Embryology - User contributions [en-gb]

User:Z3332629

2011-10-19T23:59:07Z

Z3332629:

-[[User:Z3332629|Z3332629]] 12:55, 28 July 2011 (EST)
Lab 1 Assessment

1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.

The first In Vitro Fertilization Pre-Embryo Transfer (IVF-ET) was performed in 1978 by Dr. Edwards (an embryologist) and Dr. Steptoe in England.
In 2010, Robert G. Edwards was awarded with a Nobel Prize “for the development of human in vitro fertilization (IVF) therapy”.

2. Identify a recent paper on fertilisation and describe its key findings.

Title: Enzymatic isolation of human primordial and primary ovarian follicles with Liberase DH: protocol for application in a clinical setting
Authors: Julie Vanacker M.Bio.Sc.a, Alessandra Camboni M.D., Ph.D.a, Catherine Dath M.D.a, Anne Van Langendonckt Ph.D.a, Marie-Madeleine Dolmans M.D., Ph.D.a, Jacques Donnez M.D.,h.D. a, and Christiani A. Amorim V.M.D., Ph.D.a

Key findings:
- The aim or objective of the experiment was to isolate human preantral follicles with a particular enzyme (Liberase Dehydrogenase) in order to use these follicles in a clinical setting.
- After the follicles were isolated, they were analysed in terms of their morphology and structural preservation.
- In conclusion, it was founded that Liberase DH is an extremely useful enzyme for the isolate of human preantral follicles as it helps to maintain their viability and ultrastructure. This enzyme can be produced in good manufacturing practice conditions and hence is a great contribution to clinical applications.

3. Identify 2 congenital anomalies.

Two congenital anomalies include:
- Trisomy 21 (Down Syndrome): a chromosomal abnormality caused by the event of an additional copy of chromosome 21
- Cleft palate: caused by the failure of the mouth parts to join up during early foetal development which results in an open space or ‘cleft’ that can occur on one or on both sides of the face.

http://www.ivf.com/ivffaq.html
http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html
http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0015028211008600
http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Fertilization
http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Cleft_palate_and_cleft_lip

--[[User:Z3332629|z3332629]] 11:25, 29 July 2011 (EST)

--[[User:S8600021|Mark Hill]] 14:59, 29 July 2011 (EST) Well done Ashleigh. I will show you how to format the references correctly for the group project.

Something about the reference.<ref><pubmed>21719006</pubmed></ref>

References

<references />

--[[User:Z3332629|Z3332629]] 07:38, 3 August 2011 (EST)
Oh okay! Sorry I wasn't sure if references were necessary, so I just popped them in quickly at the end. The example that you have given, is that the exact way in which we should incorporate it in our group project? Should we use the Harvard or Endnote system?
--[[User:Z3332629|Z3332629]] 07:36, 3 August 2011 (EST)

--[[User:Z3332629|z3332629]] 10:52, 4 August 2011 (EST)

Lab 2 Online Assessment
1.Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilization.

The zona pellucid glycoprotein ZP-3 functions as a sperm receptor. After fertilization, it is believed that enzymes act to digest the entire zona pellucid, hence inactivating the ZP3 protein to prevent polyspermy.

Additional information of interest: “The sperm-binding activity of ZP3 is mediated by the oligosaccharide side chains of ZP3”... This observation suggests that “the oligosaccharides on ZP3 trap incoming sperm at the zona surface of unfertilized eggs and that this activity is lost after fertilization” .
After ZP3 binds to the sperm, it then triggers the sperm’s acrosome reaction that enables the selected spermatozoon to penetrate the zona pellucida .

Innovate us – Innovation and information for sustainable living. 2006-2011. What is a Zona Pellucida. InnovateUs.net. Viewed 04/08/2011 < http://www.innovateus.net/health/what-zona-pellucida>
L.Browder and L.Iten (Ed.) 1998. (Dynamic Development). Fertilization: Sperm/Egg Recognition and Contact. USA. Viewed 04/08/2011 < http://people.ucalgary.ca/~browder/fertiliz.html>
Keyon College, D.Marcey Chapter 13B: Animal Fertilization and Cleavage. Viewed 04/08/2011 < http://biology.kenyon.edu/courses/biol114/Chap13/Chapter_13B.html>
--[[User:Z3332629|z3332629]] 15:16, 4 August 2011 (EST)

Review article: Functional characteristics of dystrophic skeletal muscle: insights from animal models. Jon F. Watchko1, Terrence L. O'Day1, and Eric P. Hoffman2 http://jap.physiology.org/content/93/2/407.long

Research article: The common missense mutation D489N in TRIM32 causing limb girdle muscular dystrophy 2H leads to loss of the mutated protein in knock-in mice resulting in a Trim32-null phenotype Elena Kudryashova1, Arie Struyk2,†, Ekaterina Mokhonova1, Stephen C. Cannon2 and Melissa J. Spencer1,* http://hmg.oxfordjournals.org/content/early/2011/07/28/hmg.ddr311.long --Ashleigh Pontifex 13:31, 10 August 2011 (EST)
--[[User:Z3332629|z3332629]] 13:34, 10 August 2011 (EST)

Lab sign in --[[User:Z3332629|z3332629]] 12:22, 11 August 2011 (EST)

[[[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]

==Differentially expressed RefSeq genes in human trisomy 2==

Pone.0018493.g006.jpg

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/

Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.

Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

[[[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg|thumb|Differentially expressed RefSeq genes in human trisomy 21]]

==Lab 3 Online Assessment==

1.
• Iodine is also significant, as iodine deficiency is the biggest cause of mental retardation.

===References:===
Living Strong. 2011. Healthy Food to Help Brain Development in Early Pregnancy. Accessed 11/08/2011. <http://www.livestrong.com/article/296096-healthy-food-to-help-brain-development-in-early-pregnancy/#ixzz1Ughcky2w>
Living Strong. 2011. Vitamins for Fetal Brain Development. Accessed 11/08/2011. <http://www.livestrong.com/article/297928-vitamins-for-fetal-brain-development/>
Living Strong. 2011. Healthy Food to Help Brain Development in Early Pregnancy. Accessed 11/08/2011. <http://www.livestrong.com/article/296096-healthy-food-to-help-brain-development-in-early-pregnancy/#ixzz1Ughcky2w>

[[File:asj-5-43-g001.jpg]]

--[[User:S8600021|Mark Hill]] 15:20, 11 August 2011 (EST) OK, so you have uploaded the image OK and included all the information requested. Except the last and most important step I described, how is "File:Asj-5-43-g001.jpg" an appropriate description of the original image? Why not rename this image to "Surgical correction of Spinal Curvature" or "Surgical Spinal Deformity Correction" something descriptive so that the image can be easily identified. You will not get full marks until this has been corrected.

==X-ray examination of an 11-year-old boy, wheelchair bound for 8 months with Duchenne muscular dystrophy==

A 11-year-old boy, wheelchair bound for 8 months with Duchenne muscular dystrophy.

A) Preoperative antero-posterior radiograph right sided showing 60° curve. (B, C) Two year post-operative antero-posterior and lateral radiographs showing sublaminar wiring instrumentation with Luque rods and distal fixation to pelvis with L-rod configuration.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047897/

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

[[File:1532-429X-12-14-3.jpg|450|]]

--[[User:S8600021|Mark Hill]] 15:26, 11 August 2011 (EST) Same comment as above for this image.

==T2 histograms==

Examples of normalized (i.e. area under curve = 1) T2 histograms of DMD (Group A, B and C) and Normal control (N1) subjects show that DMD patients with normal EF but impaired εcc has higher heterogeneity in T2 compared to other groups.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846924/

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.

=X-ray examination of an 11-year-old boy, wheelchair bound for 8 months with Duchenne muscular dystrophy=

[[File:Surgical correction of a 11-year old patient suffering from Duchenne muscular dystrophy.jpg]]

Surgical_correction_of_a_11-year_old_patient_suffering_from_Duchenne_muscular_dystrophy.jpg‎ (568 × 376 pixels, file size: 127 KB, MIME type: image/jpeg)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047897/

A 11-year-old boy, wheelchair bound for 8 months with Duchenne muscular dystrophy. (A) Preoperative antero-posterior radiograph right sided showing 60° curve. (B, C) Two year post-operative antero-posterior and lateral radiographs showing sublaminar wiring instrumentation with Luque rods and distal fixation to pelvis with L-rod configuration.

=Results of the AGEP analysis of microarray data from two Duchenne muscular dystrophy samples against the reference database.=

[[File:Results of the AGEP analysis of microarray data from two Duchenne muscular dystrophy samples against the reference database.jpg|450px|]]

====Figure 2====
Results of the AGEP analysis of microarray data from two Duchenne muscular dystrophy samples against the reference database.

A) The sample from patient 3 resembles most closely striated muscle among the 44 reference tissues. B) Alignment of the patient's transcriptome at the level of individual genes. On the x-axis are genes (17 330) and on the y-axis the three most similar tissues. Green color indicates that the genes have an expression level typical for that tissue, whereas red indicates atypical expression levels. Genes have been ordered according to their level of similarity against the most similar tissue (striated muscle). C) View of distinct gene sets and pathways for the most similar tissue (striated muscle). Relative enrichment of atypical genes is shown on the right side to illustrate aberrant gene expression levels for individual patient samples. Genes involved in inflammation response, complement mediated immunity and muscle contraction had more atypical expression levels as compared to healthy striated muscle (198.6, 70.9 and 7.1 fold enrichment of atypical genes, respectively), indicating that these processes were altered in DMD in comparison to healthy muscle. D-F) The gene expression profile from patient 4 resembled mostly striated muscle (primary match), but revealed adipose tissue as the second best matching tissue. As compared to patient 3, this patient had a larger number of muscle typical genes involved in inflammation response, complement mediated immunity and muscle contraction suggesting a less severe disease for patient 4.

===Copyright Notice===
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.

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3080808/

Mark Hill, I have been having implications uploading files! I correct the file name, however I have uploaded 3 files and they have all come up with a little red cross symbol. I'm not sure as to what has happened, I have attempted the task multiple times with different images and it keeps occuring. Please take this into account for my marks for the online lab submission.

Kind regards

--[[User:Z3332629|z3332629]] 13:20, 17 August 2011 (EST)

=DMD patients and causes of higher heterogeneity=

[[File: DMD patients and causes of higher heterogeneity.jpg]]

===T2 histograms.===

Examples of normalized (i.e. area under curve = 1) T2 histograms of DMD (Group A, B and C) and Normal control (N1) subjects show that DMD patients with normal EF but impaired εcc has higher heterogeneity in T2 compared to other groups.

Accessed via: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846924/

===Copyright Notice===

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.

Lab week 5 sign on
--[[User:Z3332629|z3332629]] 11:02, 18 August 2011 (EST)

Lab 5, Week 6 Online Assessment
1. Which side (L/R) is most common for diaphragmatic hernia and why?
A diaphragmatic hernia is a condition where there is a hole in the diaphragm and organs from the abdomen go up into the chest cavity. It is most common on the left side as the contents such as the stomach, spleen and intestines (that are all positioned to the left side of the body) move up into the chest region displacing the chest organs to the contralateral side, leaving very little room for lungs to grow and develop properly.

--[[User:Z3332629|z3332629]] 22:00, 26 August 2011 (EST)

--[[User:Z3332629|z3332629]] 11:18, 1 September 2011 (EST)

==Individual Assessment – Week 7==
1. What week of development do the palatal shelves fuse?
Week 9.
2. What animal model helped elucidate the neural crest origin and migration of cells?
The chicken model.
3. What abnormality results from neural crest not migrating into the cardiac outflow tract?
Tetralogy of Fallot
--[[User:Z3332629|z3332629]] 12:32, 10 September 2011 (EST)

==Lab Week 8 Sign on==
--[[User:Z3332629|z3332629]] 11:01, 15 September 2011 (EST)

==Lab 7, Week 8 Online Assessment==

1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?
A) No
B) Yes they are generally involved and proliferate during hypertrophy – satellite cells are important for sustaining hypertrophy by increasing the amount of myonuclei present.

2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?

Slow-twitch skeletal muscle fibres contain a larger number of myonuclei and satellite cells in comparison to fast-twitch muscles. Chronic low-frequency stimulation (CLFS) causes a fast to slow fibre type shift by imitating the “electrical discharge pattern of slow motoneurons innervating slow-twitch muscles” resulting in the recruitment of satellite cells.

==Lab 8, Week 9 Sign on==
--[[User:Z3332629|z3332629]] 10:41, 22 September 2011 (EST)

==Peer Assessments==

Group 1:
* Your page was extremely in depth which was really great.
* Its great that you’ve linked words to the glossary
* The use of a range of different images was good and I like how you made the effort to copyright your own image!
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
* The dot point form of clinical manifestations perhaps could have been better formatted into a table as I personally found your formatting confusing and slightly not a well-organised.

Group 2:
* A very clear format has been used. The mixed use of dot points and paragraph form were used appropriately in most sections and made your web-page easy to read and follow
* Good use of self drawn images, however the large image of Angelo DiGeorge seemed slightly irrelevant and took up a large portion of your page. Your first two images should probably have small heading below the image, just to make them a bit more clear to the reader.
* A coherent history/timeline was used.
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section. Some references are incompletely, or have no linking information such as reference 49.
* Your current research section was good but perhaps could have been tabulated just for easier reading and to really draw out the main points.
* Your table for clinical manifestations could have been summarised otherwise it should maybe just be written in paragraph form.
* Your page definitely reflects the time and effort you have placed into the assignment. I really liked the range of formatting you used and the use of colour made your page easy to read and follow. Another great feature was the section based on the example of Tetralogy of fallot. It was interesting to read how other defects that we have discussed in class, linked in with your studied abnormality.

Group 3:
* Great amount of depth, you have covered each subheading quite well
* It was great to see a comparison to other similar defects
* Non-disjunction is discussed twice, can it be summarised into just the one section?
* In the signs and symptoms section, the images seem to be arranged in a disorderly fashion, maybe place them elsewhere. Also your image comparing age and intellect is extremely small. The sizing of a larger majority of your photos needs to b adjusted
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
* There were only two examples of management strategies, are there anymore out there? Maybe you could do a comparisons table for this section

Group 4:
* 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.

Group 5:
* I liked your page as it had a simple and easy-to-follow lay out
* Some of the images could have been made larger on your actual page just so that it adds dynamics to your page
* I was left wanting to know more about the diagnosis, this section was quite brief
* I personally found your treatment table hard to read because there was so much information. Personally I believe that maybe dot-point form could have been used to get your main points across.
* Perhaps expand upon your glossary as there were some words that weren’t in there that maybe should have been.

Group 6:
* I would suggest placing the history section into a timeline or table format just so that significant dates are more clear and emphasised.
* The gene profile section was great. It was in detail, it was coherent and the inclusion of gene images enhanced my understanding of this particular section.
* Maybe for the “how the procedure works” section of the diagnostics table could have been summarised into a flow diagram or through images, rather than having a chunk of text. This could make it more straight forward to the reader.
* Your website was generally well-written and to the point. You varied your formatting regularly which made your page entertaining.
* My last suggestion would to only use the image of the shunt once and finding a different image as the repetitiveness of this is slightly disengaging

Group 7:
* Your pathogenesis section was good, it was thorough and went into significant depth. The use of animal models and the support of recent studies was also a positive aspect
* The photo of the ub pathway should be smaller or be placed as a thumb nail as it isn’t something that directly contributes to your defect
* It is a shame that there is such a large gap in your Aetiology section, but i do realise that this is slightly out of your control due to wiki formatting issues.
* I personally found the signs and symptoms section to be slightly confusing in format. Perhaps placing this info into a table would make it more concise.
* Treatment and management section had lots of detail and highlighted a few different methods which gave a good insight of the current technologies and strategies out there in the market.

Group 8:
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.
* Maybe include a glossary so you can accommodate for all readers.
* It was good to see that you grouped your references 

Group 9:

* Great use of student drawn images
* You must work on summarising your information, dense regions of text in the history section makes it extremely heavy on the reader .. perhaps the use of dot points would help improve this section and aim to be more straight to the point
* Good referencing, however needs to be properly formatted
* Images are poorly detailed, more info would be great
* Poor glossary, this needs to be worked on, try hyperlinking!!
* After reading the current research section, I was left wanting to know more. Perhaps provide a few links to pages in pubmed that detail current research papers etc.

Group 10:
* Intro was good, it was brief and straight to the point
* The beginning paragraphs of the history could be more summarised especially considering that you have a timeline beneath
* Your use of a table for the genetics’ component was great. It was easy to read and concise. It was a different approach but it worked well.
* More information could have been added to the treatment section such as comparisons between key methods/strategies, the pros and cons
* The phenotype section was well set out although I believe it should have been placed up after the genetics section so that the information flows more consistently
* The layout of the implications section was slightly unclear. Maybe here you could have large heading for implications, followed by a list (dot point) of the implications occurred then have in paragraph form a description of each. Having headings such as: Other problems and other associated medical conditions tended to drag on this segment.
* The inclusion of the supportive associations was a nice little touch!
* Great use of referencing

Group 11:
* I would suggest expanding on the current and future research section, maybe add in links to current research institutes or research papers.
* Perhaps add an image in for problems associated with cleft palate, just to add some dynamics and colour to the page.
* Perhaps tabulate the treatment section just so that the information is clearer
* Placing words in bold, although it was just a little touch, helped to highlight the main points you were trying to get across which was good.
* Good incorporation of tables and different formatting styles
* Your introduction was clear, simple and straight to the point.
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
* Your timeline was extremely spaced out, I would suggest deleting the space between your dot points just so that it reads easier.

==Lab Week 10==
--[[User:Z3332629|z3332629]] 12:32, 29 September 2011 (EST)

==Lab Week 11==
--[[User:Z3332629|z3332629]] 12:00, 6 October 2011 (EST)

Lab Assessment:

1. Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.

Congenital rubella syndrome (CRS) – transmitted from infected mother via the placenta.

2. Identify 3 factors that contribute to poor neonatal drainage of the middle ear.

Blockage, abnormal formation and the relative short length of the auditory tube can contribute to poor neonatal drainage.

3. Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)

Beckwith-Wiedemann syndrome - caused by mutation of genes located 11p15.5 chromosome region.

Entry number: 130650

Phenotype MIM number: 130650

Gene/Locus MIM number: 103280

==Lab Week 12==

sign on not working
11:04am - z3332629

Lab Online Assessment:

1.Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.

The interatrial septum is formed by the fusion of the septum primum and septum secundum. The two passages that connect the right and left atria is the foramen ovale and the foramen socumdum.

2.Identify the cardiac defects that arise through abnormal development of the outflow tract

* Ebstein’s anomaly tricuspid atresia
* Aortic stenosis
* Coarctation of the aorta
* Ventricular septal defect (VSD)
* Atrial septal defect (ASD)
* Double outlet right ventricle (DORV)
* Transposition of the great arteries (TGA)

==Lab Week 12==

sign on not working again
10:58am 20/10/2011- z3332629

User:Z3332629

2011-10-18T23:39:06Z

Z3332629: /* Lab Week 12 */

User:Z3332629

2011-10-13T00:04:37Z

Z3332629: /* Lab Week 12 */

User:Z3332629

2011-10-12T23:41:35Z

Z3332629: /* Lab Week 11 */

User:Z3332629

2011-10-12T23:29:29Z

Z3332629: /* Lab Week 11 */

User:Z3332629

2011-10-12T11:22:26Z

Z3332629: /* Lab Week 11 */

Talk:2011 Group Project 10

2011-10-12T06:28:32Z

Z3332629: /* Group Discussion Week 10-12 */

[[2011_Group_Project_10|'''Group 10''']]: [[User:z3332327]] | [[User:z3332629]] | [[User:z3332824]] | [[User:z3330313]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_10_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_10_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Group Discussion Week 10-12==
Hey ladddiiess :)
Are we all cool for tomorrow?
Still meeting straight after lecture?
message me if any problems :)
ASH

Hey guys, so I tried researching information on Dr W J Little and there's nothing much I can write about him that relates to DMD. This doctor was just one of the earlier men in history that first accountered the disease & he briefly described it as a disorder.
And thanks for adding the utrophin part to the table!! I was thinking it would be nice to add an internal link to our "Important Current Research - Utrophin" section, I've been trying to do it for the past 15mins & I can't seem to figure it out. Do any of u guys know how to do it? If not I'll ask Mark tomorrow.
Jo

--[[User:Z3330313|z3330313]] 03:12, 10 October 2011 (EST)

Hey Rhiannon!

Ash here. Just read over your section and just have a few pointers or suggestions :)

“this includes skeletal muscles, smooth muscle and cardiac muscle” – maybe this could be written as just: this includes skeletal, smooth and cardiac muscle”.

“which causes many problems” – which can cause numerous implications maybe?

Many of your sentences states something then has a ‘-‘ then gives an example, this sort of seems informal and distrupts the flow of reading .. i personally would suggest using more complete and formal sentences, but just an idea.

These are only suggestions, I am happy if you do leave it the way it is but I know your a perfectionist :)

Let me know what you think

--[[User:Z3332629|z3332629]] 18:11, 9 October 2011 (EST)

Hey guys,

So I've finished my part of the assignment now (WOOOOO!) so if there is anything that I should edit/change, or if anyone needs a hand with anything, then let me know, ''I'm breezy!'' *Monica's Geller's voice*

'''Lisa:''' my mum just raised an important point for the diagnosis section - are you able to, when you are pregnant, genetically test the baby to see if it is affected? can you see if its actually affected or a carrier? when can you test this?
-I think this is an important point, and highly relevant as that is a concern for many people. Do you think you can include this somewhere?

Hope everyone else's parts are going ok,

--[[User:Z3332824|Rhiannon Bice]] 17:39, 7 October 2011 (EST)

Nice drawings!

Just some videos for my section, just placing them somewhere so i know where they are :)
http://www.youtube.com/watch?v=dOhMLZCvb50
http://www.youtube.com/watch?v=GWachrbiU58
--[[User:Z3332629|Ashleigh Pontifex]] 12:01, 3 October 2011 (EST)

Joanna : http://emedicine.medscape.com/article/1173204-overview#a0199
Great over view for epidemiology, perhaps a table or some stats would be great in this section :)

- http://www.ncbi.nlm.nih.gov/pubmed/19834452 -

hey guys I changed some of the stuff on history, if you think its too much info let me know!
I deleted alot of information, and I just can't bring myself to delete more because the stuff remaining now seems so relevant. But let me know what you think!
And what do you guys think about putting an image of the Duchenne dude in the history? do you reckon that'll make that section too long?
--[[User:Z3330313|Joanna Pak]] 02:56, 5 October 2011 (EST)

Hey Jo! I had a read of the history section and it sounds good. Just an idea, where you've listed Duchenne's definition of the disease, would you prefer if those were added under DIAGNOSIS- clinical or SIGNS AND SYMPTOMS? And we could add an internal link? Maybe that'll cut down your section a bit?

Just a suggested change, i just rearranged the words around a little, dont have to. =)

*'Meryon conducted several necropsies and found intact spinal cords which indicated the disease was not from the nervous system.'

Minor edit

*'Further microscopic examination of the muscle showed that the muscular fibres '''broke''' down and converted into granular, fatty matter.'
--[[User:Z3332327|Lisa Xiao]] 11:38, 5 October 2011 (EST)

Hey Jo its Ash!! It looks heaps better, more straight forward and the table inclusion is great :)
Is everyone happy with my student drawn image in the introduction? it is appropriate in this section?
Also my table in the genetics section???

And lastly, ive notice that Rhiannon has hyperlinked all glossary terms in her section, is everyone happy to carry that across all areas???
--[[User:Z3332629|z3332629]] 12:29, 5 October 2011 (EST)

Actually one last suggestion jo, maybe change the table colour to teal so that the colour schemme consistent throughout the page :)
--[[User:Z3332629|z3332629]] 12:32, 5 October 2011 (EST)

Hey rhiannon! I tried searching for that image of the heart, turns out its not open access. I'll keep an eye out for you though in case i find anything useful.--[[User:Z3332327|z3332327]] 14:03, 7 October 2011 (EST)

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

==Peer Review==

'''Peer Review'''
* The introduction is detailed but a bit “in your face.” It may even be a bit too detailed, going into the pathogenesis of the disorder.
* History is very detailed, perhaps slightly story-like but enjoyable nonetheless. Could use a picture or two. Sufficiently referenced.
* Epidemiology is very thorough and well referenced.
* The tone of Aetiology/Genetics is a bit conversational; needs to be more detached. Good use of picture, although the legend to it is not in the correct format.
* Pathogenesis could use more references, especially for the last paragraph. Could potentially use some pictures to make clearer the specific structures discussed in the text (although they are elaborated on in the glossary).
* All the signs listed in Clinical Manifestations etc are decently elaborated upon, and the section is well-referenced. Smooth Muscle has strange “&&&” signs though. Respiratory Problems needs cleaning, notably with the line “[Effects of high CO2 and the problems it can cause]”
* Diagnosis is nicely laid out, although more references are needed.
* Treatment is decently set up and clearly explains each of the treatment plans.
--[[User:Z3290689|z3290689]] 14:44, 29 September 2011 (EST)

Group 10:
This project looks fine but it seems a little short? You want to expand the content in sections.
History is well researched but it’s quite long. You can add more images (add the reference in the description) and make the dates in Bald.
There are some spelling errors and extra signs that are not related to the work such as &&&.
Some of the references are repeated and others need to be reformatted.
Overall, Great effort.

