhibits [[#Histone deacetylases (HDAC)|histone deacetylases]].<ref><pubmed>17514356</pubmed></ref>
| align="center"|[[#Renal toxicity|renal toxicity]] <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, [[#Hepatoxicity|hepatoxicity]] <ref><pubmed>21492891</pubmed></ref>, [[#Encephalopathy|encephalopathy]] <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the [[#HPA axis|HPA axis]]. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, [[#Toxic epidermal necrolysis|toxic epidermal necrolysis]] <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|[[#Somnolence|somnolence]] <ref><pubmed>18728811</pubmed></ref>, [[#Asthenia|asthenia]] <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits [[#Serotonin|serotonin]] reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|[[#Mania|mania]] <ref><pubmed>3485926</pubmed></ref>, [[#Akathisia|akathisia]] <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| [[#Norepinephrine (noradrenaline)|Norepinephrine (noradrenaline)]] as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, restless legs syndrome (RLS) <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of [[#Dopamine|dopamine]] to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute [[#Dystonia|dystonia]], [[#Parkinsonism|parkinsonism]] <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, [[#Myocarditis|myocarditis]] <ref><pubmed>17194170</pubmed></ref>, [[#Gastrointestinal hypomotility|gastrointestinal hypomotility]] <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, nystagmus <ref><pubmed>12552061</pubmed></ref>, teratogenicity <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Coagulopathies"></div>'''Coagulopathies:''' A disease or condition affecting the blood's ability to coagulate.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hemorrhagic pancreatitis"></div>'''Hemorrhagic pancreatitis:''' Inflammation of the pancreas accompanied by the formation of necrotic areas on the surface of the pancreas and in the omentum and, frequently, also accompanied by hemorrhages into the substance of the gland.

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hypotension"></div>'''Hypotension:''' Low blood pressure.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A catecholamine, which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Rhinitis"></div>'''Rhinitis:''' Irritation and inflammation of some internal areas of the nose, resulting in ‘stuffy nose’.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic[1] imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

<div id="Xerostomia"></div>'''Xerostomia:''' Dry mouth resulting from reduced or absent saliva flow.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-08T23:59:15Z

Z3389806: /* History */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| [[#Restriction fragment-length polymorphisms (RFLPs)|Restriction fragment-length polymorphisms (RFLPs)]] were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| [[#Linkage disequilibrium|Linkage disequilibrium]] between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss cognitive abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is asymptomatic, by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe neuropathological changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the atrophy of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of '''computed tomography (CT) scans''', '''magnetic resonance images (MRIs)''', '''single-photon emission computed tomography (SPECT)''' as well as '''positron emission tomography (PET)'''.<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, visuospatial skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using '''linkage analysis'''. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the vesicular monoamine transporters (VMAT).

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances gamma-aminobutyric acid-mediated (GABA) neurotransmission, which decreases the excitability of neurons and inhibits histone deacetylases.<ref><pubmed>17514356</pubmed></ref>
| align="center"|renal toxicity <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, hepatoxicity <ref><pubmed>21492891</pubmed></ref>, encephalopathy <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the HPA axis. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, toxic epidermal necrolysis <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|somnolence <ref><pubmed>18728811</pubmed></ref>, asthenia <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits serotonin reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|mania <ref><pubmed>3485926</pubmed></ref>, akathisia <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| Norepinephrine (noradrenaline) as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, restless legs syndrome (RLS) <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of dopamine to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute dystonia, parkinsonism <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, myocarditis <ref><pubmed>17194170</pubmed></ref>, gastrointestinal hypomotility <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, nystagmus <ref><pubmed>12552061</pubmed></ref>, teratogenicity <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Coagulopathies"></div>'''Coagulopathies:''' A disease or condition affecting the blood's ability to coagulate.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hemorrhagic pancreatitis"></div>'''Hemorrhagic pancreatitis:''' Inflammation of the pancreas accompanied by the formation of necrotic areas on the surface of the pancreas and in the omentum and, frequently, also accompanied by hemorrhages into the substance of the gland.

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hypotension"></div>'''Hypotension:''' Low blood pressure.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A catecholamine, which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Rhinitis"></div>'''Rhinitis:''' Irritation and inflammation of some internal areas of the nose, resulting in ‘stuffy nose’.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic[1] imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

<div id="Xerostomia"></div>'''Xerostomia:''' Dry mouth resulting from reduced or absent saliva flow.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-08T23:53:45Z

Z3389806: /* Introduction */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by [[#Degeneration|degeneration]] and dysfunction of the [[#Cerebral Cortex|cerebral cortex]] and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in [[#Allele|alleles]] with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| Restriction fragment-length polymorphisms (RFLPs) were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| Linkage disequilibrium between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss cognitive abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is asymptomatic, by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe neuropathological changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the atrophy of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of '''computed tomography (CT) scans''', '''magnetic resonance images (MRIs)''', '''single-photon emission computed tomography (SPECT)''' as well as '''positron emission tomography (PET)'''.<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, visuospatial skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using '''linkage analysis'''. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the vesicular monoamine transporters (VMAT).

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances gamma-aminobutyric acid-mediated (GABA) neurotransmission, which decreases the excitability of neurons and inhibits histone deacetylases.<ref><pubmed>17514356</pubmed></ref>
| align="center"|renal toxicity <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, hepatoxicity <ref><pubmed>21492891</pubmed></ref>, encephalopathy <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the HPA axis. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, toxic epidermal necrolysis <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|somnolence <ref><pubmed>18728811</pubmed></ref>, asthenia <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits serotonin reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|mania <ref><pubmed>3485926</pubmed></ref>, akathisia <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| Norepinephrine (noradrenaline) as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, restless legs syndrome (RLS) <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of dopamine to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute dystonia, parkinsonism <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, myocarditis <ref><pubmed>17194170</pubmed></ref>, gastrointestinal hypomotility <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, nystagmus <ref><pubmed>12552061</pubmed></ref>, teratogenicity <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Coagulopathies"></div>'''Coagulopathies:''' A disease or condition affecting the blood's ability to coagulate.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hemorrhagic pancreatitis"></div>'''Hemorrhagic pancreatitis:''' Inflammation of the pancreas accompanied by the formation of necrotic areas on the surface of the pancreas and in the omentum and, frequently, also accompanied by hemorrhages into the substance of the gland.

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hypotension"></div>'''Hypotension:''' Low blood pressure.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A catecholamine, which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Rhinitis"></div>'''Rhinitis:''' Irritation and inflammation of some internal areas of the nose, resulting in ‘stuffy nose’.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic[1] imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

<div id="Xerostomia"></div>'''Xerostomia:''' Dry mouth resulting from reduced or absent saliva flow.

==References==
<references/>

----

{{2011Projects}}

2011 Group Project 4

2011-10-08T23:49:44Z

Z3389806: /* Introduction */

{{2011ProjectsMH}}

----

=Huntington's Disease=
==Introduction==

[[File:HD patients.jpg|right|250px]]

Huntington’s disease (HD) is an [[#Autosomal dominant|autosomal dominant]] disease caused by the mutated huntingtin protein gene. HD is under the family of neurodegenerative diseases which only becomes identified by an expanded, repeated CAG trinucleotide tract, resulting in the formation of abnormal long proteins called polyglutamine seen at the molecular level.<ref name="PMID15459747"><pubmed>15459747</pubmed></ref>

HD is characterised by degeneration and dysfunction of the cerebral cortex and [[#Striatum|striatum]] causing deterioration in neurons which may be the reason for its clinical manifestations in jerky, involuntary movements such as [[#Chorea|chorea]].<ref><pubmed>21841917</pubmed></ref><ref><pubmed>21847326</pubmed></ref> HD was originally known as chorea before great detail of the disease was found, and in 1872, physician George Huntington first documented the clinical profile of the disease and HD was named after him.<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>