--[[User:Z3284061|z3284061]] 11:51, 29 September 2011 (EST)

'''Peer Assessment'''
*introduction is well written and descriptive. Good use of image to make it look appealing. No references in the first paragraph.
*History section is too long, text heavy and a bit boring. Try to summarize the details on a timeline. You can include an image e.g. of Dr Edward Meryon if possible.
*Epidemiology and aetiology; well written. The image in the aetiology needs to be linked with the text.
*Pathogenesis; too brief. Needs more information and explanation of the disease process. Include an image or flowchart to compliment the text.
*Signs and symptoms; needs to be expanded a bit more. I suggest using a table to present the information that just as dot points. Same goes for the diagnosis section, which also needs to be expanded. Try and use more images, tables, graphs etc to break up the texts and make the page look more appealing.
*I suggest hyperlinking words in the page with the glossary to make the page more user friendly.
*Like the use of table in the "current and future prospects". It's better to present information like this rather than in big long paragraphs.
*The glossary needs to be expanded more.
--[[User:Z3291622|Z3291622]] 11:07, 29 September 2011 (EST)

'''''Duchenne (Group 10) Peer Review:'''''

Could you include “Duchenne Muscular Dystrophy” as the first subheading so that the reader knows exactly what the disease is at first glance? Just a suggestion.

Introduction: Topic well introduced and good use of image. Image, however, is lacking a student template.

History: Very extensive. Possibly include an image to break up the text.

Epidemiology: Sound. Some sentences are not worded/ structured properly.

Aetiology – Genetics: Information is good. Impressive self-drawn image. Well done.

Pathogenesis: An image would definitely work well in this section. Information is otherwise good, however possibly have a greater focus on the genetic component?

General Signs and Symptoms of Duchenne’s Muscular Dystrophy: This section seems too brief. Elaborate further.

Clinical manifestations and complications: Information is good. Possibly more detail for the subheading “smooth muscle.” Image lacks a student template. “&&&” – what is this? Many references in this section which is good to see!

Diagnosis: Could be elaborated further.

Treatment: Current and Future Prospects: The first paragraph lacks referencing. Possibly include an image? Table is a good idea, however colours chosen are slightly off-putting.
Glossary of terms: Could be more extensive. Not complete.

Well done. --[[User:Z3290808|z3290808]] 10:50, 29 September 2011 (EST)

Duchenne Muscular Dystrophy – Group 10

* Excellent introduction and good use of image. Is there some referencing missing in the first few sentences? Some formatting should be done on the image either to make it within the intro section or more shared between the history sections. Looks a little out of place.
* History is well written but very text heavy. Use of a timeline good improve this section and make it more succinct. Also I thought an image could be good.
* Epidemiology seems to cover all necessary information and is well referenced. Maybe an image or graph here could be good.
* I like the student drawn image in the etiology section, maybe the sizing could be improved though? Also some a more detailed description of what the image shows would also be good.
* Pathogenesis section is very informative. Maybe the pathophysiology could be covered in this section as well? Image could be added.
* General signs and symptoms would perhaps look better in a table. Otherwise it is quite brief, maybe some more elaboration aswell.
* I think diagnosis looks incomplete. Not much detail is given about how the diagnosis actually works. Very little referencing. Addition of an image would improve this section.
* Treatment looks great. I like how you have included current and future prospects. Just wondering if there was room for a heading for current and future research, as Im sure there is more research being undertaken than just in the area of treatment. This could make this project more informative, and perhaps could be another heading.
* Glossary needs improving.
* Some issues with referencing such as multiple entries for the same article and some issues with web page referencing.

--[[User:Z3288196|Z3288196]] 10:48, 29 September 2011 (EST)

'''GROUP 10: Duchenne Muscular Dystrophy'''
*Title of the whole page should just be Duchenne Muscular Dystrophy, not Introduction...
*The intro is very descriptive and comprehensive
*Image in intro needs proper referencing
*consider rephrasing this sentence "In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction"
*History has good info, but could this be better formatted in a table? this section is text heavy and could maybe use an image, it also could be extended into more recent years
*Epidemiology is summarised well and contains good statistics
*I feel that Aetiology - Genetics section has good info, easy to understand and informative but maybe it could be researched a little more
*General Signs and Symptoms of Duchenne’s Muscular Dystrophy section needs a lot more work, the list of symptoms i don't feel is enough, more expansion on these is needed. An image would improve this section too
*"diarrhoea&&&." -this needs to be fixed

Overall:
*More images are needed to break up the text
*glossary needs a bit more work, consider linking glossary words to text
*I feel that the page overall needs some more work, some sections are lacking content
*Proof reading to fix grammar and sentence structure

--[[User:Z3331556|z3331556]] 10:44, 29 September 2011 (EST)

'''Peer Review'''

This wiki still feels like what Mark Hill mentioned earlier, like a backbone for content to be built upon. The foundations are there, but still very incomplete. Comparing the sections, some have done a lot of effort, others not so much, and it is very visible.

:*Should start the wiki with this code:

<wiki>=Duchenne Muscular Dystrophy (DMD)= </wiki>

then

<wiki>==Introduction == </wiki>

:*History is far too text heavy and it shouldn't be like that, as this makes it a chore to read. A timeline would be better suited and summarise into the timeline.

:*Should be more student drawn images, since there's only one. If getting pictures is hard to find, then draw your own.

:*The one student drawn image is not referenced correctly, needs the disclaimer info.

:*Diagnosis needs to be expanded. There is 300+ articles, there has to be more info or an image to be found.

:*Pathogenesis needs to be expanded, maybe an image.

:*Signs and symptoms need more referencing. Also, just leave the title as Signs and Symptons.

:*Treatment needs to be expanded on. It isn't any good just listing drugs into a table.

:*Split the Treatment to include Managment and give a separate section for Current Research.

:*Glossary is incomplete.

--[[User:Z3293267|z3293267]] 10:37, 29 September 2011 (EST)

Group 10:

Clear and conscise but still needs more work breaking up the long slabs of writing. Perhaps more subheadings esp. in the first sections.

More pics are needed to break up the work.

Treatment includes a good table.

Glossary needs a bit of work and expanding on the explanations.

References needs to be fixed as there is duplications of references.

z3332178 =]

Peer Review

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*History section would benefit by placing the information into a timeline rather than paragraphs as it is a bit hard to follow.

:*Epidemiology section could be expanded and written in more flowing way rather than long sentences.

:*Needs more images, lots of large blocks of text. And images need to be formatted into the text as formatting currently looks awkward.

:*Further Research could be added, for example papers or groups that are researching as currently it is just being referred to.

:*Glossary could be expanded.

:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed. Also perhaps research from MORE sources is necessary as there is only a few when you cut out the double references.

--[[User:Z3217043|z3217043]] 10:02, 29 September 2011 (EST)

Group 10 Peer Review

*Headings are well organised and structured
*Too much text in history section-a table or image would be good
*Information is there however images/graphs/tables would help break up large chunks of text
*Diagnosis seems brief-perhaps merge with treatment section?
*Signs and symptoms could be expanded
*Great table in treatment
*Needs to be proof read-grammar and spelling mistakes
*Double referencing
*Glossary needs to be extended
--[[User:Z3308965|Fleur McGregor]] 09:54, 29 September 2011 (EST)

Group 10

*Introduction – Great intro, well referenced apart from the first paragraph.
*History has a lot of text, a timeline could work well here and also an image if possible just to break up the text.
*Epidemiology – well referenced and structured, text could be broken up but that’s nothing major as it’s a small section.
*Aetiology – A link between the image provided and the text would work well, and also the image could be formatted on the right of the page, to add to continuity and flow as other images are located on the right.
*Signs and Symptoms – Needs to be more information here, a description of each symptom and maybe its direct causes.
*Clinical manifestations – need a link between the image and the text, other than that it is well referenced and easy to understand.
*Treatment – table formatting is great and information is helpful
*Glossary – needs to include more terms form the page.
*There’s some doubling up in the reference section that needs to be fixed, other than that good job.

--[[User:Z3331469|z3331469]] 08:25, 29 September 2011 (EST)

peer review:

*Intro: One of the very few groups to use an image of the disease in the intro, well done! Like how you have referred to Duchenne’s as DMD in brackets initial heading to avoid confusion.

*History: A lot of writing, no techniques to break it up, which will basically bore your reader. Use a timeline perhaps.

*Epidemiology: Subheading will benefit this segment.

*Aetiology: The image could use some colour, but it is still very well done. It would be worthy to refer to the drawing as your explaining the genetics, just to bring them together.

*Pathogenesis: Very brief, not very informative and lacking subheadings or an image. Hopefully this will be fixed.

*Signs and Symptoms:Poorly done. Dot-points are a good way to initiate the writing but not appropriate as a final copy. Needs more description and research.

*Clinical manifestations:
The image used is excellent but needs more explanation.

*Diagnosis:Very short, looks incomplete and there’s only one reference for the entire section.

*Treatment: Well done, I like the colour and the table structure, makes it much easier to understand.

*Glossary: Incomplete, much more terminology has been used.

*References: Double referencing is a big problem here.

*Text:image ratio: could use more images.

--[[User:Z3290270|z3290270]] 02:16, 29 September 2011 (EST)

*history should be broken up with dates on side or within a table.
*how about a short summary table to use for epidemiology
*no picture of Guillaume Benjamin Amand Duchenne?
*no copyright permission for the drawn image in genetics.
*pathogenesis seems very small for a section that is very important.
*describe how the signs and symptoms impact on patients to show the significance of the disease.
*diagnosis needs a lot of work, this section is very important. also very little references in this section.
*not enough pictures to accompany the text
*very short glossary
*multiple references of same articles
--[[User:Z3291423|Jasjit Walia]] 00:17, 29 September 2011 (EST)

'''Peer Review for Group 10'''

*The introduction was well written, however the picture in it is not referenced as instructed. Please fix that then your intro is perfect.
*In the history section, the first sentence is oddly placed, even though it’s informative, please put that somewhere where it will flow in the paragraph.
*The history is verbose, please re write so it’s easier to follow.
*Epidemiology needs to be reevaluated as some sentences are not constructed properly
*Etiology has sound information but the paragraphs are not structured so it flows. It also seems repetitive.
*The picture in the etiology can have its caption better structured
*Pathogenesis should include some component of genetics to explain how the abnormalities bring about the pathogenesis in the genetics level.
*Explanation of how the signs and symptoms comes along from the dystrophy should be explained
*The image of the spine is not completely referenced as url of the image and the page must also be given
*Information under ‘respiratory problems’ and smooth muscle needs some reviewed as it includes words there that shouldn’t be present
*The diagnosis section could be expanded upon so it includes more information on the details of how it is detected, and images should complement the tools to diagnose the condition.
*An introduction to the table should be given. Having the table there by itself doesn’t look good.
*Further explanation should be made on the type of physical activity that would be made for therapy
*Glossary should be expanded
*There is repetitive referencing; it should be reformatted to fit in the way multiple references is made.
*You need much more pics as without the pics the page looks word heavy.

--[[User:Z3291317|Z3291317]] 23:57, 28 September 2011 (EST)

'''Group 10'''

Introduction: Good introduction. The picture could be a bit bigger. Also, a picture of the chromosome would be great.

History and epidemiology: Both sections are clear and flow well. Pictures are needed to break up the text though.

Genetics: The image is great and the text is well written.

Pathogenesis: The pathogenesis is well explained. Again, pictures would be good in this section to improve it.

Clinical manifestations: Good section. Clear, easy to understand.

Diagnosis: This section might need some more detail added. You could explain how each of the diagnostic tests work

Current and future treatment: This section is worded well but looks a little bit disjointed. I think it would be better having it either all in text or all in the table. --[[User:Z3291324|z3291324]] 23:27, 28 September 2011 (EST)

'''Group 10 Peer Review'''
* Interesting introduction, with a good amount of information. The history is also quite well outlined, although as you have no doubt seen with many of the other groups by now, a timeline woud be adequate in the history section (this also helps to break the text up and help us get a "break" from large blocks of text!)
* Epidemiology section is short but sweet - all the required information is there and summarised well. Perhaps mention the rate of mortality? (although this may be obvious)
* The student-drawn image in the aetiology section doesn't have your own copyright notice, so this should be added to the description. There also might be more to write in this section, but only if you wish to seek out the information. Diagrams can be helpful in summarising excessively detailed material.
* Pathogenesis simply needs to be longer; a lot can be written on this section and there should also be the use of diagrams throughout. Explain why the pathogenesis of DMD is so destructive; it has more than just the function of securing the sarcolemma to the cytoskeleton and is also present in other parts of the body, so make sure you explore this completely! :) (for example, dystrophin which is affected also is found in different areas of the body which may help explain some of the other symptoms of DMD).
* General signs and symptoms could have a diagram to assist in the signs and symptoms.
* Clinical manifestations and complications could have more written and explaining some of the other symptoms that aren't purely based upon the muscle damage observed in DMD.
* Diagnosis needs to have more written, especially images regarding the methods of imaging and therapy.
* Treatment; and Current and Future Prospects are different sections and shouldn't be integrated. Think carefully about the implications that current and future directions of research will have on this disease - they are huge! Try to write more and make an individual section on current and future prospectives of research for DMD; as you know from your research so far, DMD is a very important disease requiring a lot of research.
* Glossary is incomplete; References have a lot of repeats, but these are problems that are common to almost all projects.
* Generally, you just need to find better ways of altering the information in your project. Try to add tables and images to help break up the information and make sure you've discussed all the sections in the guidelines for the project properly. Keep at it! :) There are also some obvious typos ('''&&&''')?
--[[User:Z3288827|Leonard Tiong]] 22:29, 28 September 2011 (EST)

'''Group 10:'''

•History might work better in a timeline, just to break up the text as the beginning of the page looks a little overwhelming with text.

•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template for all of the uploaded images.

•The different sections seem to be a little inconsistent, where a few of the sections such as diagnosis and treatment seem a little vague. These sections could be expanded on to give the reader a more comprehensive knowledge of what is involved, especially seeing as the diagnosis section only has one reference.

•Some typos in the smooth muscle section - ‘&&&’

•A lot of the references are repeated multiple times – this should be fixed up so that each reference only appears once. And also not all the references seem to be formatted correctly.

•Glossary is incomplete

•Overall, good use of subheadings though some of the sections need to be expanded and a few more images are needed to add a better balance to the page. Good work so far.

--[[User:Z3332183|z3332183]] 21:33, 28 September 2011 (EST)

'''Group 10'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main points are there. Content is decent in some places and lacking in others. Fixing up problematic areas would be good.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
Maybe include a time-line in history?'''
General Signs and Symptoms of Duchenne’s Muscular Dystrophy section is very poor. Getting information from an insurance website is not actual research. please consider re-doing this section with sources cited from a peer-reviewed paper. Signs and symptoms should go with diagnosis as it is part of making a diagnosis. why are there ampersands in Smooth muscle section?

'''*Content is correctly cited and referenced.'''
Fix up references, some are simply links and they repeat.

'''*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 is drawn well, explanation could do with a bit more work though. File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg needs proper citation, also there isn't many images. Try including more images.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Not as much information as i was expecting and references is not as extensive as other pages - but good in-text citation (with the exception of some places such as diagnosis and Respiratory problems), it shows that the information has come from somewhere. Information from an insurance website is not evidence of extensive research so try to fix it.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
No connection to embryology - try linking genetic defects to problems in the neonate, or even if there is a prenatal test.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Some evidence of developing the wiki page with the guidelines. Will benefit from changing some things.

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

'''Group 10: Peer Assessment'''
* Your page is relatively short overall and could use some more pictures, especially in the first few sections.
* You have forgotten to put a title on you page
* The introduction is good
* You have got quite a bid of text in the history section, may be you can make a bid lighter with a time line?
* Epidemiology is nice to read and relevant
* Signs and symptoms belong into the clinical manifestation section
* Diagnostics could be more in detail
* The green and blue in the table is a bid too much colour all on a sudden. May be you can have some more colour overall or do the table in just one colour?
* It would be great to have more terms in the glossary
* I would put the diagnosis section right after pathogenesis
* Overall you have got good information on your page. May be you can work on the overall structure and some references. --z3279511 17:15, 28 September 2011 (EST)

'''Group 10'''

*Introduction: well done

*History: lots of information, some parts have no references, subheadings and a time line would be advantageous

*Epidemiology: good contend

*Aetiology: the contend seems fine, but more structure would be good

*Pathogenesis: looks good

*Signs and symptoms: that’s more like a list that a section, maybe combine it with manifestations

*Manifestations: well done, except for smooth muscle- seems incomplete?

*Diagnosis: you could add more information and details

*Treatment: the heading seems inappropriate, separate treatment and research, the contend could be more explained

*Glossary: is incomplete

*More images would be nice
--[[User:Z3387190|Z3387190]] 14:28, 28 September 2011 (EST)

'''Group 10'''

*Very poor image/text ratio – you need more images to break up the text
*Good intro
*History would work better in a timeline- you also mention nothing after the 1800s, more recent findings need to be included
*An image would be nice for pathogenesis to help the reader follow
*Not sure why you have made signs and symptoms a different heading to clinical manifestation- these could be combined
*Diagnosis is very brief and needs to be extended
*Glossary needs to be added to
*Maybe add a current research heading

===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.

--Z3389806 07:04, 27 September 2011 (EST)

'''Group 10 Peer assessment'''
*Heading order needs to re-arranged and done properly with diagnosis above before signs and symptoms.
*Introduction done sort of well needs to integrate image as an example of the myofibres.
*History rather bulky with too much text and no image, image of the founder would be fine. Also no time line present of DM needs to be added
*Epidemiology seems rather empty, images would benefit this section also more stats, further expansion of sub headings would also do well for this section
*Genetics aetiology needs to be expanded where seems to be cramped, though usage of image needs to be noted
*Pathogenesis needs images and further information
*Signs and symptoms needs to be expanded and image of some signs or tables
*Clinical manifestation done well with image and further sub-headings
*Diagnosis requires more attention with further methods of detection of DM
*Treatment is well done with the usage of the table
*Glossary needs to further expanded also linked to the pages so easy to follow the page
*References are not complete with links and repeats of the references
z3332250 23:59, 26 September 2011 (EST)

'''Group 10 Critique'''

#• The introduction was very good. Good use of images to give it a little decoration!
#• History is good
#• Epidemiology is good, however if possible try and make it longer/ include more information
#• The Genetics section is a bit too short. Add more information. Good hand drawn image!
#• Pathogenesis is a little short. Needs more information
#• Signs and Symptoms is good
#• Clinical manifestations is ok
#• Diagnosis, treatment and glossary are all well written. These sections should not require any change

--[[User:Z3289991|Robert Klein]] 16:27, 26 September 2011 (EST)

Group 10 ''Duchenne Muscular Dystrophy''
*The first paragraph of the introduction has no reference.
*The paragraphs in history are quite long, often with grammar mistakes, incorrect punctuations and many of the ideas within a sentence separated by a ''-''. For example the second last paragraph within history.
*The history is too verbose, a timeline with bullet points will look better
*Aetiology is quite concise and informative however gramatical errors are a distraction. For example ''There a multiple forms of dystrophin''. It might be a good idea to proofread the page.
*Well done with the student drawn image
*'Pathogenesis' is again well written however an image might have given it a balance between the text in the section and the pictures or tables
*The future therapies table is a little confusing, you might want to add more columns and define the therapy, and then discuss what the challenges and findings are and at the end column finish off with what the implication might be if the research is to be completed successfully. At the moment you have discussed all that in one big paragraph and the way the descriptions start, it sounds like there is no background to the description, just a little abrupt.
*The glossary is very short and you should include terms like de novo mutation.
*The existing definitions are unclear and incomplete

''Duchenne Muscular Dystrophy''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topics

Group 10-
* Need more images to break up the text
* The introduction was really easy to read and had relevant information in it
* History should be in bullet point form to make it easier to access or at least have the dates in BOLD
* Does the history include dates after the 1800s? or did all research stop then?
* Epidemiology was good. Had all the relevant info
* Pathogenesis would benefit an image or a diagram
* Signs and symptoms could be put with clinical manifestations.
* What is the point of the ‘&&&’? in clinical manifestations and complications?
* Diagnosis could be expanded upon to explain how and why these methods work
* Treatment could also be expanded on. A list of drugs doesn’t explain much
* There is not current/future research section
* This is a good start to the project but more research needs to be done

'''Group 10'''
* The structure and use of headings and subheadings is good, make sure you title your page.
* Good info very informative and it gives a good overview to DMD.
* HIstory has a lot of text could you use a timeline here?
* i think a picture of the pathogenesis would improve this section.
* Has your group look at the CNS and cognitive function of DMD boys its a controversial area as many people have different attitudes towards this but Dr Stewart Head a UNSW lecture actually studies DMD and is very informative in the area and recently published a article in the journal Brain.
* The CNS is highly affected by the lack of dystrophin as well as GABA receptors. I think this area is very import to consider as it highly affects the boys at school.
* Could you add some pictures to your page or break it up with the use of more tables as it a lot of text in comparison to pictures and tables.
* Make sure your reference list is not doubled.
* Ensure all your pictures are referenced properly.
* Student image is present.
* This is a good start.

'''Group 10 Assessment'''
*The history is a bit wordy… Maybe consider consolidating the information into a table format for ease of reading. Could also use a picture to add to it.
*The Epidemiology section could also use a picture and maybe some more information, if possible.
*Point vs Frameshift mutation jpg: Good drawing, but in the last portion of the picture the product is labeled as a ‘tunicated protein product.’ Isn’t it supposed to be a ‘truncated’ product?
*The Signs and Symptoms section could use some formatting; it just looks rather dull currently. Maybe a chart or add in a picture?
*Smooth muscle section: Why are there random &&&’s?
*The top portion of the Treatment section could use some more referencing… Good chart though! Only thing I’d suggest for it is to add some pictures if possible?
*Glossary term list is rather short… Are you sure there’s nothing else that needs defining for clarification for the reader?
*It would be a good idea also to have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word 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.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. 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 #...
*Overall, good information is included, just work on referencing things and the overall structure and you should be good!
--[[User:Z3391078|Z3391078]] 17:00, 27 September 2011 (EST)

'''Peer Assessment: Group Project 10'''
*I think the section heading of introduction accompanied by the question what is muscular dystrophy, works really well.
*It might be good to include an image in the history section to break up the text, such as of someone prominently involved with the disease findings.
*The information in clinical manifestations and complications is well written. There needs to be some fix to the formatting under the smooth muscle heading where some '&'s have been repeated.
*The current and future prospects section is great. You have summarised what
*Some of the definitions of words in the glossary need to be completed e.g. atrophy and protease.
*Under the information in some of the images such as the fisrt one, 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.
*An additional section of external links might provide information for those wanting to know more.
--[[User:Z3217345|z3217345]] 10:50, 28 September 2011 (EST)

'''Peer Review'''

* struture and format done well
* easy to read

--[[User:Z3060621|z3060621]] 21:58, 28 September 2011 (EST)

*'''Intro''': Fine
*'''History''': Nicely detailed, but missing a timeline.
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.
*'''Pathogenesis''': Content seems fine, could do with a figure?
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?
*'''Clinical manifestations and complications''': Fine
*'''Diagnosis''': Clinical Diagnosis is a bit short?
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.
*'''Glossary''': Poor. More terms need explanations.
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.

==Discussion==

'''GROUP 10!'''

'''To make everything easier to follow, we have agreed to write any updates, info, discussion etc at the BOTTOM of this page, it will just stop us having to keep going up and down and wasting time trying to find the information we want.'''

----

Hey Everyone,

So Mark went through each group today during the lab and the webpages and discussed where we should be up to. By next week, he expects the subheadings & some content to be up and running. He also recommended that we should have some more research going on in our discussion page. E.g. Research articles links, interesting sites etc.