The disease is developed familially or sporadically. The majority of cases of development of HD is familial, caused by the inherited defective gene from the parent to the child. However in some rare cases, it is sporadically developed from new genetic mutation in alleles with no relation to inheritance.<ref name="Clinical">H L Paulson, R L Albin '''Huntington’s Disease: Clinical Features and Routes to Therapy.''' In: D C Lo, R E Hughes (editors). Neurobiology of Huntington's Disease: Applications to Drug Discovery (2nd ed.), Boca Raton (FL): CRC Press; 2011. Chapter 1. Frontiers in Neuroscience. PMID:21882418[http://www.ncbi.nlm.nih.gov/pubmed/21882418]</ref>

HD has a late onset of symptoms thus it is possible for someone to be the carrier of the mutated huntingtin gene without showing any symptoms of HD until in their later years. Diagnosis of the disease is made by the onset of symptoms and may vary between different people but is commonly revealed between the ages of 35-42. The tendency for symptoms to arise earlier is the result of further expansion of the CAG tract.<ref name="PMID6451036"><pubmed>6451036</pubmed></ref>

While there is no current cure for HD, there are treatments and medications available to help ease the symptoms of HD.<ref name="PMID19588393"><pubmed>19588393</pubmed></ref>

==History==
[[Image:George Huntington.jpg|thumb|right|George Huntington]]
Huntington's disease has existed since at least the seventeenth century and several physicians provided earlier descriptions of hereditary chorea but without much detail. In 1872, Huntington’s disease was first documented with great details by George Huntington in “On Chorea”, a paper published in ''The Medical and Surgical Reporter: A Weekly Journal''.<ref>Huntington G (1872). "On Chorea". Medical and Surgical Reporter of Philadelphia (The Hague: Nijhoff) 26 (15): 317–321. ISBN 9061860113. [http://en.wikisource.org/wiki/On_Chorea] </ref> Huntington’s disease was initially known as chorea, derived from the Greek word ''khoreia'' which means dancing in unison. George Huntington described the disease as “an heirloom from generations away back in the dim past” as he realized that Huntington's disease was hereditary. This conclusion was reached when he observed that if one of the parents had the disease, the offspring will inevitably have the disease too. In his paper, “On Chorea”, he described:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#eeeeff"
|"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease."<ref name="PMID11232352"><pubmed>11232352</pubmed></ref>
|}

Huntington thus was able to explain the precise pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.

'''TIMELINE OF HUNTINGTON'S DISEASE RESEARCH''' <ref><pubmed>16136077</pubmed></ref>

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1842'''
| Huntington's disease was first described by Charles Oscar Waters in a letter in Robley Dunglinson's "Practice of Medicine." <ref name="OxfordMonographHistory">Harper P (2002). "Huntington's disease: a historical background". In Bates G, Harper P, and Jones L. Huntington's Disease – Third Edition. Oxford: Oxford University Press. pp. 3–24. ISBN 0-19-851060-8.</ref>
|- style="background:#eeeeff"
|align="center"|'''1846'''
| Charles Gorman noticed that the symptoms associated with the disease seemed to affect many people in particular regions. Huntington's disease is observed as being localised.<ref name="OxfordMonographHistory"/>
|-
|align="center"|'''1860'''
| Johan Christian Lund produced the first description of Huntington's disease while working at Jefferson Medical College.<ref>Wexler A, Wexler N (2008). [http://yalepress.yale.edu/yupbooks/book.asp?isbn=9780300105025 The Woman Who Walked Into the Sea: Huntington's and the Making of a Genetic Disease.] Yale University Press. p. 288. ISBN 978-0-300-10502-5.</ref>
|- style="background:#eeeeff"
|align="center"|'''1872'''
| George Huntington’s paper, "On Chorea" was published.<ref name="PMID11232352"/>
|-
|align="center"|'''1888'''
| Hoffman describes juvenile Huntington's disease.<ref>Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German)</ref>
|- style="background:#eeeeff"
|align="center"|'''1900'''
| Mendel’s work on inheritance patterns of certain traits was rediscovered.<ref>On the Origin of Mendelian Genetics Amer. Zool. (1986) 26 (3): 753-768. [http://icb.oxfordjournals.org/content/26/3/753.abstract#fn-1]</ref>
|-
|align="center"|'''1908'''
| Punnett cites Huntington's disease as autosomal dominant.<ref>Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908)</ref>
|- style="background:#eeeeff"
|align="center"|'''1978'''
| Restriction fragment-length polymorphisms (RFLPs) were first described. This was used to locate the gene associated with Huntington's disease in 1983.<ref><pubmed>281713</pubmed></ref>
|-
|align="center"|'''1981'''
| The US–Venezuela Huntington's Disease Collaborative Research Project was initiated. This project aims to find a cure by studying individuals in Venezeula which has the highest concentration of Huntington's disease.<ref><pubmed>2881213</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1983'''
| The HD Huntingtin (HTT) gene was mapped to the short arm of chromosome 4.<ref name="PMID6316146"><pubmed>6316146</pubmed></ref>
|-
|align="center"|'''1989'''
| Linkage disequilibrium between HD gene and the loci ''D4S95'' and ''D4S98'' indicated a 2 Mb candidate region for localisation of HD gene near the loci.<ref><pubmed>2531223</pubmed></ref><ref><pubmed>2531224</pubmed></ref><ref><pubmed>1680285</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1993'''
| The HD gene was isolated and a CAG repeat mutation was identified.<ref><pubmed>8504314</pubmed></ref>
|-
|align="center"|'''1994'''
| The Working Group on Huntington's disease of the WFN/IHA published guidelines on counseling for predictive testing of Huntington's disease.<ref><pubmed>7966192</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1995'''
| A study done by Kremer et al. showed that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene.<ref><pubmed>7668260</pubmed></ref>
|-
|align="center"|'''1996'''
| The first mouse model for Huntington's disease was described.<ref><pubmed>9267033</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''1997'''
| Aggregates were described in mouse <ref><pubmed>8898202</pubmed></ref> and patient brains with Huntington's disease.<ref><pubmed>9302293</pubmed></ref>
|-
|align="center"|'''2000'''
| An inducible mouse model of Huntington's disease was described.<ref><pubmed>10778856</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2001'''
| The first phase-III clinical trials for Huntington's disease were published.<ref><pubmed>11502903</pubmed></ref>
|-
|align="center"|'''2001'''
| Huntington's disease-like 2 was first described. It is associated with a novel CAG repeat expansion.<ref><pubmed>11761463</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2002'''
| The first high-throughput screen was published. High-throughput screening is useful in the discovery of HD therapeutics.<ref><pubmed>12200548</pubmed></ref><ref><pubmed>18336216</pubmed></ref>
|-
|align="center"|'''2004'''
| A study revealed that 40% of the variance remaining in onset age of Huntington's disease is attributable to genes other than the HD gene and 60% is environmental.<ref><pubmed>14993615</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2004'''
| Langbehn et al. devised a formula based on CAG expansions that may predict whether an HD gene carrier of a given age is “close to” or “far from” onset.<ref><pubmed>15025718</pubmed></ref><ref><pubmed>21626556</pubmed></ref>
|-
|align="center"|'''2006'''
| The mitochondrial master gene, PGC1alpha, was found to be abnormally transcribed in Huntington's disease, thus resulting in mitochondrial dysfunction.<ref><pubmed>17055784</pubmed></ref>
|- style="background:#eeeeff"
|align="center"|'''2009'''
| Gene therapy stalls development of Huntington's disease in mice.<ref><pubmed>19864571</pubmed></ref>
|}

==Epidemiology==

There seems to be an increased prevalence of Huntington's disease among Europeans as compared to Africans and Asians. European populations exhibit a comparatively high prevalence with 4-8 per 100,000 individuals suffering from HD.<ref><pubmed>1535611</pubmed></ref> Two of the most well-known populations in which high prevalence of HD is found was notably in the state of Zulia, Venezuela<ref><pubmed>2139171</pubmed></ref> and Northern Ireland.<ref name="PMID7562964"><pubmed>7562964</pubmed></ref> The overall prevalence of HD in Mexico was also expected to be comparable or even higher to that of European populations.<ref><pubmed>19672992</pubmed></ref>.