Topics have been allocated so please begin your research and typing up some content. We can further divide our headings if necessary, take a look at some other groups, they have some pretty good ideas. Mark will be checking this next week during our lab. He'll be coming around to each of us.

So hopefully see you all next week !

--[[User:Z3332327|z3332327]] 12:53, 25 August 2011 (EST)

==Subheadings for assignment==

Intro what is DMD

History/timeline

Genetic component

Why is it an abnormality - Symptoms effect

Diagnosis, future/current prospect (treatments?)

2 case studies

Glossary of terms

====Post online any preferences you may have in terms of the topics you wish to research and by Sunday we will allocate sub topics====
--[[User:Z3332629|z3332629]] 13:09, 18 August 2011 (EST)

Okay hey guys just to get the discussion going, umm I don't mind doing the first 2 on the list. And the "Why is it an abnormality - Symptoms effect" sounds pretty interesting as well.
What are your preferences?? :)

--[[User:Z3330313|z3330313]] 14:55, 23 August 2011 (EST)

Hey Everyone, Im happy to do the diagnosis/current/future prospects point and a case study.

--z3332327 15:36

2011 Group Project 10

2011-10-10T07:17:55Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|175px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, [[#Glossary of terms|'''dystrophin''']]. In humans this [[#Glossary of terms|'''gene''']] is located on the [[#Glossary of terms|'''X chromosome''']], thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref>. In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is [[#Glossary of terms|'''fibrosis''']] <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD [[#Glossary of terms|'''phenotype''']] <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently, procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

'''Historical Background of DMD'''

{|border="1"
|-style="background:cadetblue" align="center"
|'''Date'''
|'''Brief description'''
|-style="background:"
|1847
|
Dr W J Little reported two affect boys aged 12 & 14 that were unable to walk. Both were later found to have most of their leg muscles replaced with fat <ref name="PMID8326496"><pubmed>8326496</pubmed></ref>.

|-style="background:"
| 1851
|
Meryon described at a meeting of the Royal Medical and Chirurgical Society 8 boys presumed to be affected with Duchenne Muscular Dystrophy <ref name="PMID8326496"/>

|-style="background:"
| 1861
|
Duchenne first describes the disease, a young boy whose condition characterised by the hypertrophy of the boy's calf muscles <ref name="PMID16225184"/>

|-style="background:"
| 1868
|
Duchenne provided a much more detailed account of the boy's disease, DMD <ref name="PMID16225184"/>

|-style="background:"
| 1930-1960
|
Discovery of Becker Muscular Dystrophy, a less severe form form of DMD. The x-linked pattern of inheritance for DMD is confirmed.<ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)">MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)</ref>.

|-style="background:"
|1985-1988
|
Gene responsible for DMD is found by Louis Kunkel's team & the protein made from this gene is described and named dystrophin <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>

|-style="background:"
|1989-1994
|
The reason for severity of DMD is found. It is determined by the amount of dystrophin present in the muscle-fibre membrane. The less dystrophin the more severe the symptoms <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>

|-style="background:"
|1995-2000
|
Dystrophin gene is miniturised to facilitate gene therapy and research into stem cells is on its way to cure DMD <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>.

|-style="background:"
|2001-2005
|
Corticosteroid prednisone trials found effective in slowing down the progression of DMD <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>.

|-style="background:"
|2005-present
|
Important research on the autosomal homologue of dystrophin, ''utrophin''. It is found to have a strong ameliorating effect on the pathogenesis of DMD and has extreme potential for being effective treatment for all genetic mutations of Duchenne and Becker's muscular dystrophy.
For more information regarding utrophin: [[#See also|Important Current Research - Utrophin]].

|}

'''Dr Edward Meryon'''

Throughout history there have been cases that suggested muscular dystrophy, however, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>. The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as Duchenne Muscular Dystrophy<ref name="PMID8326496"><pubmed>8326496</pubmed></ref>. His findings were reported in the Transactions of the Medical and Chirurgical Society in December 1851 <ref name="Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12">Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. The first systematic and detailed study of the disorder was made by Edward Meryon.

In his studies of the disease, Meryon conducted several necropsies and found the spinal cords were intact which concluded that the disease was not from the nervous system. Instead, he found that the muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres were broken down and converted into granular, fatty matter <ref name="PMID8326496"/>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref name="Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12"/>.

Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne. He characterised the disorder as a progressive muscle wasting disease leading to premature death in the late teens, that begins in early childhood. The disease was later to be referred to as Duchenne muscular dystrophy.

[[File:Duchenne.JPG| right| 200px| Guillaume Benjamin Amand Duchenne | thumb]]
'''Guillaume Benjamin Amand Duchenne'''

Guillaume Benjamin Amand Duchenne was the first to describe DMD, and thus the disease is named after him. He was born in Boulogne-sur-Mer in France, on 17 September 1806 <ref name="PMID16225184"><pubmed>16225184</pubmed></ref>. Duchenne was a family doctor for 11 years who was interested in the study of electrical stimulation of muscle <ref name="PMID16225184"/>. He first became interested in muscular dystrophy in 1858, and formally described it in 1861. Duchenne also invented the “harpoon” which was a needle system that he utilised to obtain percutaneous samples of muscular tissue without anesthesia <ref name="PMID16225184"/>. This technique allowed study of material from the same patient at different stages of the disease.

Duchenne defined the disorder as:
* progressive weakness of movement first affecting the lower limb then later the upper

* pathologically; loss of striation of muscle replaced by granular matter and fat vesicles. Furthermore an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages

* a gradual increase in the size of many affected muscles

* an onset during early childhood or early adolescence that is, more prevalent in boys than girls

* can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

== Epidemiology ==

{| align="left" style="border: solid 1px #a0a0ff"
|- align="left" style="background:#8eb2ec"
|-style="background:cadetblue" align="left"
|'''State'''
|'''Incident rate (per 100 000 Male-liveborns)'''
|-style="background:"
| Western Australia
|
20.2 <ref name="PMID7205898"><pubmed>7205898</pubmed></ref>

|-style="background:"
| Victoria
|
21.9 <ref name="PMID7205898"/>

|-style="background:"
| Queensland
|
16.4 <ref name="PMID7205898"/>

|-style="background:"
| NSW & ACT
|
18.6 <ref name="PMID7205898"/>

|}

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchenne Muscular Dystrophy is regarded as an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==
[[File:Dystrophin within the plasma membrane of muscle fibres.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human [[#Glossary of terms|'''genome''']] is called the [[#Glossary of terms|'''dystrophin''']] [[#Glossary of terms|'''gene''']] and is contained at the [[#Glossary of terms|'''sacroplasmic''']] surface of the plasma membrane or [[#Glossary of terms|'''sarcolemma''']] of muscle fibers.<ref name=Davies>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of [[#Glossary of terms|'''muscle fibres''']].

The dystrophin gene, also known as DMD, is located on the short arm of the [[#Glossary of terms|'''X chromosome''']] at position 21.2. In 1987, it was found that this particular gene was identified as being located from [[#Glossary of terms|'''base pair''']] 31,137,344 to base pair 33,357,725 on the X chromosome. <ref name=DMD>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref name=Davies/> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref name=DMD/>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during [[#Glossary of terms|'''muscle contraction''']].

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the [[#Glossary of terms|'''actin''']] [[#Glossary of terms|'''cytoplasm''']]
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref name=Davies/>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the [[#Glossary of terms|'''cytoskeleton''']] through [[#Glossary of terms|'''filamentous''']] actin whilst the other binds to the [[#Glossary of terms|'''dystrophin-associated protein complex (DAPC)''']].
*The DAPC consists of cytoplasmic, [[#Glossary of terms|'''transmembrane''']] and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the [[#Glossary of terms|'''extracellular matrix''']].
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.<ref name=Davies/>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.<ref name=Davies/>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as [[#Glossary of terms|'''dominant''']] or [[#Glossary of terms|'''recessive''']] traits, or can be due to new mutations of a specific gene. <ref name=Davies/>As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle tissue. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

== Clinical Manifestations & Complications ==
[[Image:Symptoms of DMD.JPG|300px|thumb|right|Symptoms of DMD]]
====Signs and Symptoms of Duchenne Muscular Dystrophy====

Many of the symptoms associated with DMD are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. However, he general signs and symptoms of DMD are not usually apparent until the child is 3 years old<ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, or when major milestones such as learning to walk, are missed or delayed. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

Some typical symptoms include:
* Delayed motor movements<ref name=Medscape>http://emedicine.medscape.com/article/1173204-clinical</ref>
* Frequent falls and poor balance<ref name=Nelson>Kliegman RM, Behrman RE, Jenson HB, Stanton BF. Muscular dystrophies. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, Pa:Saunders Elsevier; 2007:chap 608.</ref>
* Weak skeletal muscles - causes difficulty running, jumping, and getting up from a sitting or lying down position<ref name=Nelson/>
* Large calf muscles (pseudohypertrophy) <ref name=Nelson/>
* Walking on toes or waddling gait<ref name=Medscape/>
* Abnormal curvature of the spine<ref name=Bushby>Bushby, K., Bourke, J., Bullock, R., Eagle, M., Gibson, M. & Quinby, J. (2005) The multidisciplinary management of Duchenne muscular dystrophy. Current Paediatrics, 15, 292-300</ref>
* Cardiac, respiratory and cognitive impairment<ref name=Nelson/>

====Skeletal muscle====
[[File:Gower's sign - a symptom of DMD.JPG|300px|thumb|right|Gower's sign]]
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]
The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD.<ref name =Medscape/> As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand.
A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref name= Bushby/> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref name = Bushby/>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly (peristalsis), resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition), [[#Glossary of terms| '''pulmonary aspiration''']], heartburn from reflux of gastric acid<ref><pubmed>7037523</pubmed></ref>. Some may have delayed gastric emptying and sphincter dysfunction.<ref name=Smuscle><pubmed>PMID3380114</pubmed></ref> The stomach may lose its strength, or in the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref name=Smuscle/>

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby/>Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====
In the central nervous system (CNS), dystrophin is found:
*on the [[#Glossary of terms|'''soma''']] and [[#Glossary of terms|'''proximal''']] [[#Glossary of terms|'''dendrites''']] of pyramidal cells in the [[#Glossary of terms|'''cerebral cortex''']] and [[#Glossary of terms|'''hippocampus''']].<ref name =Poysky><pubmed>17720499</pubmed></ref> Pyramidal cells are implicated in cognitive ability and play a role in vision-guided motor movement.<ref><pubmed>18632946</pubmed></ref>
*in Purkinje cells in the cerebellum<ref name= Poysky/> - Purkinje cells are large inhibitory neurons in the cortex of the cerebellum. Their main function is in controlling motor movement.<ref>Rose, S. (2005) The future of the brain: the promise and perils of tomorrow's neuroscience. Oxford University Press: Oxford, England.</ref>

The ''exact'' role of dystrophin in brain function is not known as research in this field is still in its infancy. From what has been found so far, it is believed that it affects the electrophysiology of neurons, calcium homeostasis and synaptic plasticity.<ref name= Poysky/> In particular reference to the locations above, an absence of dystrophin causes a disruption in normal brain function.

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. In a study of 1224 DMD patients and intelligence, it was found the average IQ was lower by one standard deviation than the normal population, and 35% of the boys had IQ scores in the mental retardation range (<70).<ref name=Cotton/> In particular, verbal skills are predominately affected, with similar learning problems to people with dysphonetic-dyseidetic dyslexia- they have difficulties with phonetics, recognising the shape of words and the synthesis of words.<ref name=Cotton><pubmed>11463183</pubmed></ref> They may also find it difficult when asked to repeat long or large pieces of information.<ref><pubmed>18764980</pubmed></ref>

== Diagnosis ==
[[File:Electrocardiograph_findings_in_dogs_affected_with_DMD.JPG|250px|thumb|Electrocardiograph Findings in DMD dogs]]

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is [[#Glossary of terms| '''caulking''']] around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.
[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code might go undetected by the methods used.<ref name="genome">http://www.genome.gov/19518854#4</ref>
**Prenatal Diagnosis - is performed by observing gene rearrangements and deletions using probes, during Week 4 to Week 18 of the pregnancy. The use of the these probes has improved carrier risk predictions but is not able to detect 100% of DMD cases prenatally and is still undergoing research.<ref>P A Ward, J F Hejtmancik, J A Witkowski, L L Baumbach, S Gunnell, J Speer, P Hawley, U Tantravahi, C T Caskey. 1989, Prenatal diagnosis of Duchenne muscular dystrophy: prospective linkage analysis and retrospective dystrophin cDNA analysis. Am J Hum Genet.44(2): 270–281.</ref>

* '''Clinical Diagnosis''' - male, progressive symmetrical muscle weakness, symptoms present before age 5, elevated [[#Glossary of terms| '''creatine kinase''']] (CK) blood levels and high levels of liver enzymes (AST and ALT).<ref>http://www.parentprojectmd.org/site/DocServer/Family_Guide.pdf?docID=9321</ref>
**Creatine kinase is also known as Total CK, Creatine phosphokinase or CPK.<ref>http://labtestsonline.org/understanding/analytes/ck/tab/test</ref> It is an enzyme found in brain and muscle tissue and its primary function is to catalyse the conversion of creatine to phosphocreatine.<ref>http://www.creatinejournal.com/creatine-supplement-creatine-kinase/</ref> In a normal healthy human being, there are low levels of CK circulating in the blood. Elevated CK levels suggest that the muscle or brain tissue has undergone damage. Therefore a blood test showing elevated levels of CK may indicate the following injuries: myocardial infarction, myocarditis, myositis etc.

* '''Physical Examination''' - Myocardial function is an important indicator of DMD. In recent years, it has increasingly become an important cause of death.<ref name="yugeta ">Naoko Yugeta, Nobuyuki Urasawa, Yoko Fujii, Madoka Yoshimura, Katsutoshi Yuasa, Michiko R Wada et al. Cardiac involvement in Beagle-based canine X-linked muscular dystrophy in Japan (CXMDJ): electrocardiographic, echocardiographic, and morphologic studies.BMC Cardiovascular Disorders 2006, 6:47</ref> Therefore, physical examination of cardiac rhythmn and function is essential in the process of diagnosing a patient with DMD. Dystrophin-deficient cardiac muscle is replaced by [[#Glossary of terms| '''fibrotic''']] tissue which can lead to wall motion abnormality, particularly in the left ventricle. These abnormalities can be detected by the following methods:<ref name="Spurney"/>
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']]. On a electrocardiograph this will appear as tall R-waves and deep Q-waves.<ref name="yugeta "/> Other indicators include an increased heart rate, shortened PQ (PR) interval and arrythmias.
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image. Echocardiography can detect myocardial thickening, wall motion abnormalities, enlargement of the left ventricle, and left ventricular [[#Glossary of terms| '''systolic''']] and [[#Glossary of terms| '''dialostic''']] function.<ref name="yugeta "/>
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.

A combination of these components along with family history confirms the diagnosis.

Further Reading: [http://www.ncbi.nlm.nih.gov/pubmed/2897793 Prenatal Diagnosis Methods]| [http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/mus.22097/full Cardiomyopathy of DMD]

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe [[#Glossary of terms|'''contractures''']] and [[#Glossary of terms|'''scoliosis''']].
|There are no side effects.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|There are no side effects.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle.<ref name="genome"/>

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac [[#Glossary of terms|'''myocytes''']] and consequently decreasing cardiac [[#Glossary of terms|'''hypertrophy''']].<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>It weakens the immune system and makes patients susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth.<ref name="genome"/>

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched, that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in [[#Glossary of terms|'''sickle cell disease''']].<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial[[#Glossary of terms|''' fibrosis''']] and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic [[#Glossary of terms|'''analog''']] of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on [[#Glossary of terms|'''myoblast''']] transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, [[#Glossary of terms|'''satellite cells''']], muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Important Current Research - Utrophin==

Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

{| align="left" style="width:50%; height:100px" border="1"
|- align="center"
| colspan="4" | Sedentary ''mdx'' mice
| colspan="4" | Exercising ''mdx'' mice
|- style="height:50px"
| rowspan="2" colspan="2" | Control (vehicle)
| rowspan="2" colspan="2" | SMT C1100
| rowspan="2" | Control (vehicle)
| rowspan="2" | SMT C1100
| rowspan="2" | Prednisone
| rowspan="2" | SMT C1100 + Prednisone
|}

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Actin:''' a protein that forms the contractile units of muscle cells

*'''Acute gastric dilation:''' short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Analog:''' a compound that resembles another in structure

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury

*'''Autosomal:''' a non-sex chromosome

*'''Base pair:''' two complementary bases in a nucleic acid molecule

*'''Cardiomyopathy:''' heart muscle disease

*'''Caulking:''' to make airtight or watertight by sealing or filling

*'''Cerebral cortex:''' unmyelinated neurons (grey matter) that forms the outer layer of the cerebrum

*'''Cytoplasm:''' material within a cell

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage

*'''Dendrites:''' thin extension of a nerve cell, branches out to receive nerve impulses from other neurons

*'''Dominant:''' a trait determined by an allele that is expressed over another present allele

*'''Dystrophin:''' a protein involved in muscular contraction

*'''Dystrophin-associated protein complex (DAPC):''' a multiprotein complex that includes dystrophin and other associated proteins

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Extracellular matrix:''' network of connective tissues and fibres that provide support and exist outside the cell

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Fibrotic:'''excess of fibrous connective tissue in an organ

*'''Filamentous:''' thread-like cells

*'''Gene:''' sequence of nucleotides forming part of a chromosome

*'''Genome:''' the complete set of genetic material in a cell or organism

*'''Hippocampus:'''sea-horse shaped mass of grey matter found on the floor of the lateral ventricles in the brain -functions in long term memory, emotion and controls the autonomic nervous system and is classified as part of the limbic system

*'''Homologue:''' a chromosome that is similar in physical attributes and genetic information to another chromosome with which it pairs during meiosis

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Hypertrophy:'''enlargement of organ or tissue by increasing the size of cells

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris

*'''Muscle contraction:''' process in which muscles shorter and are made tighter under neuronal control

*'''Muscle fiber:''' elongated contractile cell

*'''Myoblast:''' precursor of skeletal muscle tissue. Fusion of myoblasts gives rise to myotubes which eventually develop into skeletal muscle fibres

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Nucleotides:''' compounds that form the basic structural units of nucleic acids

*'''Phenotype:''' the physical expression of the genotype

*'''Plasma membrane:''' composed of lipids and proteins, forms the external boundary of the cytoplasm

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Proximal:''' towards the point of attachment

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Recessive:''' the opposite of Dominant

*'''Sarcolemma:''' the thin membrane of striated muscle fibers

*'''Satellite Cells:'''

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Signal transduction:''' internal cell signalling process

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Soma:'''body of the neuron cell

*'''Systolic:''' maximum blood pressure during contraction of the heart

*'''Transmembrane:''' existing across a membrane

*'''X chromosome:''' sex chromosome, two are represent in females and only one is present in male cells

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

==Related Links==

File:Dystrophin within the plasma membrane of muscle fibres.jpg

2011-10-10T07:16:47Z

Z3332629: This image is a visual display of the muscle fibre membrane and the location of dystrophin within the sarcolemma surrounding each muscle fibre. There are 4 main transmembrane proteins that compose the dystrophin-glycoprotein complex (DGP), also referred

This image is a visual display of the muscle fibre membrane and the location of dystrophin within the sarcolemma surrounding each muscle fibre.

There are 4 main transmembrane proteins that compose the dystrophin-glycoprotein complex (DGP), also referred to as the dystrophin-associated protein complex (DAPC), located in the muscle fibre membrane.

These proteins include:

• Sarcoglycans: a family of transmembrane proteins that work in conjunction with other proteins (namely dystrophin) to protect muscle fibres during contraction. There are 4 main types present in striated muscle, including: α-sarcoglycan, β-sarcoglycan, γ-sarcoglycan and δ-sarcoglycan. The sarcoglycan complex is disrupted and destabilized from the plasma membrane when dystrophin is mutated and hence leads to eccentric contraction-induced disruption of the plasma membrane of smooth and cardiac muscle. [1]

• Dystroglycan: connects the extracellular matrix and cytoskeleton and also forms a linkage between the dystrophin-glycoprotein complex and the basal lamina. When dystrophin is mutated, these linkages formed by dystroglycan are lost and also cause the disruption of the plasma membrane.[2]

• Syntrophin: links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC and therefore when dystrophin is mutated, this crucial signalling pathway is lost. [3]

• Dystrobrevinis: the functional role of this complex has not yet been clearly identified, however studies show that dystrobrevin disappears from the muscle membrane in Duchenne muscular dystrophy (DMD). [4]

C terminus or terminal refers to the end of an amino acid chain. This end is terminated by a carboxyl group. N terminus or terminal refers to the beginning of an amino acid chain. This starts the chain with an amine group.

Image creator: Ashleigh Pontifex (z3332629)
Student image constructed based on the image presented on: http://www.mda.org/publications/fa-dmdbmd-what.html

Additional information obtained from: http://www.mda.org/publications/Quest/q134resup.html

Location of dystrophin within the muscle fibre membrane by Ashleigh Pontifex is licensed under a Creative Commons Attribution-NoDerivs 3.0 Unported License. Based on a work at www.mda.org.

<a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nd/3.0/88x31.png" /></a>
Location of dystrophin within the muscle fibre membrane by Ashleigh Pontifex is licensed under a <a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/">Creative Commons Attribution-NoDerivs 3.0 Unported License</a>.
Based on a work at <a xmlns:dct="http://purl.org/dc/terms/" href="http://www.mda.org/publications/fa-dmdbmd-what.html" rel="dct:source">www.mda.org</a>.

{{Template:2011 Student Image}}.

Talk:2011 Group Project 10

2011-10-09T07:11:17Z

Z3332629: /* Group Discussion Week 10-12 */

[[2011_Group_Project_10|'''Group 10''']]: [[User:z3332327]] | [[User:z3332629]] | [[User:z3332824]] | [[User:z3330313]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_10_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_10_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Group Discussion Week 10-12==

Hey Rhiannon!

Ash here. Just read over your section and just have a few pointers or suggestions :)

“this includes skeletal muscles, smooth muscle and cardiac muscle” – maybe this could be written as just: this includes skeletal, smooth and cardiac muscle”.

“which causes many problems” – which can cause numerous implications maybe?

Many of your sentences states something then has a ‘-‘ then gives an example, this sort of seems informal and distrupts the flow of reading .. i personally would suggest using more complete and formal sentences, but just an idea.

These are only suggestions, I am happy if you do leave it the way it is but I know your a perfectionist :)

Let me know what you think

--[[User:Z3332629|z3332629]] 18:11, 9 October 2011 (EST)

Hey guys,

So I've finished my part of the assignment now (WOOOOO!) so if there is anything that I should edit/change, or if anyone needs a hand with anything, then let me know, ''I'm breezy!'' *Monica's Geller's voice*

'''Lisa:''' my mum just raised an important point for the diagnosis section - are you able to, when you are pregnant, genetically test the baby to see if it is affected? can you see if its actually affected or a carrier? when can you test this?
-I think this is an important point, and highly relevant as that is a concern for many people. Do you think you can include this somewhere?

Hope everyone else's parts are going ok,

--[[User:Z3332824|Rhiannon Bice]] 17:39, 7 October 2011 (EST)

Nice drawings!

Just some videos for my section, just placing them somewhere so i know where they are :)
http://www.youtube.com/watch?v=dOhMLZCvb50
http://www.youtube.com/watch?v=GWachrbiU58
--[[User:Z3332629|Ashleigh Pontifex]] 12:01, 3 October 2011 (EST)

Joanna : http://emedicine.medscape.com/article/1173204-overview#a0199
Great over view for epidemiology, perhaps a table or some stats would be great in this section :)

- http://www.ncbi.nlm.nih.gov/pubmed/19834452 -

hey guys I changed some of the stuff on history, if you think its too much info let me know!
I deleted alot of information, and I just can't bring myself to delete more because the stuff remaining now seems so relevant. But let me know what you think!
And what do you guys think about putting an image of the Duchenne dude in the history? do you reckon that'll make that section too long?
--[[User:Z3330313|Joanna Pak]] 02:56, 5 October 2011 (EST)

Hey Jo! I had a read of the history section and it sounds good. Just an idea, where you've listed Duchenne's definition of the disease, would you prefer if those were added under DIAGNOSIS- clinical or SIGNS AND SYMPTOMS? And we could add an internal link? Maybe that'll cut down your section a bit?

Just a suggested change, i just rearranged the words around a little, dont have to. =)

*'Meryon conducted several necropsies and found intact spinal cords which indicated the disease was not from the nervous system.'