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:220px"|'''Country/Region'''
|style="width:300px"|'''Prevalence of HD (individuals per 100,000)'''
|- align="center"
|Venezuela
| 700 <ref>R. Avila-Giron '''Medical and Social Aspects of Huntington's Chorea in the State of Zulia, Venezuela''' in: Advances in Neurology, Vol 1 (eds A. Barbeau, T.N. Chase and G.W. Paulson) New York: Raven Press, 1973, pp. 261-266 [http://www.ahdansw.asn.au/information/faq_prevalence.html]</ref>
|- align="center" style="background:#eeeeff"
|Tasmania (Australia)
| 12.1 <ref><pubmed>2142982</pubmed></ref>
|- align="center"
| Northern Ireland
| 6.4 <ref name="PMID7562964"/>
|- align="center" style="background:#eeeeff"
| South East Wales (UK)
| 6.2 <ref><pubmed>9231935</pubmed></ref>
|- align="center"
| Olmsted County, Minnesota (US)
| 6 - 6.6 (1960) & 1.8 - 2 (1990) <ref><pubmed>8018043</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Valencia Region (Spain)
| 5.38 <ref><pubmed>9528016</pubmed></ref>
|- align="center"
| Slovenia
| 5.16 <ref>Peterlin B, Kobal J, Teran N, Flisar D, Lovrecić L.'''Epidemiology of Huntington’s disease in Slovenia.''' Acta Neurol Scand.: 2009 PMID:18976322 [http://www.ncbi.nlm.nih.gov/pubmed/18976322]</ref>
|- align="center" style="background:#eeeeff"
| Oxford Region (UK)
| 4.0 <ref><pubmed>21088431</pubmed></ref><ref><pubmed>8108531</pubmed></ref>
|- align="center"
| New South Wales (Australia)
| 0.65 <ref><pubmed>11008591</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Japan
| 0.65 <ref><pubmed>8752454</pubmed></ref>
|- align="center"
| Finland
| 0.5 <ref><pubmed>2889026</pubmed></ref>
|- align="center" style="background:#eeeeff"
| Taiwan
| 0.42 <ref name="PMID20881427"><pubmed>20881427</pubmed></ref>
|- align="center"
| Hong Kong
| 0.37 <ref><pubmed>7586664</pubmed></ref>
|}
{| align="center"
|'''Table 1:''' ''Prevalence of Huntington's Disease in various parts of the world''
|}

Table 1 shows the prevalence of HD in different parts of the world, with regions ranked according to how prevalent HD is.
Countries with the highest prevalence are from Europe with most appearing at the top of the table whereas Asian countries are found at the bottom half of this table. This indicates the lower prevalence of HD in Asia as compared to that in European populations. This observation is further supported by a study done by Shiwach and Lindenbaum (1990), it was found that the minimum prevalence of HD among immigrants from the Indian subcontinent was found to be almost half that found in the indigenous UK population.<ref><pubmed>2151860</pubmed></ref> For those areas where there are intermarriages with Europeans, there is a higher occurrence of the disease. This is related to the higher frequency of huntingtin alleles with 28–35 CAG repeats in Europeans and the fact the disease is autosomal dominant. <ref>DC Rubinsztein, Molecular biology of Huntington's disease (HD) and HD-like disorders. In: S Pulst, Editor, Genetics of movement disorders, Academic Press, California (2003), pp. 365–377.</ref>

In a paper by Warby et al. (2011), it was reported that Huntingtin (HTT) gene haplotypes contribute to the difference in prevalence of HD between European and East Asian populations. A haplotype is a set of closely linked genetic markers present on a chromosome which tend to be inherited together. Different HTT haplotypes have different mutation rates which results in expansion of CAG tract (marker for Huntington’s disease).<ref name="PMID19249009"><pubmed>19249009</pubmed></ref> Hence, for HTT haplotypes with higher mutation risk such as A1 and A2 halotypes, individuals are more susceptible to HD due to CAG expansion and this corresponds to higher prevalence. This is supported by the findings that higher risk A1 and A2 HTT halotypes composed the majority of HD chromosomes in Europe whereas it is absent in China and Japan.<ref><pubmed>21248742</pubmed></ref>

{| align="center" style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|rowspan="2" style="width:150px"|'''HD Halotypes'''
|colspan="2" style="width:150px"|'''General Population'''
|colspan="2" style="width:150px"|'''HD Chromosomes'''
|- align="center" style="background:#9ea1ff"
|East Asia
|Europe
|East Asia
|Europe
|- align="center"
|A1
|0.00
|0.07
|0.00
|0.50
|- align="center" style="background:#eeeeff"
|A2
|0.00
|0.13
|0.00
|0.29
|- align="center"
|B
|0.16
|0.04
|0.10
|0.00
|- align="center" style="background:#eeeeff"
|C
|0.40
|0.47
|0.77
|0.02
|}
{| align="center"
|'''Table 2:''' ''HTT haplotype frequency in East Asia and Europe'' <ref name="PMID19249009"/>
|}

The incidence rate of HD increases with age. It was reported in Taiwan that the range of age at which most onset of HD occurs is between 40-49 years in males and between 50-59 years in females.<ref name="PMID20881427"/> This trend is similar to that reflected in a Northern Ireland study, whereby the age group in which the highest number of HD onset occurs is 40-44 years.<ref name="PMID7562964"/> Both of the above-mentioned studies concluded that there is no significant difference for the age of onset between males and females, indicating no sexual predominance for HD.

==Genetics==

===Inheritance===
[[File:Inheritance pattern in Huntington's Disease.jpeg|thumb|left|250px|Inheritance pattern in Huntington's Disease]]

Huntington's disease is an autosomal-dominant disorder caused by a faulty gene on the 4th autosomal chromosome (meaning it’s found on one of the first 22 pairs of chromosomes). Since it is not expressed on the last two sex chromosomes, it can equally affect both males and females.

An affected parent is capable of passing either the HD gene or the healthy gene to their offspring. Due to its autosomal dominant nature, if the individual has a HD gene it will ‘overpower’ the healthy gene and the offspring will become affected by HD. Hence, with each pregnancy, the child is at 50% chance of inheriting HD if one parent is affected.
In rare cases where both parents are affected, the child will have a 75% chance of inheriting HD. <ref><pubmed>15100720</pubmed></ref>

===Huntingtin Gene===
[[File:Huntingtin gene.jpeg|thumb|300px|Huntingtin gene]]
Huntington’s Disease is due to a mutation causing an expanded CAG (cytosine-adenine-glutamine) trinucleotide repeat tract in the Huntingtin (HTT) gene.

'''HTT & normal functions:'''

The HTT gene is comprised of 67 exons and is located between the markers D45127 and D45180 on the short arm 4th chromosome (4p) at position 16.3, spanning over a genomic region of over 200kb.<ref name="MM"><pubmed>20664076</pubmed></ref> The huntingtin protein is found in the nucleus, cell body, dendrites and nerve terminals and is also associated with cellular organelles such as golgi apparatus, endoplasmic retiniculum and mitochondria. It is found in many body tissues but is predominantly active in the brain, specifically in the striatum (integral part of basal ganglia).

The precise function of HTT remains unknown. Many studies have tried to determine the pathological effects of HTT, with conclusion that it has a complex role at several cellular levels.

* HTT is a primary constituent of the dynactin complex which networks with microtubules in dendrites, signifying a role in vesicle transport and cytoskeleton anchoring. <ref name="MM"/>

* It has been shown to have a significant role in endocytosis, neuronal transport and postsynaptic signalling.

* Additionally, HTT is capable of protecting neuronal cells from apoptotic stress, hence having pro-survival role in neural tissue.

* A study by Bates & Murphy, 2001 showed that knocking out the HTT gene in mice will result in death of the embryo by day 7.5 due to atypical brain development. It was therefore concluded that HTT is necessary for cell survival and its loss is most likely to cause neurodegeneration. <ref> Bates GP, Murphy KP (2002) '''in Huntington's Disease''' (eds Bates GP, Harper PS, Jones AL) 387–426. Oxford, UK: Oxford University Press. </ref>

HTT contains a polymorphic region containing the CAG repeat, normally 10-35 times (i.e. CAGCAGCAG...).

'''HTT & Huntington’s Disease:'''
[[File:Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease.jpg|thumb|400px|Healthy Huntingtin protein and Huntingtin gene mutated by Huntington's Disease]]

Huntington Disease - caused by a mutation on the 1st exon of the HTT gene.

As previously discussed the huntingtin protein is found in unaffected individuals, It is however associated with HD when the CAG trinucleotide is repeated more than 36 times. This abnormal repeat of CAG leads to formation of long proteins known as polyglutamine. <ref name="HD Modelling"> Zala, D. (2004). '''Huntington’s Disease modelling and treatment: from primary neuronal cultures to rodents'''. </ref> In unaffected individuals the polyglutamine chains are formed by maximum 36 repetitions of CAG. Conversely, in HD patients the repeats vary from 36-121 times with increasing number of repeats being inversely correlated with the age of HD onset and severity of the loss cognitive abilities.<ref name="MM"/>

Patients with repeats of 36-40 times may or may not develop the clinical manifestations of HD, whilst those with CAG repeats of more than 40 almost always develop the disorder.

With each altered pass of the HTT gene to the next generation, the CAG repeat length elongates leading to more severe and earlier onset of symptoms.

Individuals with CAG repeats of 27-35 in HTT gene do not develop HD; however their offspring is at high risk of developing the disease with CAG repeats of more than 35 in the HTT gene. <ref><pubmed>21601164</pubmed></ref>
CAG expansions are therefore the biomarkers used for genetic tests to identify mutant HTT carriers.<ref name="Patho"><pubmed>15459747</pubmed></ref>

==Molecular Mechanisms & Pathogenesis ==

Although HD is a broad area of current research, the exact pathogenesis by which HTT mutation leads to the neurodegeneration and serious loss of cognitive abilities has not yet been fully understood.
There are key unproven pathological mechanisms that seem to be used to explain the pathways by which a mutation in the HTT gene can cause cellular and clinical complications.

The neurodegenerative changes that occur in HD patients are most commonly localised to the putamen and caudate nuclei which are substructures of the basal ganglia forming the striatum region of the brain.<ref><pubmed>17999380</pubmed></ref> The function of the basal ganglia has major consequences on the organisation of motor behaviour. Destruction of neural tissue is also located within the temporal and frontal lobes of the cerebral cortex which are significant in mental functioning, movement and sensation. <ref><pubmed>10665265</pubmed></ref>

===Destruction of Striatal cells===
The nerve cells of the striatum known as medium-sized spiny neurons (MSN) are the predominant nerve cells affected by mutant HTT. These specific neurons are responsible for the release of gamma-aminobutyric acid (GABA), which is capable of inhibiting neurotransmitter release by other nerve cells.<ref name="HD Modelling"/>
The striatum is the main target for glutamatergic output from the afferant neurons pf thalamus and the cortex, making striatal cells highly sensitive to glutamate. Even though striatal cells depend on glutamate for function and survival, glutamate in excessive amounts found in autoptic human brain tissues of HD patients is shown to an an excitotoxin. Neurodegenration and excitotoxicity is therefore inducible by directly injecting glutamate into the striatum. Hence the accumulation of long polyglutamine chains in the striatum of a patient affected with HD, is strongly linked to the degeneration of MSN which will disturb it’s key functions.
<ref> Morton, J. (2004). '''Molecular Pathogenesis of Huntington's Disease'''. ''Advances in Clinical Neuroscience and Rehabilitation,'' 1(4),617-628.</ref>It has been suggested that MSN destruction leads to decreased inhibition of the thalamus, hence increasing thalamus activity and the release of its contents to certain regions of the brain. It is speculated that this inhibition results in disorganised and hyperkinetic movements known as chorea.

[[File:Key cellular pathogenic mechanisms in HD.jpg|center|thumb|500px|Key cellular pathogenic mechanisms in Huntington's Disease]]

===Aggregate formation===
The mutated HTT protein causes unfolding or abnormal folding of this protein. This toxic protein is recognised by molecular chaperones which are involved with assembly of proteins. Once unsuccessful the misshapen proteins are tagged and targeted by proteosomes in the cytoplasm for degradation.<ref name="MM"/> HTT is cleaved by a different number of proteases such as ''caspases'' and calcium-dependent proteases such as ''calpain''. However proteosome efficiency is highly reduced in HD patients, which not only leads to aggregating toxic material in striatal cells but it also means that the proteases become incapable of breaking down other toxic products in the cell.<ref><pubmed>10770929</pubmed></ref>

===Abnormal protein-protein interaction===
HTT protein is widespread through many neural tissues, hence when the mutated protein carries an expanded polyglutamine tract, interactions between these tissues are altered.
HTT is known to react with HTT-associated protein1 (HAP1) and HTT-interacting protein 1 (HIP1).<ref><pubmed>18466116</pubmed></ref>
In HD, the polyglutamine chain on the mutant HTT increases the binding capacity for HAP1 and therefore reduces its availability in neural tissue. HAP1 is involved in regulating the stabilisation of membrane receptors on the cell surface that are involved in neural response to neurotransmitters and neutrophic factors. <ref><Pubmed>19262167</pubmed></ref>

HTT protein interaction with HIP1 is however decreased with lengthening polyglutamine chains. An over-expression of HIP1 is known to be neurotoxic, therefore if mutated HTT has a reduced binding capacity for HIPI, it can easily accumulate in cells and become pathological.<ref><pubmed>18637945</pubmed></ref> <ref name="HD Modelling"/>

===Calcium Signalling===
The accumulation of toxic HTT proteins with elongated polyglutamine chains impairs the calcium signalling pathway and disrupts cellular homeostasis and mitochondrial function. In transgenic mice with mutated HD, the mutated HTT has shown to trigger mitochondrial membrane permeabilization and apoptotic cell death by impairing proteosome activity and interfering with Ca2+ signaling. <ref><pubmed>11331615</pubmed></ref>

Additionally, mutant HTT protein is also able to bind to the inositol 1,4,5- triphosphate receptor 1 (InsP3R1) on the endoplasmic reticulum and stimulate the inositol triphosphate (IP3) signalling pathway. The activation of the IP3 pathway leads to elevated calcium release from InsP3R1 of cells containing mutant HTT.<ref><pubmed>15336977</pubmed></ref> Over time, this increase in cystolic calcium levels causes the mitochondrial calciumm intake to also increase, which eventually leads to mitochondrial swelling and the subsequent release of proapoptotic factors such as cytochrome ''c'' and apoptosis-inducing factor.<ref><pubmed>18193642</pubmed></ref>

==='''Role in transcription inhibition'''===
The mutant HTT fragments are able to translocate into the nucleus where they most commonly interrupt DNA transcription or form intracellular inclusions.
Studies have shown that unusually long polyglutamine tracts such as those in HD are able to disrupt normal function of transcription factors and inhibit or alter DNA transcription.<ref name="Patho"/>
Transcription factors such as p53, CREB-binding protein (CBP), specifity protein 1 (S1) and TATA-binding protein can bind to the polyglutamine chain of mutated HTT and inhibit RNA polymerase binding to the promoter region of the DNA strand. Several of the transcription factors such as CBP contain glutamine as part of their integral structure, which is able to interact with the polyglutamine chain on the mutant HTT protein and aggregate; hence repressing DNA transcription of specific proteins such as brain-derived neutrophic factor (BDNF).<ref><pubmed>12087131</pubmed></ref> BDNF belongs to the neutrophin family of growth factors found specifically in the hippocampus, cortex and basal ganglia. It functions to assist in neuron cell survival and also to support growth and differentiation of new neurons.<ref><pubmed>11408619</pubmed></ref>

==Clinical Manifestations==

As previously mentioned, Huntington’s Disease is a hyperkinetic disorder which is caused by the degeneration of neurons in the cerebral cortex and striatum. Clinical manifestations that occur from a hyperkinetic disorder, in particular reference to HD is marked by five specific features:

[[Image:Peripheral and Central Nervous System impairment in Huntington's Disease..JPG|thumb|right|Symptoms and impairment of the human body that manifests in patients diagnosed of Huntington's Disease regardless of gender|300px]]

* Chorea movements
* Heritability; HD is autosomally dominant
* Physical and behavioural disturbances; unbalanced stance and personality changes
* Cognitive impairment; causes depression, dementia
* Death common in 15-20 years after intial onset <ref><pubmed>15036808</pubmed></ref><ref><pubmed>21209352</pubmed></ref>

A diverse range of signs and symptoms can develop in those who are affected thus making symptoms clinically unique for different individuals. However, the typical symptoms that manifest in the majority of HD carriers are chorea and behavioural changes which occur at adult-onset between the ages 35-42.<ref name="PMID6451036"/><ref><pubmed>11442329</pubmed></ref> The progression of the disease continues to develop from the first signs of onset over 10-30 years, eventually leading to death.