Minor edit

*'Further microscopic examination of the muscle showed that the muscular fibres '''broke''' down and converted into granular, fatty matter.'
--[[User:Z3332327|Lisa Xiao]] 11:38, 5 October 2011 (EST)

Hey Jo its Ash!! It looks heaps better, more straight forward and the table inclusion is great :)
Is everyone happy with my student drawn image in the introduction? it is appropriate in this section?
Also my table in the genetics section???

And lastly, ive notice that Rhiannon has hyperlinked all glossary terms in her section, is everyone happy to carry that across all areas???
--[[User:Z3332629|z3332629]] 12:29, 5 October 2011 (EST)

Actually one last suggestion jo, maybe change the table colour to teal so that the colour schemme consistent throughout the page :)
--[[User:Z3332629|z3332629]] 12:32, 5 October 2011 (EST)

Hey rhiannon! I tried searching for that image of the heart, turns out its not open access. I'll keep an eye out for you though in case i find anything useful.--[[User:Z3332327|z3332327]] 14:03, 7 October 2011 (EST)

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

==Peer Review==

'''Peer Review'''
* The introduction is detailed but a bit “in your face.” It may even be a bit too detailed, going into the pathogenesis of the disorder.
* History is very detailed, perhaps slightly story-like but enjoyable nonetheless. Could use a picture or two. Sufficiently referenced.
* Epidemiology is very thorough and well referenced.
* The tone of Aetiology/Genetics is a bit conversational; needs to be more detached. Good use of picture, although the legend to it is not in the correct format.
* Pathogenesis could use more references, especially for the last paragraph. Could potentially use some pictures to make clearer the specific structures discussed in the text (although they are elaborated on in the glossary).
* All the signs listed in Clinical Manifestations etc are decently elaborated upon, and the section is well-referenced. Smooth Muscle has strange “&&&” signs though. Respiratory Problems needs cleaning, notably with the line “[Effects of high CO2 and the problems it can cause]”
* Diagnosis is nicely laid out, although more references are needed.
* Treatment is decently set up and clearly explains each of the treatment plans.
--[[User:Z3290689|z3290689]] 14:44, 29 September 2011 (EST)

Group 10:
This project looks fine but it seems a little short? You want to expand the content in sections.
History is well researched but it’s quite long. You can add more images (add the reference in the description) and make the dates in Bald.
There are some spelling errors and extra signs that are not related to the work such as &&&.
Some of the references are repeated and others need to be reformatted.
Overall, Great effort.

--[[User:Z3284061|z3284061]] 11:51, 29 September 2011 (EST)

'''Peer Assessment'''
*introduction is well written and descriptive. Good use of image to make it look appealing. No references in the first paragraph.
*History section is too long, text heavy and a bit boring. Try to summarize the details on a timeline. You can include an image e.g. of Dr Edward Meryon if possible.
*Epidemiology and aetiology; well written. The image in the aetiology needs to be linked with the text.
*Pathogenesis; too brief. Needs more information and explanation of the disease process. Include an image or flowchart to compliment the text.
*Signs and symptoms; needs to be expanded a bit more. I suggest using a table to present the information that just as dot points. Same goes for the diagnosis section, which also needs to be expanded. Try and use more images, tables, graphs etc to break up the texts and make the page look more appealing.
*I suggest hyperlinking words in the page with the glossary to make the page more user friendly.
*Like the use of table in the "current and future prospects". It's better to present information like this rather than in big long paragraphs.
*The glossary needs to be expanded more.
--[[User:Z3291622|Z3291622]] 11:07, 29 September 2011 (EST)

'''''Duchenne (Group 10) Peer Review:'''''

Could you include “Duchenne Muscular Dystrophy” as the first subheading so that the reader knows exactly what the disease is at first glance? Just a suggestion.

Introduction: Topic well introduced and good use of image. Image, however, is lacking a student template.

History: Very extensive. Possibly include an image to break up the text.

Epidemiology: Sound. Some sentences are not worded/ structured properly.

Aetiology – Genetics: Information is good. Impressive self-drawn image. Well done.

Pathogenesis: An image would definitely work well in this section. Information is otherwise good, however possibly have a greater focus on the genetic component?

General Signs and Symptoms of Duchenne’s Muscular Dystrophy: This section seems too brief. Elaborate further.

Clinical manifestations and complications: Information is good. Possibly more detail for the subheading “smooth muscle.” Image lacks a student template. “&&&” – what is this? Many references in this section which is good to see!

Diagnosis: Could be elaborated further.

Treatment: Current and Future Prospects: The first paragraph lacks referencing. Possibly include an image? Table is a good idea, however colours chosen are slightly off-putting.
Glossary of terms: Could be more extensive. Not complete.

Well done. --[[User:Z3290808|z3290808]] 10:50, 29 September 2011 (EST)

Duchenne Muscular Dystrophy – Group 10

* Excellent introduction and good use of image. Is there some referencing missing in the first few sentences? Some formatting should be done on the image either to make it within the intro section or more shared between the history sections. Looks a little out of place.
* History is well written but very text heavy. Use of a timeline good improve this section and make it more succinct. Also I thought an image could be good.
* Epidemiology seems to cover all necessary information and is well referenced. Maybe an image or graph here could be good.
* I like the student drawn image in the etiology section, maybe the sizing could be improved though? Also some a more detailed description of what the image shows would also be good.
* Pathogenesis section is very informative. Maybe the pathophysiology could be covered in this section as well? Image could be added.
* General signs and symptoms would perhaps look better in a table. Otherwise it is quite brief, maybe some more elaboration aswell.
* I think diagnosis looks incomplete. Not much detail is given about how the diagnosis actually works. Very little referencing. Addition of an image would improve this section.
* Treatment looks great. I like how you have included current and future prospects. Just wondering if there was room for a heading for current and future research, as Im sure there is more research being undertaken than just in the area of treatment. This could make this project more informative, and perhaps could be another heading.
* Glossary needs improving.
* Some issues with referencing such as multiple entries for the same article and some issues with web page referencing.

--[[User:Z3288196|Z3288196]] 10:48, 29 September 2011 (EST)

'''GROUP 10: Duchenne Muscular Dystrophy'''
*Title of the whole page should just be Duchenne Muscular Dystrophy, not Introduction...
*The intro is very descriptive and comprehensive
*Image in intro needs proper referencing
*consider rephrasing this sentence "In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction"
*History has good info, but could this be better formatted in a table? this section is text heavy and could maybe use an image, it also could be extended into more recent years
*Epidemiology is summarised well and contains good statistics
*I feel that Aetiology - Genetics section has good info, easy to understand and informative but maybe it could be researched a little more
*General Signs and Symptoms of Duchenne’s Muscular Dystrophy section needs a lot more work, the list of symptoms i don't feel is enough, more expansion on these is needed. An image would improve this section too
*"diarrhoea&&&." -this needs to be fixed

Overall:
*More images are needed to break up the text
*glossary needs a bit more work, consider linking glossary words to text
*I feel that the page overall needs some more work, some sections are lacking content
*Proof reading to fix grammar and sentence structure

--[[User:Z3331556|z3331556]] 10:44, 29 September 2011 (EST)

'''Peer Review'''

This wiki still feels like what Mark Hill mentioned earlier, like a backbone for content to be built upon. The foundations are there, but still very incomplete. Comparing the sections, some have done a lot of effort, others not so much, and it is very visible.

:*Should start the wiki with this code:

<wiki>=Duchenne Muscular Dystrophy (DMD)= </wiki>

then

<wiki>==Introduction == </wiki>

:*History is far too text heavy and it shouldn't be like that, as this makes it a chore to read. A timeline would be better suited and summarise into the timeline.

:*Should be more student drawn images, since there's only one. If getting pictures is hard to find, then draw your own.

:*The one student drawn image is not referenced correctly, needs the disclaimer info.

:*Diagnosis needs to be expanded. There is 300+ articles, there has to be more info or an image to be found.

:*Pathogenesis needs to be expanded, maybe an image.

:*Signs and symptoms need more referencing. Also, just leave the title as Signs and Symptons.

:*Treatment needs to be expanded on. It isn't any good just listing drugs into a table.

:*Split the Treatment to include Managment and give a separate section for Current Research.

:*Glossary is incomplete.

--[[User:Z3293267|z3293267]] 10:37, 29 September 2011 (EST)

Group 10:

Clear and conscise but still needs more work breaking up the long slabs of writing. Perhaps more subheadings esp. in the first sections.

More pics are needed to break up the work.

Treatment includes a good table.

Glossary needs a bit of work and expanding on the explanations.

References needs to be fixed as there is duplications of references.

z3332178 =]

Peer Review

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*History section would benefit by placing the information into a timeline rather than paragraphs as it is a bit hard to follow.

:*Epidemiology section could be expanded and written in more flowing way rather than long sentences.

:*Needs more images, lots of large blocks of text. And images need to be formatted into the text as formatting currently looks awkward.

:*Further Research could be added, for example papers or groups that are researching as currently it is just being referred to.

:*Glossary could be expanded.

:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed. Also perhaps research from MORE sources is necessary as there is only a few when you cut out the double references.

--[[User:Z3217043|z3217043]] 10:02, 29 September 2011 (EST)

Group 10 Peer Review

*Headings are well organised and structured
*Too much text in history section-a table or image would be good
*Information is there however images/graphs/tables would help break up large chunks of text
*Diagnosis seems brief-perhaps merge with treatment section?
*Signs and symptoms could be expanded
*Great table in treatment
*Needs to be proof read-grammar and spelling mistakes
*Double referencing
*Glossary needs to be extended
--[[User:Z3308965|Fleur McGregor]] 09:54, 29 September 2011 (EST)

Group 10

*Introduction – Great intro, well referenced apart from the first paragraph.
*History has a lot of text, a timeline could work well here and also an image if possible just to break up the text.
*Epidemiology – well referenced and structured, text could be broken up but that’s nothing major as it’s a small section.
*Aetiology – A link between the image provided and the text would work well, and also the image could be formatted on the right of the page, to add to continuity and flow as other images are located on the right.
*Signs and Symptoms – Needs to be more information here, a description of each symptom and maybe its direct causes.
*Clinical manifestations – need a link between the image and the text, other than that it is well referenced and easy to understand.
*Treatment – table formatting is great and information is helpful
*Glossary – needs to include more terms form the page.
*There’s some doubling up in the reference section that needs to be fixed, other than that good job.

--[[User:Z3331469|z3331469]] 08:25, 29 September 2011 (EST)

peer review:

*Intro: One of the very few groups to use an image of the disease in the intro, well done! Like how you have referred to Duchenne’s as DMD in brackets initial heading to avoid confusion.

*History: A lot of writing, no techniques to break it up, which will basically bore your reader. Use a timeline perhaps.

*Epidemiology: Subheading will benefit this segment.

*Aetiology: The image could use some colour, but it is still very well done. It would be worthy to refer to the drawing as your explaining the genetics, just to bring them together.

*Pathogenesis: Very brief, not very informative and lacking subheadings or an image. Hopefully this will be fixed.

*Signs and Symptoms:Poorly done. Dot-points are a good way to initiate the writing but not appropriate as a final copy. Needs more description and research.

*Clinical manifestations:
The image used is excellent but needs more explanation.

*Diagnosis:Very short, looks incomplete and there’s only one reference for the entire section.

*Treatment: Well done, I like the colour and the table structure, makes it much easier to understand.

*Glossary: Incomplete, much more terminology has been used.

*References: Double referencing is a big problem here.

*Text:image ratio: could use more images.

--[[User:Z3290270|z3290270]] 02:16, 29 September 2011 (EST)

*history should be broken up with dates on side or within a table.
*how about a short summary table to use for epidemiology
*no picture of Guillaume Benjamin Amand Duchenne?
*no copyright permission for the drawn image in genetics.
*pathogenesis seems very small for a section that is very important.
*describe how the signs and symptoms impact on patients to show the significance of the disease.
*diagnosis needs a lot of work, this section is very important. also very little references in this section.
*not enough pictures to accompany the text
*very short glossary
*multiple references of same articles
--[[User:Z3291423|Jasjit Walia]] 00:17, 29 September 2011 (EST)

'''Peer Review for Group 10'''

*The introduction was well written, however the picture in it is not referenced as instructed. Please fix that then your intro is perfect.
*In the history section, the first sentence is oddly placed, even though it’s informative, please put that somewhere where it will flow in the paragraph.
*The history is verbose, please re write so it’s easier to follow.
*Epidemiology needs to be reevaluated as some sentences are not constructed properly
*Etiology has sound information but the paragraphs are not structured so it flows. It also seems repetitive.
*The picture in the etiology can have its caption better structured
*Pathogenesis should include some component of genetics to explain how the abnormalities bring about the pathogenesis in the genetics level.
*Explanation of how the signs and symptoms comes along from the dystrophy should be explained
*The image of the spine is not completely referenced as url of the image and the page must also be given
*Information under ‘respiratory problems’ and smooth muscle needs some reviewed as it includes words there that shouldn’t be present
*The diagnosis section could be expanded upon so it includes more information on the details of how it is detected, and images should complement the tools to diagnose the condition.
*An introduction to the table should be given. Having the table there by itself doesn’t look good.
*Further explanation should be made on the type of physical activity that would be made for therapy
*Glossary should be expanded
*There is repetitive referencing; it should be reformatted to fit in the way multiple references is made.
*You need much more pics as without the pics the page looks word heavy.

--[[User:Z3291317|Z3291317]] 23:57, 28 September 2011 (EST)

'''Group 10'''

Introduction: Good introduction. The picture could be a bit bigger. Also, a picture of the chromosome would be great.

History and epidemiology: Both sections are clear and flow well. Pictures are needed to break up the text though.

Genetics: The image is great and the text is well written.

Pathogenesis: The pathogenesis is well explained. Again, pictures would be good in this section to improve it.

Clinical manifestations: Good section. Clear, easy to understand.

Diagnosis: This section might need some more detail added. You could explain how each of the diagnostic tests work

Current and future treatment: This section is worded well but looks a little bit disjointed. I think it would be better having it either all in text or all in the table. --[[User:Z3291324|z3291324]] 23:27, 28 September 2011 (EST)

'''Group 10 Peer Review'''
* Interesting introduction, with a good amount of information. The history is also quite well outlined, although as you have no doubt seen with many of the other groups by now, a timeline woud be adequate in the history section (this also helps to break the text up and help us get a "break" from large blocks of text!)
* Epidemiology section is short but sweet - all the required information is there and summarised well. Perhaps mention the rate of mortality? (although this may be obvious)
* The student-drawn image in the aetiology section doesn't have your own copyright notice, so this should be added to the description. There also might be more to write in this section, but only if you wish to seek out the information. Diagrams can be helpful in summarising excessively detailed material.
* Pathogenesis simply needs to be longer; a lot can be written on this section and there should also be the use of diagrams throughout. Explain why the pathogenesis of DMD is so destructive; it has more than just the function of securing the sarcolemma to the cytoskeleton and is also present in other parts of the body, so make sure you explore this completely! :) (for example, dystrophin which is affected also is found in different areas of the body which may help explain some of the other symptoms of DMD).
* General signs and symptoms could have a diagram to assist in the signs and symptoms.
* Clinical manifestations and complications could have more written and explaining some of the other symptoms that aren't purely based upon the muscle damage observed in DMD.
* Diagnosis needs to have more written, especially images regarding the methods of imaging and therapy.
* Treatment; and Current and Future Prospects are different sections and shouldn't be integrated. Think carefully about the implications that current and future directions of research will have on this disease - they are huge! Try to write more and make an individual section on current and future prospectives of research for DMD; as you know from your research so far, DMD is a very important disease requiring a lot of research.
* Glossary is incomplete; References have a lot of repeats, but these are problems that are common to almost all projects.
* Generally, you just need to find better ways of altering the information in your project. Try to add tables and images to help break up the information and make sure you've discussed all the sections in the guidelines for the project properly. Keep at it! :) There are also some obvious typos ('''&&&''')?
--[[User:Z3288827|Leonard Tiong]] 22:29, 28 September 2011 (EST)

'''Group 10:'''

•History might work better in a timeline, just to break up the text as the beginning of the page looks a little overwhelming with text.

•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template for all of the uploaded images.

•The different sections seem to be a little inconsistent, where a few of the sections such as diagnosis and treatment seem a little vague. These sections could be expanded on to give the reader a more comprehensive knowledge of what is involved, especially seeing as the diagnosis section only has one reference.

•Some typos in the smooth muscle section - ‘&&&’

•A lot of the references are repeated multiple times – this should be fixed up so that each reference only appears once. And also not all the references seem to be formatted correctly.

•Glossary is incomplete

•Overall, good use of subheadings though some of the sections need to be expanded and a few more images are needed to add a better balance to the page. Good work so far.

--[[User:Z3332183|z3332183]] 21:33, 28 September 2011 (EST)

'''Group 10'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main points are there. Content is decent in some places and lacking in others. Fixing up problematic areas would be good.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
Maybe include a time-line in history?'''
General Signs and Symptoms of Duchenne’s Muscular Dystrophy section is very poor. Getting information from an insurance website is not actual research. please consider re-doing this section with sources cited from a peer-reviewed paper. Signs and symptoms should go with diagnosis as it is part of making a diagnosis. why are there ampersands in Smooth muscle section?

'''*Content is correctly cited and referenced.'''
Fix up references, some are simply links and they repeat.

'''*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 is drawn well, explanation could do with a bit more work though. File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg needs proper citation, also there isn't many images. Try including more images.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Not as much information as i was expecting and references is not as extensive as other pages - but good in-text citation (with the exception of some places such as diagnosis and Respiratory problems), it shows that the information has come from somewhere. Information from an insurance website is not evidence of extensive research so try to fix it.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
No connection to embryology - try linking genetic defects to problems in the neonate, or even if there is a prenatal test.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Some evidence of developing the wiki page with the guidelines. Will benefit from changing some things.

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

'''Group 10: Peer Assessment'''
* Your page is relatively short overall and could use some more pictures, especially in the first few sections.
* You have forgotten to put a title on you page
* The introduction is good
* You have got quite a bid of text in the history section, may be you can make a bid lighter with a time line?
* Epidemiology is nice to read and relevant
* Signs and symptoms belong into the clinical manifestation section
* Diagnostics could be more in detail
* The green and blue in the table is a bid too much colour all on a sudden. May be you can have some more colour overall or do the table in just one colour?
* It would be great to have more terms in the glossary
* I would put the diagnosis section right after pathogenesis
* Overall you have got good information on your page. May be you can work on the overall structure and some references. --z3279511 17:15, 28 September 2011 (EST)

'''Group 10'''

*Introduction: well done

*History: lots of information, some parts have no references, subheadings and a time line would be advantageous

*Epidemiology: good contend

*Aetiology: the contend seems fine, but more structure would be good

*Pathogenesis: looks good

*Signs and symptoms: that’s more like a list that a section, maybe combine it with manifestations

*Manifestations: well done, except for smooth muscle- seems incomplete?

*Diagnosis: you could add more information and details

*Treatment: the heading seems inappropriate, separate treatment and research, the contend could be more explained

*Glossary: is incomplete

*More images would be nice
--[[User:Z3387190|Z3387190]] 14:28, 28 September 2011 (EST)

'''Group 10'''

*Very poor image/text ratio – you need more images to break up the text
*Good intro
*History would work better in a timeline- you also mention nothing after the 1800s, more recent findings need to be included
*An image would be nice for pathogenesis to help the reader follow
*Not sure why you have made signs and symptoms a different heading to clinical manifestation- these could be combined
*Diagnosis is very brief and needs to be extended
*Glossary needs to be added to
*Maybe add a current research heading

===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.

--Z3389806 07:04, 27 September 2011 (EST)

'''Group 10 Peer assessment'''
*Heading order needs to re-arranged and done properly with diagnosis above before signs and symptoms.
*Introduction done sort of well needs to integrate image as an example of the myofibres.
*History rather bulky with too much text and no image, image of the founder would be fine. Also no time line present of DM needs to be added
*Epidemiology seems rather empty, images would benefit this section also more stats, further expansion of sub headings would also do well for this section
*Genetics aetiology needs to be expanded where seems to be cramped, though usage of image needs to be noted
*Pathogenesis needs images and further information
*Signs and symptoms needs to be expanded and image of some signs or tables
*Clinical manifestation done well with image and further sub-headings
*Diagnosis requires more attention with further methods of detection of DM
*Treatment is well done with the usage of the table
*Glossary needs to further expanded also linked to the pages so easy to follow the page
*References are not complete with links and repeats of the references
z3332250 23:59, 26 September 2011 (EST)

'''Group 10 Critique'''

#• The introduction was very good. Good use of images to give it a little decoration!
#• History is good
#• Epidemiology is good, however if possible try and make it longer/ include more information
#• The Genetics section is a bit too short. Add more information. Good hand drawn image!
#• Pathogenesis is a little short. Needs more information
#• Signs and Symptoms is good
#• Clinical manifestations is ok
#• Diagnosis, treatment and glossary are all well written. These sections should not require any change

--[[User:Z3289991|Robert Klein]] 16:27, 26 September 2011 (EST)

Group 10 ''Duchenne Muscular Dystrophy''
*The first paragraph of the introduction has no reference.
*The paragraphs in history are quite long, often with grammar mistakes, incorrect punctuations and many of the ideas within a sentence separated by a ''-''. For example the second last paragraph within history.
*The history is too verbose, a timeline with bullet points will look better
*Aetiology is quite concise and informative however gramatical errors are a distraction. For example ''There a multiple forms of dystrophin''. It might be a good idea to proofread the page.
*Well done with the student drawn image
*'Pathogenesis' is again well written however an image might have given it a balance between the text in the section and the pictures or tables
*The future therapies table is a little confusing, you might want to add more columns and define the therapy, and then discuss what the challenges and findings are and at the end column finish off with what the implication might be if the research is to be completed successfully. At the moment you have discussed all that in one big paragraph and the way the descriptions start, it sounds like there is no background to the description, just a little abrupt.
*The glossary is very short and you should include terms like de novo mutation.
*The existing definitions are unclear and incomplete

''Duchenne Muscular Dystrophy''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topics

Group 10-
* Need more images to break up the text
* The introduction was really easy to read and had relevant information in it
* History should be in bullet point form to make it easier to access or at least have the dates in BOLD
* Does the history include dates after the 1800s? or did all research stop then?
* Epidemiology was good. Had all the relevant info
* Pathogenesis would benefit an image or a diagram
* Signs and symptoms could be put with clinical manifestations.
* What is the point of the ‘&&&’? in clinical manifestations and complications?
* Diagnosis could be expanded upon to explain how and why these methods work
* Treatment could also be expanded on. A list of drugs doesn’t explain much
* There is not current/future research section
* This is a good start to the project but more research needs to be done

'''Group 10'''
* The structure and use of headings and subheadings is good, make sure you title your page.
* Good info very informative and it gives a good overview to DMD.
* HIstory has a lot of text could you use a timeline here?
* i think a picture of the pathogenesis would improve this section.
* Has your group look at the CNS and cognitive function of DMD boys its a controversial area as many people have different attitudes towards this but Dr Stewart Head a UNSW lecture actually studies DMD and is very informative in the area and recently published a article in the journal Brain.
* The CNS is highly affected by the lack of dystrophin as well as GABA receptors. I think this area is very import to consider as it highly affects the boys at school.
* Could you add some pictures to your page or break it up with the use of more tables as it a lot of text in comparison to pictures and tables.
* Make sure your reference list is not doubled.
* Ensure all your pictures are referenced properly.
* Student image is present.
* This is a good start.

'''Group 10 Assessment'''
*The history is a bit wordy… Maybe consider consolidating the information into a table format for ease of reading. Could also use a picture to add to it.
*The Epidemiology section could also use a picture and maybe some more information, if possible.
*Point vs Frameshift mutation jpg: Good drawing, but in the last portion of the picture the product is labeled as a ‘tunicated protein product.’ Isn’t it supposed to be a ‘truncated’ product?
*The Signs and Symptoms section could use some formatting; it just looks rather dull currently. Maybe a chart or add in a picture?
*Smooth muscle section: Why are there random &&&’s?
*The top portion of the Treatment section could use some more referencing… Good chart though! Only thing I’d suggest for it is to add some pictures if possible?
*Glossary term list is rather short… Are you sure there’s nothing else that needs defining for clarification for the reader?
*It would be a good idea also to have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word 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.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. 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 #...
*Overall, good information is included, just work on referencing things and the overall structure and you should be good!
--[[User:Z3391078|Z3391078]] 17:00, 27 September 2011 (EST)

'''Peer Assessment: Group Project 10'''
*I think the section heading of introduction accompanied by the question what is muscular dystrophy, works really well.
*It might be good to include an image in the history section to break up the text, such as of someone prominently involved with the disease findings.
*The information in clinical manifestations and complications is well written. There needs to be some fix to the formatting under the smooth muscle heading where some '&'s have been repeated.
*The current and future prospects section is great. You have summarised what
*Some of the definitions of words in the glossary need to be completed e.g. atrophy and protease.
*Under the information in some of the images such as the fisrt one, 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.
*An additional section of external links might provide information for those wanting to know more.
--[[User:Z3217345|z3217345]] 10:50, 28 September 2011 (EST)

'''Peer Review'''

* struture and format done well
* easy to read

--[[User:Z3060621|z3060621]] 21:58, 28 September 2011 (EST)

*'''Intro''': Fine
*'''History''': Nicely detailed, but missing a timeline.
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.
*'''Pathogenesis''': Content seems fine, could do with a figure?
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?
*'''Clinical manifestations and complications''': Fine
*'''Diagnosis''': Clinical Diagnosis is a bit short?
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.
*'''Glossary''': Poor. More terms need explanations.
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.

==Discussion==

'''GROUP 10!'''

'''To make everything easier to follow, we have agreed to write any updates, info, discussion etc at the BOTTOM of this page, it will just stop us having to keep going up and down and wasting time trying to find the information we want.'''

----

Hey Everyone,

So Mark went through each group today during the lab and the webpages and discussed where we should be up to. By next week, he expects the subheadings & some content to be up and running. He also recommended that we should have some more research going on in our discussion page. E.g. Research articles links, interesting sites etc.

Topics have been allocated so please begin your research and typing up some content. We can further divide our headings if necessary, take a look at some other groups, they have some pretty good ideas. Mark will be checking this next week during our lab. He'll be coming around to each of us.

So hopefully see you all next week !

--[[User:Z3332327|z3332327]] 12:53, 25 August 2011 (EST)

==Subheadings for assignment==

Intro what is DMD

History/timeline

Genetic component

Why is it an abnormality - Symptoms effect

Diagnosis, future/current prospect (treatments?)

2 case studies

Glossary of terms

====Post online any preferences you may have in terms of the topics you wish to research and by Sunday we will allocate sub topics====
--[[User:Z3332629|z3332629]] 13:09, 18 August 2011 (EST)

Okay hey guys just to get the discussion going, umm I don't mind doing the first 2 on the list. And the "Why is it an abnormality - Symptoms effect" sounds pretty interesting as well.
What are your preferences?? :)

--[[User:Z3330313|z3330313]] 14:55, 23 August 2011 (EST)

Hey Everyone, Im happy to do the diagnosis/current/future prospects point and a case study.

--z3332327 15:36

Talk:2011 Group Project 10

2011-10-09T07:11:01Z

Z3332629: /* Group Discussion Week 10-12 */

[[2011_Group_Project_10|'''Group 10''']]: [[User:z3332327]] | [[User:z3332629]] | [[User:z3332824]] | [[User:z3330313]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_10_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_10_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Group Discussion Week 10-12==

Hey Rhiannon!

Ash here. Just read over your section and just have a few pointers or suggestions :)

“this includes skeletal muscles, smooth muscle and cardiac muscle” – maybe this could be written as just: this includes skeletal, smooth and cardiac muscle”.

“which causes many problems” – which can cause numerous implications maybe?

Many of your sentences states something then has a ‘-‘ then gives an example, this sort of seems informal and distrupts the flow of reading .. i personally would suggest using more complete and formal sentences, but just an idea.

These are only suggestions, I am happy if you do leave it the way it is but I know your a perfectionist :)

Let me know what you think

--[[User:Z3332629|Ashleigh Pontifex]] 18:11, 9 October 2011 (EST)

Hey guys,

So I've finished my part of the assignment now (WOOOOO!) so if there is anything that I should edit/change, or if anyone needs a hand with anything, then let me know, ''I'm breezy!'' *Monica's Geller's voice*

'''Lisa:''' my mum just raised an important point for the diagnosis section - are you able to, when you are pregnant, genetically test the baby to see if it is affected? can you see if its actually affected or a carrier? when can you test this?
-I think this is an important point, and highly relevant as that is a concern for many people. Do you think you can include this somewhere?

Hope everyone else's parts are going ok,

--[[User:Z3332824|Rhiannon Bice]] 17:39, 7 October 2011 (EST)

Nice drawings!

Just some videos for my section, just placing them somewhere so i know where they are :)
http://www.youtube.com/watch?v=dOhMLZCvb50
http://www.youtube.com/watch?v=GWachrbiU58
--[[User:Z3332629|Ashleigh Pontifex]] 12:01, 3 October 2011 (EST)

Joanna : http://emedicine.medscape.com/article/1173204-overview#a0199
Great over view for epidemiology, perhaps a table or some stats would be great in this section :)

- http://www.ncbi.nlm.nih.gov/pubmed/19834452 -

hey guys I changed some of the stuff on history, if you think its too much info let me know!
I deleted alot of information, and I just can't bring myself to delete more because the stuff remaining now seems so relevant. But let me know what you think!
And what do you guys think about putting an image of the Duchenne dude in the history? do you reckon that'll make that section too long?
--[[User:Z3330313|Joanna Pak]] 02:56, 5 October 2011 (EST)

Hey Jo! I had a read of the history section and it sounds good. Just an idea, where you've listed Duchenne's definition of the disease, would you prefer if those were added under DIAGNOSIS- clinical or SIGNS AND SYMPTOMS? And we could add an internal link? Maybe that'll cut down your section a bit?

Just a suggested change, i just rearranged the words around a little, dont have to. =)

*'Meryon conducted several necropsies and found intact spinal cords which indicated the disease was not from the nervous system.'

Minor edit

*'Further microscopic examination of the muscle showed that the muscular fibres '''broke''' down and converted into granular, fatty matter.'
--[[User:Z3332327|Lisa Xiao]] 11:38, 5 October 2011 (EST)

Hey Jo its Ash!! It looks heaps better, more straight forward and the table inclusion is great :)
Is everyone happy with my student drawn image in the introduction? it is appropriate in this section?
Also my table in the genetics section???

And lastly, ive notice that Rhiannon has hyperlinked all glossary terms in her section, is everyone happy to carry that across all areas???
--[[User:Z3332629|z3332629]] 12:29, 5 October 2011 (EST)

Actually one last suggestion jo, maybe change the table colour to teal so that the colour schemme consistent throughout the page :)
--[[User:Z3332629|z3332629]] 12:32, 5 October 2011 (EST)

Hey rhiannon! I tried searching for that image of the heart, turns out its not open access. I'll keep an eye out for you though in case i find anything useful.--[[User:Z3332327|z3332327]] 14:03, 7 October 2011 (EST)

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

==Peer Review==

'''Peer Review'''
* The introduction is detailed but a bit “in your face.” It may even be a bit too detailed, going into the pathogenesis of the disorder.
* History is very detailed, perhaps slightly story-like but enjoyable nonetheless. Could use a picture or two. Sufficiently referenced.
* Epidemiology is very thorough and well referenced.
* The tone of Aetiology/Genetics is a bit conversational; needs to be more detached. Good use of picture, although the legend to it is not in the correct format.
* Pathogenesis could use more references, especially for the last paragraph. Could potentially use some pictures to make clearer the specific structures discussed in the text (although they are elaborated on in the glossary).
* All the signs listed in Clinical Manifestations etc are decently elaborated upon, and the section is well-referenced. Smooth Muscle has strange “&&&” signs though. Respiratory Problems needs cleaning, notably with the line “[Effects of high CO2 and the problems it can cause]”
* Diagnosis is nicely laid out, although more references are needed.
* Treatment is decently set up and clearly explains each of the treatment plans.
--[[User:Z3290689|z3290689]] 14:44, 29 September 2011 (EST)

Group 10:
This project looks fine but it seems a little short? You want to expand the content in sections.
History is well researched but it’s quite long. You can add more images (add the reference in the description) and make the dates in Bald.
There are some spelling errors and extra signs that are not related to the work such as &&&.
Some of the references are repeated and others need to be reformatted.
Overall, Great effort.

--[[User:Z3284061|z3284061]] 11:51, 29 September 2011 (EST)

'''Peer Assessment'''
*introduction is well written and descriptive. Good use of image to make it look appealing. No references in the first paragraph.
*History section is too long, text heavy and a bit boring. Try to summarize the details on a timeline. You can include an image e.g. of Dr Edward Meryon if possible.
*Epidemiology and aetiology; well written. The image in the aetiology needs to be linked with the text.
*Pathogenesis; too brief. Needs more information and explanation of the disease process. Include an image or flowchart to compliment the text.
*Signs and symptoms; needs to be expanded a bit more. I suggest using a table to present the information that just as dot points. Same goes for the diagnosis section, which also needs to be expanded. Try and use more images, tables, graphs etc to break up the texts and make the page look more appealing.
*I suggest hyperlinking words in the page with the glossary to make the page more user friendly.
*Like the use of table in the "current and future prospects". It's better to present information like this rather than in big long paragraphs.
*The glossary needs to be expanded more.
--[[User:Z3291622|Z3291622]] 11:07, 29 September 2011 (EST)

'''''Duchenne (Group 10) Peer Review:'''''

Could you include “Duchenne Muscular Dystrophy” as the first subheading so that the reader knows exactly what the disease is at first glance? Just a suggestion.

Introduction: Topic well introduced and good use of image. Image, however, is lacking a student template.

History: Very extensive. Possibly include an image to break up the text.

Epidemiology: Sound. Some sentences are not worded/ structured properly.

Aetiology – Genetics: Information is good. Impressive self-drawn image. Well done.

Pathogenesis: An image would definitely work well in this section. Information is otherwise good, however possibly have a greater focus on the genetic component?

General Signs and Symptoms of Duchenne’s Muscular Dystrophy: This section seems too brief. Elaborate further.

Clinical manifestations and complications: Information is good. Possibly more detail for the subheading “smooth muscle.” Image lacks a student template. “&&&” – what is this? Many references in this section which is good to see!

Diagnosis: Could be elaborated further.

Treatment: Current and Future Prospects: The first paragraph lacks referencing. Possibly include an image? Table is a good idea, however colours chosen are slightly off-putting.
Glossary of terms: Could be more extensive. Not complete.

Well done. --[[User:Z3290808|z3290808]] 10:50, 29 September 2011 (EST)

Duchenne Muscular Dystrophy – Group 10

* Excellent introduction and good use of image. Is there some referencing missing in the first few sentences? Some formatting should be done on the image either to make it within the intro section or more shared between the history sections. Looks a little out of place.
* History is well written but very text heavy. Use of a timeline good improve this section and make it more succinct. Also I thought an image could be good.
* Epidemiology seems to cover all necessary information and is well referenced. Maybe an image or graph here could be good.
* I like the student drawn image in the etiology section, maybe the sizing could be improved though? Also some a more detailed description of what the image shows would also be good.
* Pathogenesis section is very informative. Maybe the pathophysiology could be covered in this section as well? Image could be added.
* General signs and symptoms would perhaps look better in a table. Otherwise it is quite brief, maybe some more elaboration aswell.
* I think diagnosis looks incomplete. Not much detail is given about how the diagnosis actually works. Very little referencing. Addition of an image would improve this section.
* Treatment looks great. I like how you have included current and future prospects. Just wondering if there was room for a heading for current and future research, as Im sure there is more research being undertaken than just in the area of treatment. This could make this project more informative, and perhaps could be another heading.
* Glossary needs improving.
* Some issues with referencing such as multiple entries for the same article and some issues with web page referencing.

--[[User:Z3288196|Z3288196]] 10:48, 29 September 2011 (EST)

'''GROUP 10: Duchenne Muscular Dystrophy'''
*Title of the whole page should just be Duchenne Muscular Dystrophy, not Introduction...
*The intro is very descriptive and comprehensive
*Image in intro needs proper referencing
*consider rephrasing this sentence "In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction"
*History has good info, but could this be better formatted in a table? this section is text heavy and could maybe use an image, it also could be extended into more recent years
*Epidemiology is summarised well and contains good statistics
*I feel that Aetiology - Genetics section has good info, easy to understand and informative but maybe it could be researched a little more
*General Signs and Symptoms of Duchenne’s Muscular Dystrophy section needs a lot more work, the list of symptoms i don't feel is enough, more expansion on these is needed. An image would improve this section too
*"diarrhoea&&&." -this needs to be fixed

Overall:
*More images are needed to break up the text
*glossary needs a bit more work, consider linking glossary words to text
*I feel that the page overall needs some more work, some sections are lacking content
*Proof reading to fix grammar and sentence structure

--[[User:Z3331556|z3331556]] 10:44, 29 September 2011 (EST)

'''Peer Review'''

This wiki still feels like what Mark Hill mentioned earlier, like a backbone for content to be built upon. The foundations are there, but still very incomplete. Comparing the sections, some have done a lot of effort, others not so much, and it is very visible.

:*Should start the wiki with this code:

<wiki>=Duchenne Muscular Dystrophy (DMD)= </wiki>

then

<wiki>==Introduction == </wiki>

:*History is far too text heavy and it shouldn't be like that, as this makes it a chore to read. A timeline would be better suited and summarise into the timeline.

:*Should be more student drawn images, since there's only one. If getting pictures is hard to find, then draw your own.

:*The one student drawn image is not referenced correctly, needs the disclaimer info.

:*Diagnosis needs to be expanded. There is 300+ articles, there has to be more info or an image to be found.

:*Pathogenesis needs to be expanded, maybe an image.

:*Signs and symptoms need more referencing. Also, just leave the title as Signs and Symptons.

:*Treatment needs to be expanded on. It isn't any good just listing drugs into a table.

:*Split the Treatment to include Managment and give a separate section for Current Research.

:*Glossary is incomplete.

--[[User:Z3293267|z3293267]] 10:37, 29 September 2011 (EST)

Group 10:

Clear and conscise but still needs more work breaking up the long slabs of writing. Perhaps more subheadings esp. in the first sections.

More pics are needed to break up the work.

Treatment includes a good table.

Glossary needs a bit of work and expanding on the explanations.

References needs to be fixed as there is duplications of references.

z3332178 =]

Peer Review

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*History section would benefit by placing the information into a timeline rather than paragraphs as it is a bit hard to follow.

:*Epidemiology section could be expanded and written in more flowing way rather than long sentences.

:*Needs more images, lots of large blocks of text. And images need to be formatted into the text as formatting currently looks awkward.

:*Further Research could be added, for example papers or groups that are researching as currently it is just being referred to.

:*Glossary could be expanded.

:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed. Also perhaps research from MORE sources is necessary as there is only a few when you cut out the double references.

--[[User:Z3217043|z3217043]] 10:02, 29 September 2011 (EST)

Group 10 Peer Review

*Headings are well organised and structured
*Too much text in history section-a table or image would be good
*Information is there however images/graphs/tables would help break up large chunks of text
*Diagnosis seems brief-perhaps merge with treatment section?
*Signs and symptoms could be expanded
*Great table in treatment
*Needs to be proof read-grammar and spelling mistakes
*Double referencing
*Glossary needs to be extended
--[[User:Z3308965|Fleur McGregor]] 09:54, 29 September 2011 (EST)

Group 10

*Introduction – Great intro, well referenced apart from the first paragraph.
*History has a lot of text, a timeline could work well here and also an image if possible just to break up the text.
*Epidemiology – well referenced and structured, text could be broken up but that’s nothing major as it’s a small section.
*Aetiology – A link between the image provided and the text would work well, and also the image could be formatted on the right of the page, to add to continuity and flow as other images are located on the right.
*Signs and Symptoms – Needs to be more information here, a description of each symptom and maybe its direct causes.
*Clinical manifestations – need a link between the image and the text, other than that it is well referenced and easy to understand.
*Treatment – table formatting is great and information is helpful
*Glossary – needs to include more terms form the page.
*There’s some doubling up in the reference section that needs to be fixed, other than that good job.

--[[User:Z3331469|z3331469]] 08:25, 29 September 2011 (EST)

peer review:

*Intro: One of the very few groups to use an image of the disease in the intro, well done! Like how you have referred to Duchenne’s as DMD in brackets initial heading to avoid confusion.

*History: A lot of writing, no techniques to break it up, which will basically bore your reader. Use a timeline perhaps.

*Epidemiology: Subheading will benefit this segment.

*Aetiology: The image could use some colour, but it is still very well done. It would be worthy to refer to the drawing as your explaining the genetics, just to bring them together.

*Pathogenesis: Very brief, not very informative and lacking subheadings or an image. Hopefully this will be fixed.

*Signs and Symptoms:Poorly done. Dot-points are a good way to initiate the writing but not appropriate as a final copy. Needs more description and research.

*Clinical manifestations:
The image used is excellent but needs more explanation.

*Diagnosis:Very short, looks incomplete and there’s only one reference for the entire section.

*Treatment: Well done, I like the colour and the table structure, makes it much easier to understand.

*Glossary: Incomplete, much more terminology has been used.

*References: Double referencing is a big problem here.

*Text:image ratio: could use more images.

--[[User:Z3290270|z3290270]] 02:16, 29 September 2011 (EST)

*history should be broken up with dates on side or within a table.
*how about a short summary table to use for epidemiology
*no picture of Guillaume Benjamin Amand Duchenne?
*no copyright permission for the drawn image in genetics.
*pathogenesis seems very small for a section that is very important.
*describe how the signs and symptoms impact on patients to show the significance of the disease.
*diagnosis needs a lot of work, this section is very important. also very little references in this section.
*not enough pictures to accompany the text
*very short glossary
*multiple references of same articles
--[[User:Z3291423|Jasjit Walia]] 00:17, 29 September 2011 (EST)

'''Peer Review for Group 10'''

*The introduction was well written, however the picture in it is not referenced as instructed. Please fix that then your intro is perfect.
*In the history section, the first sentence is oddly placed, even though it’s informative, please put that somewhere where it will flow in the paragraph.
*The history is verbose, please re write so it’s easier to follow.
*Epidemiology needs to be reevaluated as some sentences are not constructed properly
*Etiology has sound information but the paragraphs are not structured so it flows. It also seems repetitive.
*The picture in the etiology can have its caption better structured
*Pathogenesis should include some component of genetics to explain how the abnormalities bring about the pathogenesis in the genetics level.
*Explanation of how the signs and symptoms comes along from the dystrophy should be explained
*The image of the spine is not completely referenced as url of the image and the page must also be given
*Information under ‘respiratory problems’ and smooth muscle needs some reviewed as it includes words there that shouldn’t be present
*The diagnosis section could be expanded upon so it includes more information on the details of how it is detected, and images should complement the tools to diagnose the condition.
*An introduction to the table should be given. Having the table there by itself doesn’t look good.
*Further explanation should be made on the type of physical activity that would be made for therapy
*Glossary should be expanded
*There is repetitive referencing; it should be reformatted to fit in the way multiple references is made.
*You need much more pics as without the pics the page looks word heavy.

--[[User:Z3291317|Z3291317]] 23:57, 28 September 2011 (EST)

'''Group 10'''

Introduction: Good introduction. The picture could be a bit bigger. Also, a picture of the chromosome would be great.

History and epidemiology: Both sections are clear and flow well. Pictures are needed to break up the text though.

Genetics: The image is great and the text is well written.

Pathogenesis: The pathogenesis is well explained. Again, pictures would be good in this section to improve it.

Clinical manifestations: Good section. Clear, easy to understand.

Diagnosis: This section might need some more detail added. You could explain how each of the diagnostic tests work

Current and future treatment: This section is worded well but looks a little bit disjointed. I think it would be better having it either all in text or all in the table. --[[User:Z3291324|z3291324]] 23:27, 28 September 2011 (EST)

'''Group 10 Peer Review'''
* Interesting introduction, with a good amount of information. The history is also quite well outlined, although as you have no doubt seen with many of the other groups by now, a timeline woud be adequate in the history section (this also helps to break the text up and help us get a "break" from large blocks of text!)
* Epidemiology section is short but sweet - all the required information is there and summarised well. Perhaps mention the rate of mortality? (although this may be obvious)
* The student-drawn image in the aetiology section doesn't have your own copyright notice, so this should be added to the description. There also might be more to write in this section, but only if you wish to seek out the information. Diagrams can be helpful in summarising excessively detailed material.
* Pathogenesis simply needs to be longer; a lot can be written on this section and there should also be the use of diagrams throughout. Explain why the pathogenesis of DMD is so destructive; it has more than just the function of securing the sarcolemma to the cytoskeleton and is also present in other parts of the body, so make sure you explore this completely! :) (for example, dystrophin which is affected also is found in different areas of the body which may help explain some of the other symptoms of DMD).
* General signs and symptoms could have a diagram to assist in the signs and symptoms.
* Clinical manifestations and complications could have more written and explaining some of the other symptoms that aren't purely based upon the muscle damage observed in DMD.
* Diagnosis needs to have more written, especially images regarding the methods of imaging and therapy.
* Treatment; and Current and Future Prospects are different sections and shouldn't be integrated. Think carefully about the implications that current and future directions of research will have on this disease - they are huge! Try to write more and make an individual section on current and future prospectives of research for DMD; as you know from your research so far, DMD is a very important disease requiring a lot of research.
* Glossary is incomplete; References have a lot of repeats, but these are problems that are common to almost all projects.
* Generally, you just need to find better ways of altering the information in your project. Try to add tables and images to help break up the information and make sure you've discussed all the sections in the guidelines for the project properly. Keep at it! :) There are also some obvious typos ('''&&&''')?
--[[User:Z3288827|Leonard Tiong]] 22:29, 28 September 2011 (EST)

'''Group 10:'''

•History might work better in a timeline, just to break up the text as the beginning of the page looks a little overwhelming with text.

•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template for all of the uploaded images.

•The different sections seem to be a little inconsistent, where a few of the sections such as diagnosis and treatment seem a little vague. These sections could be expanded on to give the reader a more comprehensive knowledge of what is involved, especially seeing as the diagnosis section only has one reference.

•Some typos in the smooth muscle section - ‘&&&’

•A lot of the references are repeated multiple times – this should be fixed up so that each reference only appears once. And also not all the references seem to be formatted correctly.

•Glossary is incomplete

•Overall, good use of subheadings though some of the sections need to be expanded and a few more images are needed to add a better balance to the page. Good work so far.

--[[User:Z3332183|z3332183]] 21:33, 28 September 2011 (EST)

'''Group 10'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main points are there. Content is decent in some places and lacking in others. Fixing up problematic areas would be good.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
Maybe include a time-line in history?'''
General Signs and Symptoms of Duchenne’s Muscular Dystrophy section is very poor. Getting information from an insurance website is not actual research. please consider re-doing this section with sources cited from a peer-reviewed paper. Signs and symptoms should go with diagnosis as it is part of making a diagnosis. why are there ampersands in Smooth muscle section?

'''*Content is correctly cited and referenced.'''
Fix up references, some are simply links and they repeat.

'''*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 is drawn well, explanation could do with a bit more work though. File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg needs proper citation, also there isn't many images. Try including more images.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Not as much information as i was expecting and references is not as extensive as other pages - but good in-text citation (with the exception of some places such as diagnosis and Respiratory problems), it shows that the information has come from somewhere. Information from an insurance website is not evidence of extensive research so try to fix it.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
No connection to embryology - try linking genetic defects to problems in the neonate, or even if there is a prenatal test.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Some evidence of developing the wiki page with the guidelines. Will benefit from changing some things.

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

'''Group 10: Peer Assessment'''
* Your page is relatively short overall and could use some more pictures, especially in the first few sections.
* You have forgotten to put a title on you page
* The introduction is good
* You have got quite a bid of text in the history section, may be you can make a bid lighter with a time line?
* Epidemiology is nice to read and relevant
* Signs and symptoms belong into the clinical manifestation section
* Diagnostics could be more in detail
* The green and blue in the table is a bid too much colour all on a sudden. May be you can have some more colour overall or do the table in just one colour?
* It would be great to have more terms in the glossary
* I would put the diagnosis section right after pathogenesis
* Overall you have got good information on your page. May be you can work on the overall structure and some references. --z3279511 17:15, 28 September 2011 (EST)

'''Group 10'''

*Introduction: well done

*History: lots of information, some parts have no references, subheadings and a time line would be advantageous

*Epidemiology: good contend

*Aetiology: the contend seems fine, but more structure would be good

*Pathogenesis: looks good

*Signs and symptoms: that’s more like a list that a section, maybe combine it with manifestations

*Manifestations: well done, except for smooth muscle- seems incomplete?