In the case of HD, symptoms are manifested in three classes –

'''1) motor;''' it affects the body by progressively developing a disorder in movements which is most commonly seen as chorea;

'''2) cognitive;''' a progressive impairment in the brain that leads commonly to dementia;

'''3) behaviour/psychiatric;''' also caused by a progressive impairment in the cortex, however leading to behavioural disturbances and can vary depending on the severity and the degree of the state of disease.<ref name="Clinical"/><ref name="PMID15459747"/>

'''Motor movement Impairment'''

As HD is a neurodegenerative disorder, the cortex of the brain is affected thus naturally giving rise to the impairment in motor functions. Although there are a range of defective motor movements which may occur, chorea remains to be the one typically known to characterise HD. Derived from the Greek work khoreia which means dance, this involuntary movement typically involves an involuntary jerky dance like movement. Motor impersistence is also very common in HD patients and is often classified under the same branch as chorea.<ref name="Clinical"/> The juvenile cases, individuals with a younger onset of HD may show symptoms of involuntary muscle twitching, abnormal eye movements, dystonia and parkinsonism which may be experienced rather than manifesting chorea.<ref><pubmed>10987900</pubmed></ref> Further down the track however, these involuntary movements will increase and become prevalent and spread to the arms, legs, trunk, and head of the patient and may develop into chorea. The individuals with an adult-onset of HD who start off with the symptoms of chorea, may develop an evolved complicated series of movements as the disease progresses which may include dystonia.<ref><pubmed>7753064</pubmed></ref>

'''Video of Huntington's disease patient'''

[[File:HD patient with no treatment.mov]]

==Diagnostic Tests==

Huntington’s Disease is most commonly diagnosed at the onset on symptoms, typically between the ages of 35 and 42.<ref name="PMID6451036"/> The diagnosis is relatively simple in patients with typical symptoms. Diagnosis is important to ensure that this disease is not confused with similar diseases, which mimic similar characteristics.<ref name="PMID17240289"><pubmed>17240289</pubmed></ref> These include tardive dyskinesia, chorea gravidarum, hyperthyroid chorea and Neuroacanthocytosis (refer to table below).<ref><pubmed>16003113</pubmed></ref> In children, subacute sclerosing panencephalitis can easily be mistaken for Huntington’s disease as they both present with very similar clinical presentations.<ref><pubmed>11807185</pubmed></ref> Huntington’s disease can also be diagnosed when a patient is asymptomatic, by genetic testing. This also enables detection of the disease in embryos.

===Differential Diagnosis===

[[File:Neuroacanthocytosis.jpg|right|150px|Neuroacanthocytosis|thumb]]

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:150px"|'''Disease''' ||'''Characteristics'''
|-
|align="center"|Huntington’s Disease || Random involuntary jerky movements, lack of coordination, uncompleted motions as well as saccadic eye movements <ref name="PMID17240289"/>
|- style="background:#eeeeff"
|align="center"| Tardive Dyskinesia || Involuntary movements occurring particularly in older patients. These consist of chewing movements, tongue protrusions, licking and rotating tongue movements, as well as choreoathetoid limb movements <ref><pubmed>2898870</pubmed></ref>
|-
|align="center"| Chorea Gravidarum || A complication of pregnancy which consists of involuntary, brief and nonrhtymic movements. These are non repetitive and can be associated with any limbs <ref><pubmed>21496582</pubmed></ref>
|- style="background:#eeeeff"
|align="center"| Hyperthyroid Chorea || Abnormal, involuntary movements due to an increased response of striatal dopamine receptors to dopamine <ref><pubmed>474817</pubmed></ref>
|-
|align="center"| Neuroacanthocytosis || Spicualted erythrocytes with symptoms including involuntary or slow movements, muscle weakness and abnormal body postures <ref><pubmed>1998879</pubmed></ref>
|}

===Neuropathology===

[[File:Huntington Disease patient and control MRI.gif|400px|thumb|left|Caudate,putamen, cerebral and cerebellar volumes. Huntington's disease (top) control (bottom)]]

Anton (1896) and Lannois (1897) were the first to observe neuropathological changes associated with Huntington’s disease. They independently noted the degeneration of the striatum in patients with Huntington’s disease.<ref><pubmed>2147116</pubmed></ref> Numerous other neuropathological abnormalities have now been identified in different parts of the brain including the subtalamic regions, pons and medulla oblongata, the spinal cord, cerebellum, superior olive, claustrum <ref name="PMID2932539"><pubmed>2932539</pubmed></ref> as well as the amygdala, dorsal striatum and globus pallidus.<ref name="PMID8929153"><pubmed>8929153</pubmed></ref>

Other brain areas greatly affected include the substantia nigra <ref><pubmed>8505640</pubmed></ref> and the centromedial-parafascicular complex of the thalamus.<ref><pubmed>10378380</pubmed></ref> The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic projection neurons of the neostriatum. This is accompanied with the atrophy of the caudate of nucleus, putamen and external segment of the globus pallidus.<ref name="PMID21496571"><pubmed>21496571</pubmed></ref>

In 1895, Vonsattel et al. developed a five-tiered pathological grading system based on this hallmark, based on gross and pathological observations. A grading from 0 to 4 is given to patients based upon the amount of neuronal loss and atrophy in the striatum. Grade 0 presents with no evident cell loss and progresses to grade 4, in which a patient has approximately 95% neural loss.<ref name="PMID2932539"/>

===Imaging===

During the course of Huntington’s disease, morphological changes that occur in the brain can be observed using brain imaging techniques. These techniques include volumetric analysis of '''computed tomography (CT) scans''', '''magnetic resonance images (MRIs)''', '''single-photon emission computed tomography (SPECT)''' as well as '''positron emission tomography (PET)'''.<ref name="PMID16496032"><pubmed>16496032</pubmed></ref>

[[File:SPECT scanner.jpg|right|300px|SPECT scanner|thumb]]

Routine MRI and CT scan have proven to be extremely helpful in the detection of moderate-severe progression of Huntington's disease, however they are usually unhelpful in the detection and diagnosis of early disorder.<ref name="PMID17240289"/> Studies using scans have suggested that the earliest change in Huntington’s disease occurs in the caudate nucleus.<ref name="PMID8929153"/> The progressive bilateral atrophy of the striatum throughout a patient’s life can be detected using CT scans as well as MRIs.<ref><pubmed>2524678</pubmed></ref> During the advancement of the disease, other regions of the striatum such as the putamen and globus palidus can also be noted as being affected.<ref><pubmed>9040728</pubmed></ref> These changes in the striatum have been related with specific cognitive defects such as problems with attention and memory function.<ref><pubmed>1531910</pubmed></ref>

Harries et al found, using MRI and single-photon emission computed tomography, that the putamen was the area that showed the greatest amount of atrophy while the caudate was the area that presented with the greatest reduction in cerebral blood flow in patients with Huntington’s disease compared with controls. This correlates with some of the symptoms presented in patients with Huntington’s disease such as difficulty with motor skills.<ref name="PMID8929153"/>

[[File:Huntington's disease MRI.jpg|left|200px|MRI of patient with Huntington's disease|thumb]]