*Diagnosis: you could add more information and details

*Treatment: the heading seems inappropriate, separate treatment and research, the contend could be more explained

*Glossary: is incomplete

*More images would be nice
--[[User:Z3387190|Z3387190]] 14:28, 28 September 2011 (EST)

'''Group 10'''

*Very poor image/text ratio – you need more images to break up the text
*Good intro
*History would work better in a timeline- you also mention nothing after the 1800s, more recent findings need to be included
*An image would be nice for pathogenesis to help the reader follow
*Not sure why you have made signs and symptoms a different heading to clinical manifestation- these could be combined
*Diagnosis is very brief and needs to be extended
*Glossary needs to be added to
*Maybe add a current research heading

===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.

--Z3389806 07:04, 27 September 2011 (EST)

'''Group 10 Peer assessment'''
*Heading order needs to re-arranged and done properly with diagnosis above before signs and symptoms.
*Introduction done sort of well needs to integrate image as an example of the myofibres.
*History rather bulky with too much text and no image, image of the founder would be fine. Also no time line present of DM needs to be added
*Epidemiology seems rather empty, images would benefit this section also more stats, further expansion of sub headings would also do well for this section
*Genetics aetiology needs to be expanded where seems to be cramped, though usage of image needs to be noted
*Pathogenesis needs images and further information
*Signs and symptoms needs to be expanded and image of some signs or tables
*Clinical manifestation done well with image and further sub-headings
*Diagnosis requires more attention with further methods of detection of DM
*Treatment is well done with the usage of the table
*Glossary needs to further expanded also linked to the pages so easy to follow the page
*References are not complete with links and repeats of the references
z3332250 23:59, 26 September 2011 (EST)

'''Group 10 Critique'''

#• The introduction was very good. Good use of images to give it a little decoration!
#• History is good
#• Epidemiology is good, however if possible try and make it longer/ include more information
#• The Genetics section is a bit too short. Add more information. Good hand drawn image!
#• Pathogenesis is a little short. Needs more information
#• Signs and Symptoms is good
#• Clinical manifestations is ok
#• Diagnosis, treatment and glossary are all well written. These sections should not require any change

--[[User:Z3289991|Robert Klein]] 16:27, 26 September 2011 (EST)

Group 10 ''Duchenne Muscular Dystrophy''
*The first paragraph of the introduction has no reference.
*The paragraphs in history are quite long, often with grammar mistakes, incorrect punctuations and many of the ideas within a sentence separated by a ''-''. For example the second last paragraph within history.
*The history is too verbose, a timeline with bullet points will look better
*Aetiology is quite concise and informative however gramatical errors are a distraction. For example ''There a multiple forms of dystrophin''. It might be a good idea to proofread the page.
*Well done with the student drawn image
*'Pathogenesis' is again well written however an image might have given it a balance between the text in the section and the pictures or tables
*The future therapies table is a little confusing, you might want to add more columns and define the therapy, and then discuss what the challenges and findings are and at the end column finish off with what the implication might be if the research is to be completed successfully. At the moment you have discussed all that in one big paragraph and the way the descriptions start, it sounds like there is no background to the description, just a little abrupt.
*The glossary is very short and you should include terms like de novo mutation.
*The existing definitions are unclear and incomplete

''Duchenne Muscular Dystrophy''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topics

Group 10-
* Need more images to break up the text
* The introduction was really easy to read and had relevant information in it
* History should be in bullet point form to make it easier to access or at least have the dates in BOLD
* Does the history include dates after the 1800s? or did all research stop then?
* Epidemiology was good. Had all the relevant info
* Pathogenesis would benefit an image or a diagram
* Signs and symptoms could be put with clinical manifestations.
* What is the point of the ‘&&&’? in clinical manifestations and complications?
* Diagnosis could be expanded upon to explain how and why these methods work
* Treatment could also be expanded on. A list of drugs doesn’t explain much
* There is not current/future research section
* This is a good start to the project but more research needs to be done

'''Group 10'''
* The structure and use of headings and subheadings is good, make sure you title your page.
* Good info very informative and it gives a good overview to DMD.
* HIstory has a lot of text could you use a timeline here?
* i think a picture of the pathogenesis would improve this section.
* Has your group look at the CNS and cognitive function of DMD boys its a controversial area as many people have different attitudes towards this but Dr Stewart Head a UNSW lecture actually studies DMD and is very informative in the area and recently published a article in the journal Brain.
* The CNS is highly affected by the lack of dystrophin as well as GABA receptors. I think this area is very import to consider as it highly affects the boys at school.
* Could you add some pictures to your page or break it up with the use of more tables as it a lot of text in comparison to pictures and tables.
* Make sure your reference list is not doubled.
* Ensure all your pictures are referenced properly.
* Student image is present.
* This is a good start.

'''Group 10 Assessment'''
*The history is a bit wordy… Maybe consider consolidating the information into a table format for ease of reading. Could also use a picture to add to it.
*The Epidemiology section could also use a picture and maybe some more information, if possible.
*Point vs Frameshift mutation jpg: Good drawing, but in the last portion of the picture the product is labeled as a ‘tunicated protein product.’ Isn’t it supposed to be a ‘truncated’ product?
*The Signs and Symptoms section could use some formatting; it just looks rather dull currently. Maybe a chart or add in a picture?
*Smooth muscle section: Why are there random &&&’s?
*The top portion of the Treatment section could use some more referencing… Good chart though! Only thing I’d suggest for it is to add some pictures if possible?
*Glossary term list is rather short… Are you sure there’s nothing else that needs defining for clarification for the reader?
*It would be a good idea also to have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word 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.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. 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 #...
*Overall, good information is included, just work on referencing things and the overall structure and you should be good!
--[[User:Z3391078|Z3391078]] 17:00, 27 September 2011 (EST)

'''Peer Assessment: Group Project 10'''
*I think the section heading of introduction accompanied by the question what is muscular dystrophy, works really well.
*It might be good to include an image in the history section to break up the text, such as of someone prominently involved with the disease findings.
*The information in clinical manifestations and complications is well written. There needs to be some fix to the formatting under the smooth muscle heading where some '&'s have been repeated.
*The current and future prospects section is great. You have summarised what
*Some of the definitions of words in the glossary need to be completed e.g. atrophy and protease.
*Under the information in some of the images such as the fisrt one, 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.
*An additional section of external links might provide information for those wanting to know more.
--[[User:Z3217345|z3217345]] 10:50, 28 September 2011 (EST)

'''Peer Review'''

* struture and format done well
* easy to read

--[[User:Z3060621|z3060621]] 21:58, 28 September 2011 (EST)

*'''Intro''': Fine
*'''History''': Nicely detailed, but missing a timeline.
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.
*'''Pathogenesis''': Content seems fine, could do with a figure?
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?
*'''Clinical manifestations and complications''': Fine
*'''Diagnosis''': Clinical Diagnosis is a bit short?
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.
*'''Glossary''': Poor. More terms need explanations.
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.

==Discussion==

'''GROUP 10!'''

'''To make everything easier to follow, we have agreed to write any updates, info, discussion etc at the BOTTOM of this page, it will just stop us having to keep going up and down and wasting time trying to find the information we want.'''

----

Hey Everyone,

So Mark went through each group today during the lab and the webpages and discussed where we should be up to. By next week, he expects the subheadings & some content to be up and running. He also recommended that we should have some more research going on in our discussion page. E.g. Research articles links, interesting sites etc.

Topics have been allocated so please begin your research and typing up some content. We can further divide our headings if necessary, take a look at some other groups, they have some pretty good ideas. Mark will be checking this next week during our lab. He'll be coming around to each of us.

So hopefully see you all next week !

--[[User:Z3332327|z3332327]] 12:53, 25 August 2011 (EST)

==Subheadings for assignment==

Intro what is DMD

History/timeline

Genetic component

Why is it an abnormality - Symptoms effect

Diagnosis, future/current prospect (treatments?)

2 case studies

Glossary of terms

====Post online any preferences you may have in terms of the topics you wish to research and by Sunday we will allocate sub topics====
--[[User:Z3332629|z3332629]] 13:09, 18 August 2011 (EST)

Okay hey guys just to get the discussion going, umm I don't mind doing the first 2 on the list. And the "Why is it an abnormality - Symptoms effect" sounds pretty interesting as well.
What are your preferences?? :)

--[[User:Z3330313|z3330313]] 14:55, 23 August 2011 (EST)

Hey Everyone, Im happy to do the diagnosis/current/future prospects point and a case study.

--z3332327 15:36

Talk:2011 Group Project 10

2011-10-09T07:10:50Z

Z3332629: /* Group Discussion Week 10-12 */

[[2011_Group_Project_10|'''Group 10''']]: [[User:z3332327]] | [[User:z3332629]] | [[User:z3332824]] | [[User:z3330313]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_10_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_10_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Group Discussion Week 10-12==

Hey Rhiannon!

Ash here. Just read over your section and just have a few pointers or suggestions :)

“this includes skeletal muscles, smooth muscle and cardiac muscle” – maybe this could be written as just: this includes skeletal, smooth and cardiac muscle”.

“which causes many problems” – which can cause numerous implications maybe?

Many of your sentences states something then has a ‘-‘ then gives an example, this sort of seems informal and distrupts the flow of reading .. i personally would suggest using more complete and formal sentences, but just an idea.

These are only suggestions, I am happy if you do leave it the way it is but I know your a perfectionist :)

Let me know what you think

Hey guys,

So I've finished my part of the assignment now (WOOOOO!) so if there is anything that I should edit/change, or if anyone needs a hand with anything, then let me know, ''I'm breezy!'' *Monica's Geller's voice*

'''Lisa:''' my mum just raised an important point for the diagnosis section - are you able to, when you are pregnant, genetically test the baby to see if it is affected? can you see if its actually affected or a carrier? when can you test this?
-I think this is an important point, and highly relevant as that is a concern for many people. Do you think you can include this somewhere?

Hope everyone else's parts are going ok,

--[[User:Z3332824|Rhiannon Bice]] 17:39, 7 October 2011 (EST)

Nice drawings!

Just some videos for my section, just placing them somewhere so i know where they are :)
http://www.youtube.com/watch?v=dOhMLZCvb50
http://www.youtube.com/watch?v=GWachrbiU58
--[[User:Z3332629|Ashleigh Pontifex]] 12:01, 3 October 2011 (EST)

Joanna : http://emedicine.medscape.com/article/1173204-overview#a0199
Great over view for epidemiology, perhaps a table or some stats would be great in this section :)

- http://www.ncbi.nlm.nih.gov/pubmed/19834452 -

hey guys I changed some of the stuff on history, if you think its too much info let me know!
I deleted alot of information, and I just can't bring myself to delete more because the stuff remaining now seems so relevant. But let me know what you think!
And what do you guys think about putting an image of the Duchenne dude in the history? do you reckon that'll make that section too long?
--[[User:Z3330313|Joanna Pak]] 02:56, 5 October 2011 (EST)

Hey Jo! I had a read of the history section and it sounds good. Just an idea, where you've listed Duchenne's definition of the disease, would you prefer if those were added under DIAGNOSIS- clinical or SIGNS AND SYMPTOMS? And we could add an internal link? Maybe that'll cut down your section a bit?

Just a suggested change, i just rearranged the words around a little, dont have to. =)

*'Meryon conducted several necropsies and found intact spinal cords which indicated the disease was not from the nervous system.'

Minor edit

*'Further microscopic examination of the muscle showed that the muscular fibres '''broke''' down and converted into granular, fatty matter.'
--[[User:Z3332327|Lisa Xiao]] 11:38, 5 October 2011 (EST)

Hey Jo its Ash!! It looks heaps better, more straight forward and the table inclusion is great :)
Is everyone happy with my student drawn image in the introduction? it is appropriate in this section?
Also my table in the genetics section???

And lastly, ive notice that Rhiannon has hyperlinked all glossary terms in her section, is everyone happy to carry that across all areas???
--[[User:Z3332629|z3332629]] 12:29, 5 October 2011 (EST)

Actually one last suggestion jo, maybe change the table colour to teal so that the colour schemme consistent throughout the page :)
--[[User:Z3332629|z3332629]] 12:32, 5 October 2011 (EST)

Hey rhiannon! I tried searching for that image of the heart, turns out its not open access. I'll keep an eye out for you though in case i find anything useful.--[[User:Z3332327|z3332327]] 14:03, 7 October 2011 (EST)

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

==Peer Review==

'''Peer Review'''
* The introduction is detailed but a bit “in your face.” It may even be a bit too detailed, going into the pathogenesis of the disorder.
* History is very detailed, perhaps slightly story-like but enjoyable nonetheless. Could use a picture or two. Sufficiently referenced.
* Epidemiology is very thorough and well referenced.
* The tone of Aetiology/Genetics is a bit conversational; needs to be more detached. Good use of picture, although the legend to it is not in the correct format.
* Pathogenesis could use more references, especially for the last paragraph. Could potentially use some pictures to make clearer the specific structures discussed in the text (although they are elaborated on in the glossary).
* All the signs listed in Clinical Manifestations etc are decently elaborated upon, and the section is well-referenced. Smooth Muscle has strange “&&&” signs though. Respiratory Problems needs cleaning, notably with the line “[Effects of high CO2 and the problems it can cause]”
* Diagnosis is nicely laid out, although more references are needed.
* Treatment is decently set up and clearly explains each of the treatment plans.
--[[User:Z3290689|z3290689]] 14:44, 29 September 2011 (EST)

Group 10:
This project looks fine but it seems a little short? You want to expand the content in sections.
History is well researched but it’s quite long. You can add more images (add the reference in the description) and make the dates in Bald.
There are some spelling errors and extra signs that are not related to the work such as &&&.
Some of the references are repeated and others need to be reformatted.
Overall, Great effort.

--[[User:Z3284061|z3284061]] 11:51, 29 September 2011 (EST)

'''Peer Assessment'''
*introduction is well written and descriptive. Good use of image to make it look appealing. No references in the first paragraph.
*History section is too long, text heavy and a bit boring. Try to summarize the details on a timeline. You can include an image e.g. of Dr Edward Meryon if possible.
*Epidemiology and aetiology; well written. The image in the aetiology needs to be linked with the text.
*Pathogenesis; too brief. Needs more information and explanation of the disease process. Include an image or flowchart to compliment the text.
*Signs and symptoms; needs to be expanded a bit more. I suggest using a table to present the information that just as dot points. Same goes for the diagnosis section, which also needs to be expanded. Try and use more images, tables, graphs etc to break up the texts and make the page look more appealing.
*I suggest hyperlinking words in the page with the glossary to make the page more user friendly.
*Like the use of table in the "current and future prospects". It's better to present information like this rather than in big long paragraphs.
*The glossary needs to be expanded more.
--[[User:Z3291622|Z3291622]] 11:07, 29 September 2011 (EST)

'''''Duchenne (Group 10) Peer Review:'''''

Could you include “Duchenne Muscular Dystrophy” as the first subheading so that the reader knows exactly what the disease is at first glance? Just a suggestion.

Introduction: Topic well introduced and good use of image. Image, however, is lacking a student template.

History: Very extensive. Possibly include an image to break up the text.

Epidemiology: Sound. Some sentences are not worded/ structured properly.

Aetiology – Genetics: Information is good. Impressive self-drawn image. Well done.

Pathogenesis: An image would definitely work well in this section. Information is otherwise good, however possibly have a greater focus on the genetic component?

General Signs and Symptoms of Duchenne’s Muscular Dystrophy: This section seems too brief. Elaborate further.

Clinical manifestations and complications: Information is good. Possibly more detail for the subheading “smooth muscle.” Image lacks a student template. “&&&” – what is this? Many references in this section which is good to see!

Diagnosis: Could be elaborated further.

Treatment: Current and Future Prospects: The first paragraph lacks referencing. Possibly include an image? Table is a good idea, however colours chosen are slightly off-putting.
Glossary of terms: Could be more extensive. Not complete.

Well done. --[[User:Z3290808|z3290808]] 10:50, 29 September 2011 (EST)

Duchenne Muscular Dystrophy – Group 10

* Excellent introduction and good use of image. Is there some referencing missing in the first few sentences? Some formatting should be done on the image either to make it within the intro section or more shared between the history sections. Looks a little out of place.
* History is well written but very text heavy. Use of a timeline good improve this section and make it more succinct. Also I thought an image could be good.
* Epidemiology seems to cover all necessary information and is well referenced. Maybe an image or graph here could be good.
* I like the student drawn image in the etiology section, maybe the sizing could be improved though? Also some a more detailed description of what the image shows would also be good.
* Pathogenesis section is very informative. Maybe the pathophysiology could be covered in this section as well? Image could be added.
* General signs and symptoms would perhaps look better in a table. Otherwise it is quite brief, maybe some more elaboration aswell.
* I think diagnosis looks incomplete. Not much detail is given about how the diagnosis actually works. Very little referencing. Addition of an image would improve this section.
* Treatment looks great. I like how you have included current and future prospects. Just wondering if there was room for a heading for current and future research, as Im sure there is more research being undertaken than just in the area of treatment. This could make this project more informative, and perhaps could be another heading.
* Glossary needs improving.
* Some issues with referencing such as multiple entries for the same article and some issues with web page referencing.

--[[User:Z3288196|Z3288196]] 10:48, 29 September 2011 (EST)

'''GROUP 10: Duchenne Muscular Dystrophy'''
*Title of the whole page should just be Duchenne Muscular Dystrophy, not Introduction...
*The intro is very descriptive and comprehensive
*Image in intro needs proper referencing
*consider rephrasing this sentence "In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction"
*History has good info, but could this be better formatted in a table? this section is text heavy and could maybe use an image, it also could be extended into more recent years
*Epidemiology is summarised well and contains good statistics
*I feel that Aetiology - Genetics section has good info, easy to understand and informative but maybe it could be researched a little more
*General Signs and Symptoms of Duchenne’s Muscular Dystrophy section needs a lot more work, the list of symptoms i don't feel is enough, more expansion on these is needed. An image would improve this section too
*"diarrhoea&&&." -this needs to be fixed

Overall:
*More images are needed to break up the text
*glossary needs a bit more work, consider linking glossary words to text
*I feel that the page overall needs some more work, some sections are lacking content
*Proof reading to fix grammar and sentence structure

--[[User:Z3331556|z3331556]] 10:44, 29 September 2011 (EST)

'''Peer Review'''

This wiki still feels like what Mark Hill mentioned earlier, like a backbone for content to be built upon. The foundations are there, but still very incomplete. Comparing the sections, some have done a lot of effort, others not so much, and it is very visible.

:*Should start the wiki with this code:

<wiki>=Duchenne Muscular Dystrophy (DMD)= </wiki>

then

<wiki>==Introduction == </wiki>

:*History is far too text heavy and it shouldn't be like that, as this makes it a chore to read. A timeline would be better suited and summarise into the timeline.

:*Should be more student drawn images, since there's only one. If getting pictures is hard to find, then draw your own.

:*The one student drawn image is not referenced correctly, needs the disclaimer info.

:*Diagnosis needs to be expanded. There is 300+ articles, there has to be more info or an image to be found.

:*Pathogenesis needs to be expanded, maybe an image.

:*Signs and symptoms need more referencing. Also, just leave the title as Signs and Symptons.

:*Treatment needs to be expanded on. It isn't any good just listing drugs into a table.

:*Split the Treatment to include Managment and give a separate section for Current Research.

:*Glossary is incomplete.

--[[User:Z3293267|z3293267]] 10:37, 29 September 2011 (EST)

Group 10:

Clear and conscise but still needs more work breaking up the long slabs of writing. Perhaps more subheadings esp. in the first sections.

More pics are needed to break up the work.

Treatment includes a good table.

Glossary needs a bit of work and expanding on the explanations.

References needs to be fixed as there is duplications of references.

z3332178 =]

Peer Review

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*History section would benefit by placing the information into a timeline rather than paragraphs as it is a bit hard to follow.

:*Epidemiology section could be expanded and written in more flowing way rather than long sentences.

:*Needs more images, lots of large blocks of text. And images need to be formatted into the text as formatting currently looks awkward.

:*Further Research could be added, for example papers or groups that are researching as currently it is just being referred to.

:*Glossary could be expanded.

:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed. Also perhaps research from MORE sources is necessary as there is only a few when you cut out the double references.

--[[User:Z3217043|z3217043]] 10:02, 29 September 2011 (EST)

Group 10 Peer Review

*Headings are well organised and structured
*Too much text in history section-a table or image would be good
*Information is there however images/graphs/tables would help break up large chunks of text
*Diagnosis seems brief-perhaps merge with treatment section?
*Signs and symptoms could be expanded
*Great table in treatment
*Needs to be proof read-grammar and spelling mistakes
*Double referencing
*Glossary needs to be extended
--[[User:Z3308965|Fleur McGregor]] 09:54, 29 September 2011 (EST)

Group 10

*Introduction – Great intro, well referenced apart from the first paragraph.
*History has a lot of text, a timeline could work well here and also an image if possible just to break up the text.
*Epidemiology – well referenced and structured, text could be broken up but that’s nothing major as it’s a small section.
*Aetiology – A link between the image provided and the text would work well, and also the image could be formatted on the right of the page, to add to continuity and flow as other images are located on the right.
*Signs and Symptoms – Needs to be more information here, a description of each symptom and maybe its direct causes.
*Clinical manifestations – need a link between the image and the text, other than that it is well referenced and easy to understand.
*Treatment – table formatting is great and information is helpful
*Glossary – needs to include more terms form the page.
*There’s some doubling up in the reference section that needs to be fixed, other than that good job.

--[[User:Z3331469|z3331469]] 08:25, 29 September 2011 (EST)

peer review:

*Intro: One of the very few groups to use an image of the disease in the intro, well done! Like how you have referred to Duchenne’s as DMD in brackets initial heading to avoid confusion.

*History: A lot of writing, no techniques to break it up, which will basically bore your reader. Use a timeline perhaps.

*Epidemiology: Subheading will benefit this segment.

*Aetiology: The image could use some colour, but it is still very well done. It would be worthy to refer to the drawing as your explaining the genetics, just to bring them together.

*Pathogenesis: Very brief, not very informative and lacking subheadings or an image. Hopefully this will be fixed.

*Signs and Symptoms:Poorly done. Dot-points are a good way to initiate the writing but not appropriate as a final copy. Needs more description and research.

*Clinical manifestations:
The image used is excellent but needs more explanation.

*Diagnosis:Very short, looks incomplete and there’s only one reference for the entire section.

*Treatment: Well done, I like the colour and the table structure, makes it much easier to understand.

*Glossary: Incomplete, much more terminology has been used.

*References: Double referencing is a big problem here.

*Text:image ratio: could use more images.

--[[User:Z3290270|z3290270]] 02:16, 29 September 2011 (EST)

*history should be broken up with dates on side or within a table.
*how about a short summary table to use for epidemiology
*no picture of Guillaume Benjamin Amand Duchenne?
*no copyright permission for the drawn image in genetics.
*pathogenesis seems very small for a section that is very important.
*describe how the signs and symptoms impact on patients to show the significance of the disease.
*diagnosis needs a lot of work, this section is very important. also very little references in this section.
*not enough pictures to accompany the text
*very short glossary
*multiple references of same articles
--[[User:Z3291423|Jasjit Walia]] 00:17, 29 September 2011 (EST)

'''Peer Review for Group 10'''

*The introduction was well written, however the picture in it is not referenced as instructed. Please fix that then your intro is perfect.
*In the history section, the first sentence is oddly placed, even though it’s informative, please put that somewhere where it will flow in the paragraph.
*The history is verbose, please re write so it’s easier to follow.
*Epidemiology needs to be reevaluated as some sentences are not constructed properly
*Etiology has sound information but the paragraphs are not structured so it flows. It also seems repetitive.
*The picture in the etiology can have its caption better structured
*Pathogenesis should include some component of genetics to explain how the abnormalities bring about the pathogenesis in the genetics level.
*Explanation of how the signs and symptoms comes along from the dystrophy should be explained
*The image of the spine is not completely referenced as url of the image and the page must also be given
*Information under ‘respiratory problems’ and smooth muscle needs some reviewed as it includes words there that shouldn’t be present
*The diagnosis section could be expanded upon so it includes more information on the details of how it is detected, and images should complement the tools to diagnose the condition.
*An introduction to the table should be given. Having the table there by itself doesn’t look good.
*Further explanation should be made on the type of physical activity that would be made for therapy
*Glossary should be expanded
*There is repetitive referencing; it should be reformatted to fit in the way multiple references is made.
*You need much more pics as without the pics the page looks word heavy.