PET scans as well as functional MRI studies allow the detection of changes in affected brain areas even before the onset of symptoms.<ref><pubmed>10805336</pubmed></ref> Functional brain imaging is based on the fact that neural activity is related to either regional cerebral blood blow, the local degree of glucose metabolism or regional changes in receptor binding. This can be measured by a resting-state study, where the patterns of activity are measured in a resting state or by a neurocognitive-activation study where patterns of activity are measured during the performance of a given task.<ref name="PMID16496032"/>

Studies using SPECT have shown metabolic abnormalities in the striatal and extra-striatal regions of patients with Huntington’s disease.<ref><pubmed>9313639</pubmed></ref> They have also demonstrated that there is a reduction in the regional cerebral blood flow in the striatum and prefrontal cortex of these patients.<ref><pubmed>2933014</pubmed></ref>

PET scans have also been used to identify that patients with Huntington’s disease show a marked reduction in dopamine binding in the striatum <ref><pubmed>9126061</pubmed></ref> which shows a strong correlation with verbal fluency, visuospatial skills and perceptual speed and reasoning.<ref><pubmed>9448576</pubmed></ref>

===Genetic testing and prenatal diagnosis===

After the ''Huntingtin'' gene’s discovery in 1983 <ref name="PMID6316146"/>, genetic testing first became available using '''linkage analysis'''. However it wasn’t until the 1993 when the CAG repeat on the affected chromosome was identified that accurate diagnosis could be made.<ref><pubmed>21171977</pubmed></ref>

[[File:Amniocentesis.jpg|right|Amniocentesis|thumb|250px]]

Although genetic testing is widely available to diagnose Huntington’s disease, less than 5% of at risk individuals actually chose to get tested.<ref><pubmed>10489044</pubmed></ref>. Those that choose to get tested generally do so in order to make career and family choices whereas those that choose not to get genetically tested commonly make this decision due to the lack of effective treatment. It is also important to note that suicide is very common following positive results.<ref><pubmed>10205260</pubmed></ref>

Current protocols are designed to exclude certain people from getting genetically tested as well as ensure proper genetic counseling before an individual can be tested.<ref><pubmed>1968570</pubmed></ref> Those excluded from the procedure include minors under the age of 18, persons with severe psychiatric illnesses and those who have external pressure to get tested.<ref><pubmed>8058167</pubmed></ref>

Antenatal testing is available due to the fact that genetic testing can be performed on any cell containing DNA. '''Chorionic villus sampling''' can be carried out between the 10th and 12th week of pregnancy whereas '''amniocentesis''' is performed between the 15th and 17th weeks and subsequent DNA-testing can be carried out. Parents who know their genetic status who choose not to get tested prenatally often do so in the hope that treatment will eventually become available for affected offspring.<ref><pubmed>11973620</pubmed></ref>

Preimplantation diagnoses have now recently been available in several countries. This in vitro procedure begins when the embryo is in its eight-cell stage where a single cell is screened. The embryo without the elongated CAG repeat is placed in the mother’s womb in hope for a normal pregnancy.<ref><pubmed>17245406</pubmed></ref>

==Treatment==

There is no cure for Huntington's disease. Similar to AIDS, only the symptoms of HD can be treated.<ref name="PMID19588393"/>

===Medications===
===='''Tetrabenazine'''====

[[Image:Tetrabenazine structure.JPG|thumb|right|Chemical structure of Tetrabenazine]]

Tetrabenazine was approved by the U.S. Food and Drug Administration in August 2008 to treat HD, making it the first drug approved for use in the United States to treat the disease.<ref><pubmed>20957126</pubmed></ref>

Tetrabenazine is a dopamine-depleting agent which helps to suppress chorea in HD and other hyperkinetic movement disorders such as Tourette's syndrome and tardive dyskinesia.<ref><pubmed>16466307</pubmed></ref> Its role as a dopamine-depleting agent is achieved by inhibiting the vesicular monoamine transporters (VMAT).

There are two types of VMAT: VMAT1 (located in pheripheral endocrine and paracrine cells) and VMAT2 (located predominantly in the brain and in sympathetic neurons).<ref><pubmed>8643547</pubmed></ref> Tetrabenazine binds selectively with a high affinity to VMAT2 and low affinity for VMAT1. VMAT2 is the only transporter that transports dopamine from the cytoplasm into synaptic vesicles for storage and eventual release.<ref><pubmed>2751365</pubmed></ref>

By inhibiting VMAT2, dopamine will not be packaged into vesicles and hence, unable to travel across the synaptic cleft. Tetrabenazine also binds and inhibit to dopamine receptors. This suppresses the amount of dopamine binding to the dopamine receptor located at the post synaptic nerve terminal. Thus, the neurones will not be stimulated and no cascade for the inducement of kinetic movements will be triggered.

[[Image:Mechanism of tetrabenazine.jpg|thumb|center|Mechanism of tetrabenazine inhibition|300px]]

===='''Other drugs'''====

{| align="center" style="border: solid 2px #a0a0ff" border="1"
|- align="center" style="background:#8eb2ec"
|'''Types of symptoms'''
|'''Types of medications'''
| style="width:11%"|'''Active chemical ingredient'''
| style="width:1%"|'''Drugs'''
| style="width:45%"|'''Mechanism of action'''
|'''Possible negative side-effects'''
|- align="center"
| rowspan="6" align="center" style="background:#eeeeff"|Movement disorders
| rowspan="5" align="center"|Antiseizure drugs
(anticonvulsants)
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000677/ Valproic acid] <ref><pubmed>16507108</pubmed></ref>
|Depakene Depakote
|It enhances gamma-aminobutyric acid-mediated (GABA) neurotransmission, which decreases the excitability of neurons and inhibits histone deacetylases.<ref><pubmed>17514356</pubmed></ref>
| align="center"|renal toxicity <ref><pubmed>8108303</pubmed></ref><ref><pubmed>21868496</pubmed></ref>, hepatoxicity <ref><pubmed>21492891</pubmed></ref>, encephalopathy <ref><pubmed>18201150</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000560/ Lorazepam]
| Ativan
|It increases the efficiency of GABA and has an inhibitory effect on the activity of the HPA axis. <ref><pubmed>12240908</pubmed></ref>
| align="center"|sleepiness <ref><pubmed>4341107</pubmed></ref>, withdrawal symptoms <ref><pubmed>6131080</pubmed></ref>, memory impairment <ref><pubmed>3960963</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000957/ Lamotrigine]
| Lamictal
| It blocks sodium channels and α4β2 neuronal nicotinic acetylcholine receptors (nAChRs).<ref><pubmed>20688974</pubmed></ref>
| align="center"|chorea <ref><pubmed>16900938</pubmed></ref>, toxic epidermal necrolysis <ref><pubmed>9061826</pubmed></ref><ref><pubmed>12892003</pubmed></ref>, multiorgan failure <ref><pubmed>19380079</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001067/ Levetiracetam] <ref><pubmed>16340384</pubmed></ref>
| Keppra
| It binds to synaptic vesicle protein SV2A and hence, impede nerve conduction.<ref><pubmed>15210974</pubmed></ref>
| align="center"|somnolence <ref><pubmed>18728811</pubmed></ref>, asthenia <ref><pubmed>10908898</pubmed></ref>, headache <ref><pubmed>10999557</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000635/ Clonazepam]
|Klonopin Rivotril
| Refer to Lorazepam
| align="center"|drowsiness <ref><pubmed>12390050</pubmed></ref>, disinhibition, sexual dysfunction <ref><pubmed>2889724</pubmed></ref>
|- align="center"
| Antianxiety drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000556/ Diazepam]
|Valium Antenex
| Refer to Lorazepam
| align="center"|rebound anxiety after withdrawal <ref><pubmed>6145363</pubmed></ref>
|- align="center"
| rowspan="9" style="background:#eeeeff"|Psychiatric disorders
| rowspan="5"|Antidepressants
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000214/ Escitalopram]
|Lexapro Lexamil
| It inhibits serotonin reuptake once released into the synapse, promoting serotonin transmission.<ref><pubmed>16336034</pubmed></ref>
| align="center"|insomnia<ref>US Food and Drug Administration ''' [http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf Review and Evaluation of Clinical Data: Escitalopram Oxalate]</ref>, sexual dysfunction <ref><pubmed>16430968</pubmed></ref>, suicidal ideation <ref name="PMID19832967"><pubmed>19832967</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000885/ Fluoxetine]
|Prozac Sarafem
| Refer to Escitalopram
| align="center"|mania <ref><pubmed>3485926</pubmed></ref>, akathisia <ref><pubmed>2549018</pubmed></ref>, nausea <ref>Eli Lilly and Company [http://pi.lilly.com/us/prozac.pdf '''Prescribing Information of Prozac'''](June 15, 2011) </ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001017/ Sertraline]
|Zoloft Lustral
| Refer to Escitalopram
| align="center"|similar effects to flouxetine and escitalopram <ref><pubmed>8909330</pubmed></ref><ref><pubmed>11229450</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000732/ Nortriptyline]
|Aventyl Noritren
| Norepinephrine (noradrenaline) as well as serotonin reuptake is inhibited.<ref><pubmed>20363235</pubmed></ref>
| align="center"|suicidal ideation <ref name="PMID19832967"/>, hepatic failure <ref><pubmed>8848811</pubmed></ref>, dry mouth
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000995/ Mirtazapine]
| Remeron Avanza
| It is associated with the antagonism of central presynaptic α2-adrenergic receptors.<ref><pubmed>19401164</pubmed></ref>
| align="center"|dry mouth, increases in appetite <ref><pubmed>11607047</pubmed></ref>, restless legs syndrome (RLS) <ref><pubmed>18756499</pubmed></ref>
|- align="center"
| rowspan="2"|Antipsychotic drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000604/ Haloperidol]
|Haldol Serenase
| Its antidopaminergic action inhibits binding of dopamine to dopamine D(2) receptors.<ref><pubmed>21663752</pubmed></ref>
| align="center"|acute dystonia, parkinsonism <ref><pubmed>17054159</pubmed></ref>, cognitive decline & brain damage <ref><pubmed>18228005</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000893/ Clozapine]
|Clozaril Zaponex
| It inhibits transmission of dopamine and serotonin by binding to the corresponding receptors.<ref><pubmed>21496455</pubmed></ref>
| align="center"|[[#Agranulocytosis|agranulocytosis]] <ref><pubmed>8515788</pubmed></ref>, myocarditis <ref><pubmed>17194170</pubmed></ref>, gastrointestinal hypomotility <ref><pubmed>18452342</pubmed></ref>
|- align="center"
| rowspan="2"|Mood-stabilizing drugs
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000531/ Lithium]
| Lithobid
| It is associated with the modulation of neurotransmitters as well as signals involved in cytoskeleton dynamics.<ref><pubmed>10208444</pubmed></ref>
| align="center"|renal failure <ref><pubmed>19940841</pubmed></ref>, nystagmus <ref><pubmed>12552061</pubmed></ref>, teratogenicity <ref><pubmed>11948561</pubmed></ref>
|- align="center"
| [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000620/ Carbamazepine]
|Tegretol Carbatol
| It potentiates GABA receptors <ref><pubmed>7603459</pubmed></ref> and stabilises voltage-gated sodium channels.<ref><pubmed>20561518</pubmed></ref>
| align="center"|congenital malformations <ref><pubmed>21127116</pubmed></ref>, pitch perception deficit <ref><pubmed>12581810</pubmed></ref>
|}
'''Table 3''' ''Symptomatic medications for Huntington's disease''

''Note: Some drugs have overlapping effects eg. valproic acid and lamotrigine can also used as mood-stabilising drugs.''

'''Disclaimer:''' The table above is not a comprehensive reference. Please consult your doctor for further information.

===Therapies===

'''Psychotherapy:''' Aims to help a person manage behavioural problems, develop coping strategies, manage expectations during progression of the disease and facilitate effective communication among family members.<ref><pubmed>17352944</pubmed></ref>

'''Speech therapy:''' HD significantly impairs control of muscles of the mouth and throat that are essential for speech, eating and swallowing
Hence, this therapy addresses difficulties with muscles used in eating and swallowing.<ref name="PMID11096752"><pubmed>11096752</pubmed></ref>

'''Physical Therapy:''' It helps to enhance strength, flexibility, balance and coordination. These exercises can help maintain mobility as long as possible and may reduce the risk of falls. Patients may need to use a walker or wheelchair to assist them.<ref name="PMID11096752"/>

'''Occupational Therapy:''' This therapy requires the use of assistive devices that improve functional abilities.<ref name="PMID11096752"/>
::::::*Handrails at home
::::::*Assistive devices for activities such as bathing and dressing
::::::*Eating and drinking utensils adapted for people with limited capabilities

==Current/Future Research==

[[File:Huntington disease atrophy 1.jpg|left|150px|Atrophy of the Caudate Heads|thumb]] [[File:Huntington disease atrophy 2.jpg|left|150px|Current is needed to help symptoms due to the atrophy|thumb]] [[File:Huntington disease atrophy 3.jpg|left|150px|Future research is needed in hope to one day find a cure for this fatal disease|thumb]]

The main area for future research into Huntington’s disease is aimed at finding therapeutic ways to treat the disease in the asymptomatic phase. Research is also being done into finding treatment options to cure symptoms at different stages of the disease. Animal models (mouse) have been used since the 1970s <ref><pubmed>8731</pubmed></ref> to demonstrate the degenerative progression of the disease. Success in these model as well as the advancement of effective treatments for the symptomatic phases of the disease have provided much hope for the Huntington’s disease community <ref><pubmed>16569382</pubmed></ref>

'''Cholesterol metabolism in Huntington disease. (2011)'''

Cholesterol plays an important role in neuronal development and optimal activity. Huntington’s disease has been linked to changes in cellular cholesterol metabolism. Karasinska and Hayden (2011) investigate how the changes in the synthesis and accumulation of cholesterol in neurones influence the survival of neurons and the pathogenesis of Huntington’s disease. With better understanding of this, it is hoped that effective therapies based on cholesterol regulation can eventually be found. <ref><pubmed>21894212</pubmed></ref>

'''Assessing Behavioural Manifestations Prior to Clinical Diagnosis of Huntington Disease: "Anger and Irritability" and "Obsessions and Compulsions" (2011)'''

A comprehensive rating system called the Functional Rating Scale Taskforce for pre-Huntington’s Disease (FuRST-pHD) was developed to assess symptoms and functional ability in patients who express the mutated Huntingtin gene but have not yet fully developed the symptoms. This complex system involves data from various sources including information from the patients themselves, carers and experts. Vaccarino et al. (2011) aim to assess and improve the interview questions designed to analyse "Anger and Irritability" and "Obsessions and Compulsions" using FuRST-pHD in early Huntington’s disease patients. <ref><pubmed>21826116</pubmed></ref>

'''Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.(2011)'''

Animal models of Huntington’s disease have been extremely helpful in illustrating the progress of behavioural and physiological changes in Huntington’s disease. Raymond et al (2011) have developed trangenic Huntington’s disease mice in hope to provide insights regarding the striatal neuronal dysfucntion and degernation as well as changes in the excitation and inhibiton of the straitum and cerebral cortex. The focus was on synaptic and receptor modifications of striatal medium-sized spiny and cortical pyramidal neurons in these mouse models. The changes were compared between the early stages of the disease vs changes in the late stages. The findings prove that treatments need to be varied according to which stage the disease is in as well as considering which regions of the brain are affected. <ref><pubmed>21907762</pubmed></ref>

'''Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective (2011)'''

Ho et al (2011) aimed to gather information regarding what Huntington’s disease suffers are most concerned about during the different stages of the disease progression. Very little is known about this and it therefore needed to be addressed. Interviews were conducted with 31 patients currently living with different stages of Huntington’s disease ranging from pre-clinical gene carriers to advanced stage. Different issues arose depending on which stage of the disease the individuals were in, such as physical, functional, social and emotional issues. These discoveries are then able to provide insight into possible management and interventions across different Huntington’s disease stages. <ref><pubmed>21736564</pubmed></ref>

'''Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications (2011)'''

The symptoms associated with Huntington’s disease (and other neurodegenerative disorders) have thought to be improved using cell therapy to replace degenerated neuronal cells. However, Cicchetti et al. (2011) have found that the clinical benefits of cell therapy in patients with Huntington’s disease have been very short-lived. If such therapies are to be used in the future enabling significant clinical benefits, it is essential to explain and overcome the problem of the degeneration of the grafts. This study aims to discuss problems relating to long-term graft survival including the cellular responses.<ref><pubmed>21278084</pubmed></ref>

==Glossary==

<div id="Agranulocytosis"></div>'''Agranulocytosis:''' Failure of the bone marrow to make enough white blood cells (neutrophils).

<div id="Akathisia"></div>'''Akathisia:''' Also known as the restless legs syndrome (RLS), it is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.

<div id="Allele"></div>'''Allele:''' One part of a pair of genes.

<div id="Asthenia"></div>'''Asthenia:''' The lack of strength or energy.

<div id="Asymptomatic"></div>'''Asymptomatic:''' Showing no evidence of disease.

<div id="Atrophy"></div>'''Atrophy:''' A wasting away of the body or of an organ or part, as from defective nutrition or nerve damage.

<div id="Autosomal dominant"></div>'''Autosomal dominant:''' An inheritance pattern in which a gene on one of the non-sex chromosomes that is always expressed, even if only one copy is present.

<div id="Catecholamines"></div>'''Catecholamines:''' "Fight-or-flight" hormones released by the adrenal glands in response to stress.

<div id="Cerebral Cortex"></div>'''Cerebral Cortex:''' Grey, neural tissue (1.5mm to 5mm) that covers the outermost layer of the brain. It is involved in important functions of the brain such as language, motor function, planning and organisation, attention, personality, memory, touch and consciousness.

<div id="Chorea"></div>'''Chorea:''' A disorder characterised by an abnormal involuntary jerky dance-like movement. Chorea is derived from the Greek word ''khoreia'' which means dance.

<div id="Coagulopathies"></div>'''Coagulopathies:''' A disease or condition affecting the blood's ability to coagulate.

<div id="Cognitive"></div>'''Cognitive:''' Of or pertaining to the mental processes of perception, memory, judgment, and reasoning, as contrasted with emotional and volitional processes.

<div id="Computed tomography (CT)"></div>'''Computed tomography (CT):''' A technique for producing 2-D and 3-D cross-sectional images of an object from flat X-ray images.

<div id="Degeneration"></div>'''Degeneration:''' A process by which a tissue deteriorates, loses functional activity, and may become converted into or replaced by other kinds of tissue.

<div id="Dopamine"></div>'''Dopamine:''' A catecholamine neurotransmitter.

<div id="Dystonia"></div>'''Dystonia:''' A movement disorder which causes involuntary repetitive contractions of muscles.

<div id="Encephalopathy"></div>'''Encephalopathy:''' Diseases of the brain.

<div id="Gamma-aminobutyric acid (GABA)"></div>'''Gamma-aminobutyric acid (GABA):''' The chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system.

<div id="Gastrointestinal hypomotility"></div>'''Gastrointestinal hypomotility:''' A condition resulted from the lack of gastrointestinal movement, giving rise to severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis.

<div id="Haplotype"></div>'''Haplotype:''' A group of genes within an organism that was inherited together from a single parent. [http://www.nature.com/scitable/definition/haplotype-haplotypes-142]

<div id="Hemorrhagic pancreatitis"></div>'''Hemorrhagic pancreatitis:''' Inflammation of the pancreas accompanied by the formation of necrotic areas on the surface of the pancreas and in the omentum and, frequently, also accompanied by hemorrhages into the substance of the gland.

<div id="Hepatoxicity"></div>'''Hepatoxicity:''' Poisoning of the liver.

<div id="Histone deacetylases (HDAC)"></div>'''Histone deacetylases (HDAC):''' A class of enzymes responsible for the removal of acetyl groups from lysine residues in histones.

<div id="HPA axis"></div>'''HPA axis:''' Hypothalamic-pituitary-adrenal axis.

<div id="Hypotension"></div>'''Hypotension:''' Low blood pressure.

<div id="Hyperkinetic disorder"></div>'''Hyperkinetic disorder:''' This type of disorders are characterised by excessive abnormal involuntary movements. Movements may be irregular, rhythmic, random, sustained or temporary and are commonly in the form of jerky movements or a tremor.

<div id="Linkage Analysis"></div>'''Linkage Analysis:''' Study aimed at establishing linkage between genes.

<div id="Linkage disequilibrium"></div>'''Linkage disequilibrium:''' The non-random association of alleles at two or more loci e.g. an individual with a particular allele in a loci will tend to have the 2nd allele found at another loci.

<div id="Magnetic Resonance Images (MRI)"></div>'''Magnetic Resonance Images (MRI):''' A medical imaging technique used in radiology to visualize detailed internal structures. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body.

<div id="Mania"></div>'''Mania:''' A state of abnormally elevated or irritable mood, arousal or energy levels.

<div id="Motor impersistence"></div>'''Motor impersistence:''' Inability to sustain simple voluntary muscular actions such as keeping the eyes closed.

<div id="Myocarditis"></div>'''Myocarditis:''' Inflammation of the heart muscle.

<div id="Neuronal"></div>'''Neuronal:''' A specialized, impulse-conducting cell that is the functional unit of the nervous system, consisting of the cell body and its processes, the axon and dendrites.

<div id="Neuropathological"></div>'''Neuropathological:''' The pathology of the nervous system.

<div id="Norepinephrine (noradrenaline)"></div>'''Norepinephrine (noradrenaline):''' A catecholamine, which works as both a hormone and a neurotransmitter, that is released naturally by the nerve cells.

<div id="Nystagmus"></div>'''Nystagmus:''' Involuntary eye movements.

<div id="Parkinsonism"></div>'''Parkinsonism:''' A neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.

<div id="Polymorphisms"></div>'''Polymorphisms:''' The existence of two or more clearly different phenotypes in the same population of a species.

<div id="Positron Emission Tomography (PET)"></div>'''Positron Emission Tomography (PET):''' A nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body.

<div id="Renal toxicity"></div>'''Renal toxicity:''' Poisoning of the kidney.

<div id="Restriction fragment-length polymorphisms (RFLPs)"></div>'''Restriction fragment-length polymorphisms (RFLPs):''' Genetic variations that can be detected by emzymatic digestion.

<div id="Rhinitis"></div>'''Rhinitis:''' Irritation and inflammation of some internal areas of the nose, resulting in ‘stuffy nose’.

<div id="Serotonin"></div>'''Serotonin:''' A monoamine neurotransmitter involved in the transmission of nerve impulses.

<div id="Single-photon emission computed tomography (SPECT)"></div>'''Single-photon emission computed tomography (SPECT):''' A nuclear medicine tomographic[1] imaging technique using gamma rays.

<div id="Somnolence"></div>'''Somnolence:''' Better known as drowsiness, it is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods.

<div id="Striatum"></div>'''Striatum:''' A subcortical part that is situated in the centre of the brain and is part of a larger system called the basal ganglia. It receives input from the cerebral cortex.

<div id="Teratogenicity"></div>'''Teratogenicity:''' The capability of inducing fetal malformations.

<div id="Toxic epidermal necrolysis"></div>'''Toxic epidermal necrolysis:''' A life-threatening dermatological condition in which the epidermis is deattached from the dermis all over the body.

<div id="Transcription factor"></div>''' Transcription factor:''' A protein that interacts with the promoter region on DNA and regulates a gene by initiating transcription (RNA to DNA) and hence the synthesis of the specific protein.

<div id="Vesicular monoamine transporters (VMAT)"></div>'''Vesicular monoamine transporters (VMAT):''' A membrane-embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse.

<div id="Visuospatial"></div>'''Visuospatial:''' Pertains to perception of the spatial relationships among objects within the field of vision.

<div id="Xerostomia"></div>'''Xerostomia:''' Dry mouth resulting from reduced or absent saliva flow.

==References==
<references/>

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{{2011Projects}}