--[[User:Z3291317|Z3291317]] 23:57, 28 September 2011 (EST)

'''Group 10'''

Introduction: Good introduction. The picture could be a bit bigger. Also, a picture of the chromosome would be great.

History and epidemiology: Both sections are clear and flow well. Pictures are needed to break up the text though.

Genetics: The image is great and the text is well written.

Pathogenesis: The pathogenesis is well explained. Again, pictures would be good in this section to improve it.

Clinical manifestations: Good section. Clear, easy to understand.

Diagnosis: This section might need some more detail added. You could explain how each of the diagnostic tests work

Current and future treatment: This section is worded well but looks a little bit disjointed. I think it would be better having it either all in text or all in the table. --[[User:Z3291324|z3291324]] 23:27, 28 September 2011 (EST)

'''Group 10 Peer Review'''
* Interesting introduction, with a good amount of information. The history is also quite well outlined, although as you have no doubt seen with many of the other groups by now, a timeline woud be adequate in the history section (this also helps to break the text up and help us get a "break" from large blocks of text!)
* Epidemiology section is short but sweet - all the required information is there and summarised well. Perhaps mention the rate of mortality? (although this may be obvious)
* The student-drawn image in the aetiology section doesn't have your own copyright notice, so this should be added to the description. There also might be more to write in this section, but only if you wish to seek out the information. Diagrams can be helpful in summarising excessively detailed material.
* Pathogenesis simply needs to be longer; a lot can be written on this section and there should also be the use of diagrams throughout. Explain why the pathogenesis of DMD is so destructive; it has more than just the function of securing the sarcolemma to the cytoskeleton and is also present in other parts of the body, so make sure you explore this completely! :) (for example, dystrophin which is affected also is found in different areas of the body which may help explain some of the other symptoms of DMD).
* General signs and symptoms could have a diagram to assist in the signs and symptoms.
* Clinical manifestations and complications could have more written and explaining some of the other symptoms that aren't purely based upon the muscle damage observed in DMD.
* Diagnosis needs to have more written, especially images regarding the methods of imaging and therapy.
* Treatment; and Current and Future Prospects are different sections and shouldn't be integrated. Think carefully about the implications that current and future directions of research will have on this disease - they are huge! Try to write more and make an individual section on current and future prospectives of research for DMD; as you know from your research so far, DMD is a very important disease requiring a lot of research.
* Glossary is incomplete; References have a lot of repeats, but these are problems that are common to almost all projects.
* Generally, you just need to find better ways of altering the information in your project. Try to add tables and images to help break up the information and make sure you've discussed all the sections in the guidelines for the project properly. Keep at it! :) There are also some obvious typos ('''&&&''')?
--[[User:Z3288827|Leonard Tiong]] 22:29, 28 September 2011 (EST)

'''Group 10:'''

•History might work better in a timeline, just to break up the text as the beginning of the page looks a little overwhelming with text.

•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template for all of the uploaded images.

•The different sections seem to be a little inconsistent, where a few of the sections such as diagnosis and treatment seem a little vague. These sections could be expanded on to give the reader a more comprehensive knowledge of what is involved, especially seeing as the diagnosis section only has one reference.

•Some typos in the smooth muscle section - ‘&&&’

•A lot of the references are repeated multiple times – this should be fixed up so that each reference only appears once. And also not all the references seem to be formatted correctly.

•Glossary is incomplete

•Overall, good use of subheadings though some of the sections need to be expanded and a few more images are needed to add a better balance to the page. Good work so far.

--[[User:Z3332183|z3332183]] 21:33, 28 September 2011 (EST)

'''Group 10'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main points are there. Content is decent in some places and lacking in others. Fixing up problematic areas would be good.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
Maybe include a time-line in history?'''
General Signs and Symptoms of Duchenne’s Muscular Dystrophy section is very poor. Getting information from an insurance website is not actual research. please consider re-doing this section with sources cited from a peer-reviewed paper. Signs and symptoms should go with diagnosis as it is part of making a diagnosis. why are there ampersands in Smooth muscle section?

'''*Content is correctly cited and referenced.'''
Fix up references, some are simply links and they repeat.

'''*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 is drawn well, explanation could do with a bit more work though. File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg needs proper citation, also there isn't many images. Try including more images.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Not as much information as i was expecting and references is not as extensive as other pages - but good in-text citation (with the exception of some places such as diagnosis and Respiratory problems), it shows that the information has come from somewhere. Information from an insurance website is not evidence of extensive research so try to fix it.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
No connection to embryology - try linking genetic defects to problems in the neonate, or even if there is a prenatal test.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Some evidence of developing the wiki page with the guidelines. Will benefit from changing some things.

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

'''Group 10: Peer Assessment'''
* Your page is relatively short overall and could use some more pictures, especially in the first few sections.
* You have forgotten to put a title on you page
* The introduction is good
* You have got quite a bid of text in the history section, may be you can make a bid lighter with a time line?
* Epidemiology is nice to read and relevant
* Signs and symptoms belong into the clinical manifestation section
* Diagnostics could be more in detail
* The green and blue in the table is a bid too much colour all on a sudden. May be you can have some more colour overall or do the table in just one colour?
* It would be great to have more terms in the glossary
* I would put the diagnosis section right after pathogenesis
* Overall you have got good information on your page. May be you can work on the overall structure and some references. --z3279511 17:15, 28 September 2011 (EST)

'''Group 10'''

*Introduction: well done

*History: lots of information, some parts have no references, subheadings and a time line would be advantageous

*Epidemiology: good contend

*Aetiology: the contend seems fine, but more structure would be good

*Pathogenesis: looks good

*Signs and symptoms: that’s more like a list that a section, maybe combine it with manifestations

*Manifestations: well done, except for smooth muscle- seems incomplete?

*Diagnosis: you could add more information and details

*Treatment: the heading seems inappropriate, separate treatment and research, the contend could be more explained

*Glossary: is incomplete

*More images would be nice
--[[User:Z3387190|Z3387190]] 14:28, 28 September 2011 (EST)

'''Group 10'''

*Very poor image/text ratio – you need more images to break up the text
*Good intro
*History would work better in a timeline- you also mention nothing after the 1800s, more recent findings need to be included
*An image would be nice for pathogenesis to help the reader follow
*Not sure why you have made signs and symptoms a different heading to clinical manifestation- these could be combined
*Diagnosis is very brief and needs to be extended
*Glossary needs to be added to
*Maybe add a current research heading

===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.

--Z3389806 07:04, 27 September 2011 (EST)

'''Group 10 Peer assessment'''
*Heading order needs to re-arranged and done properly with diagnosis above before signs and symptoms.
*Introduction done sort of well needs to integrate image as an example of the myofibres.
*History rather bulky with too much text and no image, image of the founder would be fine. Also no time line present of DM needs to be added
*Epidemiology seems rather empty, images would benefit this section also more stats, further expansion of sub headings would also do well for this section
*Genetics aetiology needs to be expanded where seems to be cramped, though usage of image needs to be noted
*Pathogenesis needs images and further information
*Signs and symptoms needs to be expanded and image of some signs or tables
*Clinical manifestation done well with image and further sub-headings
*Diagnosis requires more attention with further methods of detection of DM
*Treatment is well done with the usage of the table
*Glossary needs to further expanded also linked to the pages so easy to follow the page
*References are not complete with links and repeats of the references
z3332250 23:59, 26 September 2011 (EST)

'''Group 10 Critique'''

#• The introduction was very good. Good use of images to give it a little decoration!
#• History is good
#• Epidemiology is good, however if possible try and make it longer/ include more information
#• The Genetics section is a bit too short. Add more information. Good hand drawn image!
#• Pathogenesis is a little short. Needs more information
#• Signs and Symptoms is good
#• Clinical manifestations is ok
#• Diagnosis, treatment and glossary are all well written. These sections should not require any change

--[[User:Z3289991|Robert Klein]] 16:27, 26 September 2011 (EST)

Group 10 ''Duchenne Muscular Dystrophy''
*The first paragraph of the introduction has no reference.
*The paragraphs in history are quite long, often with grammar mistakes, incorrect punctuations and many of the ideas within a sentence separated by a ''-''. For example the second last paragraph within history.
*The history is too verbose, a timeline with bullet points will look better
*Aetiology is quite concise and informative however gramatical errors are a distraction. For example ''There a multiple forms of dystrophin''. It might be a good idea to proofread the page.
*Well done with the student drawn image
*'Pathogenesis' is again well written however an image might have given it a balance between the text in the section and the pictures or tables
*The future therapies table is a little confusing, you might want to add more columns and define the therapy, and then discuss what the challenges and findings are and at the end column finish off with what the implication might be if the research is to be completed successfully. At the moment you have discussed all that in one big paragraph and the way the descriptions start, it sounds like there is no background to the description, just a little abrupt.
*The glossary is very short and you should include terms like de novo mutation.
*The existing definitions are unclear and incomplete

''Duchenne Muscular Dystrophy''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topics

Group 10-
* Need more images to break up the text
* The introduction was really easy to read and had relevant information in it
* History should be in bullet point form to make it easier to access or at least have the dates in BOLD
* Does the history include dates after the 1800s? or did all research stop then?
* Epidemiology was good. Had all the relevant info
* Pathogenesis would benefit an image or a diagram
* Signs and symptoms could be put with clinical manifestations.
* What is the point of the ‘&&&’? in clinical manifestations and complications?
* Diagnosis could be expanded upon to explain how and why these methods work
* Treatment could also be expanded on. A list of drugs doesn’t explain much
* There is not current/future research section
* This is a good start to the project but more research needs to be done

'''Group 10'''
* The structure and use of headings and subheadings is good, make sure you title your page.
* Good info very informative and it gives a good overview to DMD.
* HIstory has a lot of text could you use a timeline here?
* i think a picture of the pathogenesis would improve this section.
* Has your group look at the CNS and cognitive function of DMD boys its a controversial area as many people have different attitudes towards this but Dr Stewart Head a UNSW lecture actually studies DMD and is very informative in the area and recently published a article in the journal Brain.
* The CNS is highly affected by the lack of dystrophin as well as GABA receptors. I think this area is very import to consider as it highly affects the boys at school.
* Could you add some pictures to your page or break it up with the use of more tables as it a lot of text in comparison to pictures and tables.
* Make sure your reference list is not doubled.
* Ensure all your pictures are referenced properly.
* Student image is present.
* This is a good start.

'''Group 10 Assessment'''
*The history is a bit wordy… Maybe consider consolidating the information into a table format for ease of reading. Could also use a picture to add to it.
*The Epidemiology section could also use a picture and maybe some more information, if possible.
*Point vs Frameshift mutation jpg: Good drawing, but in the last portion of the picture the product is labeled as a ‘tunicated protein product.’ Isn’t it supposed to be a ‘truncated’ product?
*The Signs and Symptoms section could use some formatting; it just looks rather dull currently. Maybe a chart or add in a picture?
*Smooth muscle section: Why are there random &&&’s?
*The top portion of the Treatment section could use some more referencing… Good chart though! Only thing I’d suggest for it is to add some pictures if possible?
*Glossary term list is rather short… Are you sure there’s nothing else that needs defining for clarification for the reader?
*It would be a good idea also to have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word 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.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. 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 #...
*Overall, good information is included, just work on referencing things and the overall structure and you should be good!
--[[User:Z3391078|Z3391078]] 17:00, 27 September 2011 (EST)

'''Peer Assessment: Group Project 10'''
*I think the section heading of introduction accompanied by the question what is muscular dystrophy, works really well.
*It might be good to include an image in the history section to break up the text, such as of someone prominently involved with the disease findings.
*The information in clinical manifestations and complications is well written. There needs to be some fix to the formatting under the smooth muscle heading where some '&'s have been repeated.
*The current and future prospects section is great. You have summarised what
*Some of the definitions of words in the glossary need to be completed e.g. atrophy and protease.
*Under the information in some of the images such as the fisrt one, 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.
*An additional section of external links might provide information for those wanting to know more.
--[[User:Z3217345|z3217345]] 10:50, 28 September 2011 (EST)

'''Peer Review'''

* struture and format done well
* easy to read

--[[User:Z3060621|z3060621]] 21:58, 28 September 2011 (EST)

*'''Intro''': Fine
*'''History''': Nicely detailed, but missing a timeline.
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.
*'''Pathogenesis''': Content seems fine, could do with a figure?
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?
*'''Clinical manifestations and complications''': Fine
*'''Diagnosis''': Clinical Diagnosis is a bit short?
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.
*'''Glossary''': Poor. More terms need explanations.
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.

==Discussion==

'''GROUP 10!'''

'''To make everything easier to follow, we have agreed to write any updates, info, discussion etc at the BOTTOM of this page, it will just stop us having to keep going up and down and wasting time trying to find the information we want.'''

----

Hey Everyone,

So Mark went through each group today during the lab and the webpages and discussed where we should be up to. By next week, he expects the subheadings & some content to be up and running. He also recommended that we should have some more research going on in our discussion page. E.g. Research articles links, interesting sites etc.

Topics have been allocated so please begin your research and typing up some content. We can further divide our headings if necessary, take a look at some other groups, they have some pretty good ideas. Mark will be checking this next week during our lab. He'll be coming around to each of us.

So hopefully see you all next week !

--[[User:Z3332327|z3332327]] 12:53, 25 August 2011 (EST)

==Subheadings for assignment==

Intro what is DMD

History/timeline

Genetic component

Why is it an abnormality - Symptoms effect

Diagnosis, future/current prospect (treatments?)

2 case studies

Glossary of terms

====Post online any preferences you may have in terms of the topics you wish to research and by Sunday we will allocate sub topics====
--[[User:Z3332629|z3332629]] 13:09, 18 August 2011 (EST)

Okay hey guys just to get the discussion going, umm I don't mind doing the first 2 on the list. And the "Why is it an abnormality - Symptoms effect" sounds pretty interesting as well.
What are your preferences?? :)

--[[User:Z3330313|z3330313]] 14:55, 23 August 2011 (EST)

Hey Everyone, Im happy to do the diagnosis/current/future prospects point and a case study.

--z3332327 15:36

File:Dystrophin in the muscle fibre membrane.jpg

2011-10-06T02:50:22Z

Z3332629:

This image is a visual display of the muscle fibre membrane and the location of dystrophin within the sarcolemma surrounding each muscle fibre. There are 4 main transmembrane proteins that compose the dystrophin-glycoprotein complex (DGP), also referred to as the dystrophin-associated protein complex (DAPC), located in the muscle fibre membrane. These proteins include:

* '''Sarcoglycans:''' a family of transmembrane proteins that work in conjunction with other proteins (namely dystrophin) to protect muscle fibres during contraction. There are 4 main types present in striated muscle, including: α-sarcoglycan, β-sarcoglycan, γ-sarcoglycan and δ-sarcoglycan. The sarcoglycan complex is disrupted and destabilized from the plasma membrane when dystrophin is mutated and hence leads to eccentric contraction-induced disruption of the plasma membrane of smooth and cardiac muscle. <ref>Hack, A.A., Lam, M, J.,Cordier, L., Shoturma, D.I (2000). “Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex”. Journal of Cell Science 113, page 2535-2544 (2000). Accessed via: http://jcs.biologists.org/content/113/14/2535.full.pdf</ref>

* '''Dystroglycan:''' connects the extracellular matrix and cytoskeleton and also forms a linkage between the dystrophin-glycoprotein complex and the basal lamina. When dystrophin is mutated, these linkages formed by dystroglycan are lost and also cause the disruption of the plasma membrane.<ref>Neuromuscular (2011). “Membrane-associated protein complexes in skeletal muscle fibres and connective tissue.” Author anonymous. Accessed via: http://neuromuscular.wustl.edu/musdist/dag2.htm#ad</ref>

* '''Syntrophin:''' links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC and therefore when dystrophin is mutated, this crucial signalling pathway is lost. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

* '''Dystrobrevinis:''' the functional role of this complex has not yet been clearly identified, however studies show that dystrobrevin disappears from the muscle membrane in Duchenne muscular dystrophy (DMD). <ref>Grisoni,K., Gieseler,K., Se´ galat,L. (2002). “Dystrobrevin requires a dystrophin-binding domain to function in Caenorhabditis elegans”. Eur. J. Biochem. 269, pages 1607±1612.</ref>

Image creator: Ashleigh Pontifex (z3332629)

Student image constructed based on the image presented on: http://www.mda.org/publications/fa-dmdbmd-what.html

Location of dystrophin within the muscle fibre membrane by Ashleigh Pontifex is licensed under a Creative Commons Attribution-NoDerivs 3.0 Unported License.
Based on a work at www.mda.org.

<a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nd/3.0/88x31.png" /></a> Location of dystrophin within the muscle fibre membrane by Ashleigh Pontifex is licensed under a <a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/">Creative Commons Attribution-NoDerivs 3.0 Unported License</a>. Based on a work at <a xmlns:dct="http://purl.org/dc/terms/" href="http://www.mda.org/publications/fa-dmdbmd-what.html" rel="dct:source">www.mda.org</a>.

{{Template:2011 Student Image}}.

File:Dystrophin in the muscle fibre membrane.jpg

2011-10-06T02:49:58Z

Z3332629:

This image is a visual display of the muscle fibre membrane and the location of dystrophin within the sarcolemma surrounding each muscle fibre.

{{Template:2011 Student Image}}.

There are 4 main transmembrane proteins that compose the dystrophin-glycoprotein complex (DGP), also referred to as the dystrophin-associated protein complex (DAPC), located in the muscle fibre membrane. These proteins include:

* '''Sarcoglycans:''' a family of transmembrane proteins that work in conjunction with other proteins (namely dystrophin) to protect muscle fibres during contraction. There are 4 main types present in striated muscle, including: α-sarcoglycan, β-sarcoglycan, γ-sarcoglycan and δ-sarcoglycan. The sarcoglycan complex is disrupted and destabilized from the plasma membrane when dystrophin is mutated and hence leads to eccentric contraction-induced disruption of the plasma membrane of smooth and cardiac muscle. <ref>Hack, A.A., Lam, M, J.,Cordier, L., Shoturma, D.I (2000). “Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex”. Journal of Cell Science 113, page 2535-2544 (2000). Accessed via: http://jcs.biologists.org/content/113/14/2535.full.pdf</ref>

* '''Dystroglycan:''' connects the extracellular matrix and cytoskeleton and also forms a linkage between the dystrophin-glycoprotein complex and the basal lamina. When dystrophin is mutated, these linkages formed by dystroglycan are lost and also cause the disruption of the plasma membrane.<ref>Neuromuscular (2011). “Membrane-associated protein complexes in skeletal muscle fibres and connective tissue.” Author anonymous. Accessed via: http://neuromuscular.wustl.edu/musdist/dag2.htm#ad</ref>

* '''Syntrophin:''' links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC and therefore when dystrophin is mutated, this crucial signalling pathway is lost. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

* '''Dystrobrevinis:''' the functional role of this complex has not yet been clearly identified, however studies show that dystrobrevin disappears from the muscle membrane in Duchenne muscular dystrophy (DMD). <ref>Grisoni,K., Gieseler,K., Se´ galat,L. (2002). “Dystrobrevin requires a dystrophin-binding domain to function in Caenorhabditis elegans”. Eur. J. Biochem. 269, pages 1607±1612.</ref>

Image creator: Ashleigh Pontifex (z3332629)

Student image constructed based on the image presented on: http://www.mda.org/publications/fa-dmdbmd-what.html

Location of dystrophin within the muscle fibre membrane by Ashleigh Pontifex is licensed under a Creative Commons Attribution-NoDerivs 3.0 Unported License.
Based on a work at www.mda.org.

<a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nd/3.0/88x31.png" /></a> Location of dystrophin within the muscle fibre membrane by Ashleigh Pontifex is licensed under a <a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/">Creative Commons Attribution-NoDerivs 3.0 Unported License</a>. Based on a work at <a xmlns:dct="http://purl.org/dc/terms/" href="http://www.mda.org/publications/fa-dmdbmd-what.html" rel="dct:source">www.mda.org</a>.

User:Z3332629

2011-10-06T01:00:39Z

Z3332629: /* Lab Week 11 */

User:Z3332629

2011-10-06T01:00:21Z

Z3332629:

User:Z3332629

2011-10-06T00:59:58Z

Z3332629: /* Peer Assessments */ i had confused myself by accidently naming a group as group 12 and therefore forgot to paste in my group 9 peer assessment

User:Z3332629

2011-10-06T00:50:59Z

Z3332629: /* Peer Assessments */ editted group page name

-[[User:Z3332629|Z3332629]] 12:55, 28 July 2011 (EST)
Lab 1 Assessment

1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.

The first In Vitro Fertilization Pre-Embryo Transfer (IVF-ET) was performed in 1978 by Dr. Edwards (an embryologist) and Dr. Steptoe in England.
In 2010, Robert G. Edwards was awarded with a Nobel Prize “for the development of human in vitro fertilization (IVF) therapy”.

2. Identify a recent paper on fertilisation and describe its key findings.

Title: Enzymatic isolation of human primordial and primary ovarian follicles with Liberase DH: protocol for application in a clinical setting
Authors: Julie Vanacker M.Bio.Sc.a, Alessandra Camboni M.D., Ph.D.a, Catherine Dath M.D.a, Anne Van Langendonckt Ph.D.a, Marie-Madeleine Dolmans M.D., Ph.D.a, Jacques Donnez M.D.,h.D. a, and Christiani A. Amorim V.M.D., Ph.D.a

Key findings:
- The aim or objective of the experiment was to isolate human preantral follicles with a particular enzyme (Liberase Dehydrogenase) in order to use these follicles in a clinical setting.
- After the follicles were isolated, they were analysed in terms of their morphology and structural preservation.
- In conclusion, it was founded that Liberase DH is an extremely useful enzyme for the isolate of human preantral follicles as it helps to maintain their viability and ultrastructure. This enzyme can be produced in good manufacturing practice conditions and hence is a great contribution to clinical applications.

3. Identify 2 congenital anomalies.

Two congenital anomalies include:
- Trisomy 21 (Down Syndrome): a chromosomal abnormality caused by the event of an additional copy of chromosome 21
- Cleft palate: caused by the failure of the mouth parts to join up during early foetal development which results in an open space or ‘cleft’ that can occur on one or on both sides of the face.

http://www.ivf.com/ivffaq.html
http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html
http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0015028211008600
http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Fertilization
http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Cleft_palate_and_cleft_lip

--[[User:Z3332629|z3332629]] 11:25, 29 July 2011 (EST)

--[[User:S8600021|Mark Hill]] 14:59, 29 July 2011 (EST) Well done Ashleigh. I will show you how to format the references correctly for the group project.

Something about the reference.<ref><pubmed>21719006</pubmed></ref>

References

<references />

--[[User:Z3332629|Z3332629]] 07:38, 3 August 2011 (EST)
Oh okay! Sorry I wasn't sure if references were necessary, so I just popped them in quickly at the end. The example that you have given, is that the exact way in which we should incorporate it in our group project? Should we use the Harvard or Endnote system?
--[[User:Z3332629|Z3332629]] 07:36, 3 August 2011 (EST)

--[[User:Z3332629|z3332629]] 10:52, 4 August 2011 (EST)

Lab 2 Online Assessment
1.Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilization.

The zona pellucid glycoprotein ZP-3 functions as a sperm receptor. After fertilization, it is believed that enzymes act to digest the entire zona pellucid, hence inactivating the ZP3 protein to prevent polyspermy.

Additional information of interest: “The sperm-binding activity of ZP3 is mediated by the oligosaccharide side chains of ZP3”... This observation suggests that “the oligosaccharides on ZP3 trap incoming sperm at the zona surface of unfertilized eggs and that this activity is lost after fertilization” .
After ZP3 binds to the sperm, it then triggers the sperm’s acrosome reaction that enables the selected spermatozoon to penetrate the zona pellucida .

Innovate us – Innovation and information for sustainable living. 2006-2011. What is a Zona Pellucida. InnovateUs.net. Viewed 04/08/2011 < http://www.innovateus.net/health/what-zona-pellucida>
L.Browder and L.Iten (Ed.) 1998. (Dynamic Development). Fertilization: Sperm/Egg Recognition and Contact. USA. Viewed 04/08/2011 < http://people.ucalgary.ca/~browder/fertiliz.html>
Keyon College, D.Marcey Chapter 13B: Animal Fertilization and Cleavage. Viewed 04/08/2011 < http://biology.kenyon.edu/courses/biol114/Chap13/Chapter_13B.html>
--[[User:Z3332629|z3332629]] 15:16, 4 August 2011 (EST)

Review article: Functional characteristics of dystrophic skeletal muscle: insights from animal models. Jon F. Watchko1, Terrence L. O'Day1, and Eric P. Hoffman2 http://jap.physiology.org/content/93/2/407.long

Research article: The common missense mutation D489N in TRIM32 causing limb girdle muscular dystrophy 2H leads to loss of the mutated protein in knock-in mice resulting in a Trim32-null phenotype Elena Kudryashova1, Arie Struyk2,†, Ekaterina Mokhonova1, Stephen C. Cannon2 and Melissa J. Spencer1,* http://hmg.oxfordjournals.org/content/early/2011/07/28/hmg.ddr311.long --Ashleigh Pontifex 13:31, 10 August 2011 (EST)
--[[User:Z3332629|z3332629]] 13:34, 10 August 2011 (EST)

Lab sign in --[[User:Z3332629|z3332629]] 12:22, 11 August 2011 (EST)

[[[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]

==Differentially expressed RefSeq genes in human trisomy 2==

Pone.0018493.g006.jpg

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/

Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.

Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

[[[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg|thumb|Differentially expressed RefSeq genes in human trisomy 21]]

==Lab 3 Online Assessment==

1.
• Iodine is also significant, as iodine deficiency is the biggest cause of mental retardation.

===References:===
Living Strong. 2011. Healthy Food to Help Brain Development in Early Pregnancy. Accessed 11/08/2011. <http://www.livestrong.com/article/296096-healthy-food-to-help-brain-development-in-early-pregnancy/#ixzz1Ughcky2w>
Living Strong. 2011. Vitamins for Fetal Brain Development. Accessed 11/08/2011. <http://www.livestrong.com/article/297928-vitamins-for-fetal-brain-development/>
Living Strong. 2011. Healthy Food to Help Brain Development in Early Pregnancy. Accessed 11/08/2011. <http://www.livestrong.com/article/296096-healthy-food-to-help-brain-development-in-early-pregnancy/#ixzz1Ughcky2w>

[[File:asj-5-43-g001.jpg]]

--[[User:S8600021|Mark Hill]] 15:20, 11 August 2011 (EST) OK, so you have uploaded the image OK and included all the information requested. Except the last and most important step I described, how is "File:Asj-5-43-g001.jpg" an appropriate description of the original image? Why not rename this image to "Surgical correction of Spinal Curvature" or "Surgical Spinal Deformity Correction" something descriptive so that the image can be easily identified. You will not get full marks until this has been corrected.

==X-ray examination of an 11-year-old boy, wheelchair bound for 8 months with Duchenne muscular dystrophy==

A 11-year-old boy, wheelchair bound for 8 months with Duchenne muscular dystrophy.

A) Preoperative antero-posterior radiograph right sided showing 60° curve. (B, C) Two year post-operative antero-posterior and lateral radiographs showing sublaminar wiring instrumentation with Luque rods and distal fixation to pelvis with L-rod configuration.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047897/

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

[[File:1532-429X-12-14-3.jpg|450|]]

--[[User:S8600021|Mark Hill]] 15:26, 11 August 2011 (EST) Same comment as above for this image.

==T2 histograms==

Examples of normalized (i.e. area under curve = 1) T2 histograms of DMD (Group A, B and C) and Normal control (N1) subjects show that DMD patients with normal EF but impaired εcc has higher heterogeneity in T2 compared to other groups.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846924/

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.

=X-ray examination of an 11-year-old boy, wheelchair bound for 8 months with Duchenne muscular dystrophy=

[[File:Surgical correction of a 11-year old patient suffering from Duchenne muscular dystrophy.jpg]]

Surgical_correction_of_a_11-year_old_patient_suffering_from_Duchenne_muscular_dystrophy.jpg‎ (568 × 376 pixels, file size: 127 KB, MIME type: image/jpeg)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047897/

A 11-year-old boy, wheelchair bound for 8 months with Duchenne muscular dystrophy. (A) Preoperative antero-posterior radiograph right sided showing 60° curve. (B, C) Two year post-operative antero-posterior and lateral radiographs showing sublaminar wiring instrumentation with Luque rods and distal fixation to pelvis with L-rod configuration.

=Results of the AGEP analysis of microarray data from two Duchenne muscular dystrophy samples against the reference database.=

[[File:Results of the AGEP analysis of microarray data from two Duchenne muscular dystrophy samples against the reference database.jpg|450px|]]

====Figure 2====
Results of the AGEP analysis of microarray data from two Duchenne muscular dystrophy samples against the reference database.

A) The sample from patient 3 resembles most closely striated muscle among the 44 reference tissues. B) Alignment of the patient's transcriptome at the level of individual genes. On the x-axis are genes (17 330) and on the y-axis the three most similar tissues. Green color indicates that the genes have an expression level typical for that tissue, whereas red indicates atypical expression levels. Genes have been ordered according to their level of similarity against the most similar tissue (striated muscle). C) View of distinct gene sets and pathways for the most similar tissue (striated muscle). Relative enrichment of atypical genes is shown on the right side to illustrate aberrant gene expression levels for individual patient samples. Genes involved in inflammation response, complement mediated immunity and muscle contraction had more atypical expression levels as compared to healthy striated muscle (198.6, 70.9 and 7.1 fold enrichment of atypical genes, respectively), indicating that these processes were altered in DMD in comparison to healthy muscle. D-F) The gene expression profile from patient 4 resembled mostly striated muscle (primary match), but revealed adipose tissue as the second best matching tissue. As compared to patient 3, this patient had a larger number of muscle typical genes involved in inflammation response, complement mediated immunity and muscle contraction suggesting a less severe disease for patient 4.

===Copyright Notice===
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.

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pmc/articles/PMC3080808/

Mark Hill, I have been having implications uploading files! I correct the file name, however I have uploaded 3 files and they have all come up with a little red cross symbol. I'm not sure as to what has happened, I have attempted the task multiple times with different images and it keeps occuring. Please take this into account for my marks for the online lab submission.

Kind regards

--[[User:Z3332629|z3332629]] 13:20, 17 August 2011 (EST)

=DMD patients and causes of higher heterogeneity=

[[File: DMD patients and causes of higher heterogeneity.jpg]]

===T2 histograms.===

Examples of normalized (i.e. area under curve = 1) T2 histograms of DMD (Group A, B and C) and Normal control (N1) subjects show that DMD patients with normal EF but impaired εcc has higher heterogeneity in T2 compared to other groups.

Accessed via: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846924/

===Copyright Notice===

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.

Lab week 5 sign on
--[[User:Z3332629|z3332629]] 11:02, 18 August 2011 (EST)

Lab 5, Week 6 Online Assessment
1. Which side (L/R) is most common for diaphragmatic hernia and why?
A diaphragmatic hernia is a condition where there is a hole in the diaphragm and organs from the abdomen go up into the chest cavity. It is most common on the left side as the contents such as the stomach, spleen and intestines (that are all positioned to the left side of the body) move up into the chest region displacing the chest organs to the contralateral side, leaving very little room for lungs to grow and develop properly.

--[[User:Z3332629|z3332629]] 22:00, 26 August 2011 (EST)

--[[User:Z3332629|z3332629]] 11:18, 1 September 2011 (EST)

==Individual Assessment – Week 7==
1. What week of development do the palatal shelves fuse?
Week 9.
2. What animal model helped elucidate the neural crest origin and migration of cells?
The chicken model.
3. What abnormality results from neural crest not migrating into the cardiac outflow tract?
Tetralogy of Fallot
--[[User:Z3332629|z3332629]] 12:32, 10 September 2011 (EST)

==Lab Week 8 Sign on==
--[[User:Z3332629|z3332629]] 11:01, 15 September 2011 (EST)

==Lab 7, Week 8 Online Assessment==

1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?
A) No
B) Yes they are generally involved and proliferate during hypertrophy – satellite cells are important for sustaining hypertrophy by increasing the amount of myonuclei present.

2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?

Slow-twitch skeletal muscle fibres contain a larger number of myonuclei and satellite cells in comparison to fast-twitch muscles. Chronic low-frequency stimulation (CLFS) causes a fast to slow fibre type shift by imitating the “electrical discharge pattern of slow motoneurons innervating slow-twitch muscles” resulting in the recruitment of satellite cells.

==Lab 8, Week 9 Sign on==
--[[User:Z3332629|z3332629]] 10:41, 22 September 2011 (EST)

==Peer Assessments==

Group 1:
* Your page was extremely in depth which was really great.
* Its great that you’ve linked words to the glossary
* The use of a range of different images was good and I like how you made the effort to copyright your own image!
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
* The dot point form of clinical manifestations perhaps could have been better formatted into a table as I personally found your formatting confusing and slightly not a well-organised.

Group 2:
* A very clear format has been used. The mixed use of dot points and paragraph form were used appropriately in most sections and made your web-page easy to read and follow
* Good use of self drawn images, however the large image of Angelo DiGeorge seemed slightly irrelevant and took up a large portion of your page. Your first two images should probably have small heading below the image, just to make them a bit more clear to the reader.
* A coherent history/timeline was used.
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section. Some references are incompletely, or have no linking information such as reference 49.
* Your current research section was good but perhaps could have been tabulated just for easier reading and to really draw out the main points.
* Your table for clinical manifestations could have been summarised otherwise it should maybe just be written in paragraph form.
* Your page definitely reflects the time and effort you have placed into the assignment. I really liked the range of formatting you used and the use of colour made your page easy to read and follow. Another great feature was the section based on the example of Tetralogy of fallot. It was interesting to read how other defects that we have discussed in class, linked in with your studied abnormality.

Group 3:
* Great amount of depth, you have covered each subheading quite well
* It was great to see a comparison to other similar defects
* Non-disjunction is discussed twice, can it be summarised into just the one section?
* In the signs and symptoms section, the images seem to be arranged in a disorderly fashion, maybe place them elsewhere. Also your image comparing age and intellect is extremely small. The sizing of a larger majority of your photos needs to b adjusted
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
* There were only two examples of management strategies, are there anymore out there? Maybe you could do a comparisons table for this section

Group 4:
* 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.

Group 5:
* I liked your page as it had a simple and easy-to-follow lay out
* Some of the images could have been made larger on your actual page just so that it adds dynamics to your page
* I was left wanting to know more about the diagnosis, this section was quite brief
* I personally found your treatment table hard to read because there was so much information. Personally I believe that maybe dot-point form could have been used to get your main points across.
* Perhaps expand upon your glossary as there were some words that weren’t in there that maybe should have been.

Group 6:
* I would suggest placing the history section into a timeline or table format just so that significant dates are more clear and emphasised.
* The gene profile section was great. It was in detail, it was coherent and the inclusion of gene images enhanced my understanding of this particular section.
* Maybe for the “how the procedure works” section of the diagnostics table could have been summarised into a flow diagram or through images, rather than having a chunk of text. This could make it more straight forward to the reader.
* Your website was generally well-written and to the point. You varied your formatting regularly which made your page entertaining.
* My last suggestion would to only use the image of the shunt once and finding a different image as the repetitiveness of this is slightly disengaging

Group 7:
* Your pathogenesis section was good, it was thorough and went into significant depth. The use of animal models and the support of recent studies was also a positive aspect
* The photo of the ub pathway should be smaller or be placed as a thumb nail as it isn’t something that directly contributes to your defect
* It is a shame that there is such a large gap in your Aetiology section, but i do realise that this is slightly out of your control due to wiki formatting issues.
* I personally found the signs and symptoms section to be slightly confusing in format. Perhaps placing this info into a table would make it more concise.
* Treatment and management section had lots of detail and highlighted a few different methods which gave a good insight of the current technologies and strategies out there in the market.

Group 8:
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.
* Maybe include a glossary so you can accommodate for all readers.
* It was good to see that you grouped your references 

Group 9:

Group 10:
* Intro was good, it was brief and straight to the point
* The beginning paragraphs of the history could be more summarised especially considering that you have a timeline beneath
* Your use of a table for the genetics’ component was great. It was easy to read and concise. It was a different approach but it worked well.
* More information could have been added to the treatment section such as comparisons between key methods/strategies, the pros and cons
* The phenotype section was well set out although I believe it should have been placed up after the genetics section so that the information flows more consistently
* The layout of the implications section was slightly unclear. Maybe here you could have large heading for implications, followed by a list (dot point) of the implications occurred then have in paragraph form a description of each. Having headings such as: Other problems and other associated medical conditions tended to drag on this segment.
* The inclusion of the supportive associations was a nice little touch!
* Great use of referencing

Group 11:
* I would suggest expanding on the current and future research section, maybe add in links to current research institutes or research papers.
* Perhaps add an image in for problems associated with cleft palate, just to add some dynamics and colour to the page.
* Perhaps tabulate the treatment section just so that the information is clearer
* Placing words in bold, although it was just a little touch, helped to highlight the main points you were trying to get across which was good.
* Good incorporation of tables and different formatting styles
* Your introduction was clear, simple and straight to the point.
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
* Your timeline was extremely spaced out, I would suggest deleting the space between your dot points just so that it reads easier.

==Lab Week 10==
--[[User:Z3332629|z3332629]] 12:32, 29 September 2011 (EST)

2011 Group Project 10

2011-10-05T01:42:46Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref>. In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently, procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

'''Dr Edward Meryon'''

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref name="PMID8326496"><pubmed>8326496</pubmed></ref>. His findings were reported in the Transactions of the Medical and Chirurgical Society in December 1851 <ref name="Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12">Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not from the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref name="PMID8326496"/>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we now call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref name="Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12"/>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens, that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

'''Guillaume Benjamin Amand Duchenne'''

[[File:Duchenne.JPG|thumb|250px|upright|right|Guillaume-Benjamin-Amand Duchenne de Boulogne]]

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>. Guillaume Benjamin Amand Duchenne was the physician that the disorder was named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref name="PMID16225184"><pubmed>16225184</pubmed></ref>. Duchenne was a family doctor for 11 years who was interested in the study of electrical stimulation of muscle <ref name="PMID16225184"/>. He first became interested in muscular dystrophy in 1858. Duchenne also invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref name="PMID16225184"/>. This technique allowed study of material from the same patient at different stages of the disease.

Duchenne defined the disorder as:

- progressive weakness of movement first affecting the lower limb then later the upper

- pathologically; loss of striation of muscle replaced by granular matter and fat vesicles. Furthermore an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages

- a gradual increase in the size of many affected muscles

- an onset during early childhood or early adolescence that is, more prevalent in boys than girls

- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

'''Brief Timeline of DMD'''

{|border="1"
|-style="background:yellow" align="center"
|'''Date'''
|'''Brief description'''
|-style="background:"
|1847
|
Dr W J Little reported two affect boys aged 12 & 14 that were unable to walk. Both were later found to have most of their leg muscles replaced with fat <ref name="PMID8326496"><pubmed>8326496</pubmed></ref>.

|-style="background:"
| 1851
|
Meryon described at a meeting of the Royal Medical and Chirurgical society 8 boys presumed to be affected with Duchenne Muscular Dystrophy <ref name="PMID8326496"/>

|-style="background:"
| 1861
|
Duchenne first describes the disease, a young boy whose condition characterised by the hypertrophy of the boy's calf muscles <ref name="PMID16225184"/>

|-style="background:"
| 1868
|
Duchenne provided a much more detailed account of the boy's disease,DMD <ref name="PMID16225184"/>

|-style="background:"
| 1868
|
Duchenne provided a much more detailed account of the boy's disease,DMD <ref name="PMID16225184"/>

|-style="background:"
| 1930-1960
|
Discovery of Becker Muscular Dystrophy, a less severe form form of DMD. The x-linked pattern of inheritance for DMD is confirmed.<ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)">MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)</ref>.

|-style="background:"
|1985-1988
|
Gene responsible for DMD is found by Louis Kunkel's team & the protein made from this gene is described and named dystrophin <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>

|-style="background:"
|1989-1994
|
The reason for severity of DMD is found. It is determined by the amount of dystrophin present in the muscle-fibre membrane. The more dystrophin correlates to less severe symptoms <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>

|-style="background:"
|1995-2000
|
Dystrophin gene is miniturised to facilitate gene therapy and research into stem cells is on its way to cure DMD <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>.

|-style="background:"
|2001-2005
|
Corticosteroid prednisone trials found effective in slowing down the progression of DMD <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>.

|}

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==
[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human [[#Glossary of terms|'''genome''']] is called the [[#Glossary of terms|'''dystrophin''']] [[#Glossary of terms|'''gene''']] and is contained at the [[#Glossary of terms|'''sacroplasmic''']] surface of the plasma membrane or [[#Glossary of terms|'''sarcolemma''']] of muscle fibers.<ref name=Davies>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of [[#Glossary of terms|'''muscle fibres''']].

The dystrophin gene, also known as DMD, is located on the short arm of the [[#Glossary of terms|'''X chromosome''']] at position 21.2. In 1987, it was found that this particular gene was identified as being located from [[#Glossary of terms|'''base pair''']] 31,137,344 to base pair 33,357,725 on the X chromosome. <ref name=DMD>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref name=Davies/> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref name=DMD/>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during [[#Glossary of terms|'''muscle contraction''']].

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the [[#Glossary of terms|'''actin''']] [[#Glossary of terms|'''cytoplasm''']]
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref name=Davies/>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the [[#Glossary of terms|'''cytoskeleton''']] through [[#Glossary of terms|'''filamentous''']] actin whilst the other binds to the [[#Glossary of terms|'''dystrophin-associated protein complex (DAPC)''']].
*The DAPC consists of cytoplasmic, [[#Glossary of terms|'''transmembrane''']] and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the [[#Glossary of terms|'''extracellular matrix''']].
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.<ref name=Davies/>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.<ref name=Davies/>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as [[#Glossary of terms|'''dominant''']] or [[#Glossary of terms|'''recessive''']] traits, or can be due to new mutations of a specific gene. <ref name=Davies/>As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

Many of the symptoms associated with DMD are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research - Utrophin==

Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Actin:''' a protein that forms the contractile units of muscle cells

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Base pair:''' two complementary bases in a nucleic acid molecule

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoplasm:''' material within a cell

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dominant:''' a trait determined by an allele that is expressed over another present allele

*'''Dystrophin:''' a protein involved in muscular contraction

*'''Dystrophin-associated protein complex (DAPC):''' a multiprotein complex that includes dystrophin and other associated proteins.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Extracellular matrix:''' network of connective tissues and fibres that provide support and exist outside the cell.

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Filamentous:''' thread-like cells

*'''Gene:''' sequence of nucleotides forming part of a chromosome

*'''Genome:''' the complete set of genetic material in a cell or organism

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Muscle contraction:''' process in which muscles shorter and are made tighter un neuronal control

*'''Muscle fiber:''' elongated contractile cell

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Nucleotides:''' compounds that form the basic structural units of nucleic acids

*'''Plasma membrane:''' composed of lipids and proteins, forms the external boundary of the cytoplasm

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Recessive:''' the opposite of Dominant

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Signal transduction:''' internal cell signalling process

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

*'''Transmembrane:''' existing across a membrane

*'''X chromosome:''' sex chromosome, two are represent in females and only one is present in male cells.

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-05T01:40:33Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref>. In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently, procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

'''Dr Edward Meryon'''

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref name="PMID8326496"><pubmed>8326496</pubmed></ref>. His findings were reported in the Transactions of the Medical and Chirurgical Society in December 1851 <ref name="Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12">Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not from the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref name="PMID8326496"/>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we now call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref name="Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12"/>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens, that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

'''Guillaume Benjamin Amand Duchenne'''

[[File:Duchenne.JPG|thumb|250px|upright|right|Guillaume-Benjamin-Amand Duchenne de Boulogne]]

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>. Guillaume Benjamin Amand Duchenne was the physician that the disorder was named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref name="PMID16225184"><pubmed>16225184</pubmed></ref>. Duchenne was a family doctor for 11 years who was interested in the study of electrical stimulation of muscle <ref name="PMID16225184"/>. He first became interested in muscular dystrophy in 1858. Duchenne also invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref name="PMID16225184"/>. This technique allowed study of material from the same patient at different stages of the disease.

Duchenne defined the disorder as:

- progressive weakness of movement first affecting the lower limb then later the upper

- pathologically; loss of striation of muscle replaced by granular matter and fat vesicles. Furthermore an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages

- a gradual increase in the size of many affected muscles

- an onset during early childhood or early adolescence that is, more prevalent in boys than girls

- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

'''Brief Timeline of DMD'''

{|border="1"
|-style="background:yellow" align="center"
|'''Date'''
|'''Brief description'''
|-style="background:"
|1847
|
Dr W J Little reported two affect boys aged 12 & 14 that were unable to walk. Both were later found to have most of their leg muscles replaced with fat <ref name="PMID8326496"><pubmed>8326496</pubmed></ref>.

|-style="background:"
| 1851
|
Meryon described at a meeting of the Royal Medical and Chirurgical society 8 boys presumed to be affected with Duchenne Muscular Dystrophy <ref name="PMID8326496"/>

|-style="background:"
| 1861
|
Duchenne first describes the disease, a young boy whose condition characterised by the hypertrophy of the boy's calf muscles <ref name="PMID16225184"/>

|-style="background:"
| 1868
|
Duchenne provided a much more detailed account of the boy's disease,DMD <ref name="PMID16225184"/>

|-style="background:"
| 1868
|
Duchenne provided a much more detailed account of the boy's disease,DMD <ref name="PMID16225184"/>

|-style="background:"
| 1930-1960
|
Discovery of Becker Muscular Dystrophy, a less severe form form of DMD. The x-linked pattern of inheritance for DMD is confirmed.<ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)">MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)</ref>.

|-style="background:"
|1985-1988
|
Gene responsible for DMD is found by Louis Kunkel's team & the protein made from this gene is described and named dystrophin <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>

|-style="background:"
|1989-1994
|
The reason for severity of DMD is found. It is determined by the amount of dystrophin present in the muscle-fibre membrane. The more dystrophin correlates to less severe symptoms <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>

|-style="background:"
|1995-2000
|
Dystrophin gene is miniturised to facilitate gene therapy and research into stem cells is on its way to cure DMD <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>.

|-style="background:"
|2001-2005
|
Corticosteroid prednisone trials found effective in slowing down the progression of DMD <ref name="MDA 2011, Milestones in Duchenne Muscular Dystrophy Research, (http://www.mdausa.org/publications/milestones-embed.html)"/>.

|}

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==
[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human [[#Glossary of terms|'''genome''']] is called the [[#Glossary of terms|'''dystrophin''']] [[#Glossary of terms|'''gene''']] and is contained at the [[#Glossary of terms|'''sacroplasmic''']] surface of the plasma membrane or [[#Glossary of terms|'''sarcolemma''']] of muscle fibers.<ref name=Davies>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of [[#Glossary of terms|'''muscle fibres''']].

The dystrophin gene, also known as DMD, is located on the short arm of the [[#Glossary of terms|'''X chromosome''']] at position 21.2. In 1987, it was found that this particular gene was identified as being located from [[#Glossary of terms|'''base pair''']] 31,137,344 to base pair 33,357,725 on the X chromosome. <ref name=DMD>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref name=Davies/> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref name=DMD/>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during [[#Glossary of terms|'''muscle contraction''']].

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the [[#Glossary of terms|'''actin''']] [[#Glossary of terms|'''cytoplasm''']]
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref name=Davies/>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the [[#Glossary of terms|'''cytoskeleton''']] through [[#Glossary of terms|'''filamentous''']] actin whilst the other binds to the [[#Glossary of terms|'''dystrophin-associated protein complex (DAPC)''']].
*The DAPC consists of cytoplasmic, [[#Glossary of terms|'''transmembrane''']] and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the [[#Glossary of terms|'''extracellular matrix''']].
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.<ref name=Davies/>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.<ref name=Davies/>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref name=Davies/>As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

Many of the symptoms associated with DMD are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research - Utrophin==

Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Actin:''' a protein that forms the contractile units of muscle cells

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Base pair:''' two complementary bases in a nucleic acid molecule

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoplasm:''' material within a cell

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dominant:''' a trait determined by an allele that is expressed over another present allele

*'''Dystrophin:''' a protein involved in muscular contraction

*'''Dystrophin-associated protein complex (DAPC):''' a multiprotein complex that includes dystrophin and other associated proteins.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Extracellular matrix:''' network of connective tissues and fibres that provide support and exist outside the cell.

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Filamentous:''' thread-like cells

*'''Gene:''' sequence of nucleotides forming part of a chromosome

*'''Genome:''' the complete set of genetic material in a cell or organism

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Muscle contraction:''' process in which muscles shorter and are made tighter un neuronal control

*'''Muscle fiber:''' elongated contractile cell

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Nucleotides:''' compounds that form the basic structural units of nucleic acids

*'''Plasma membrane:''' composed of lipids and proteins, forms the external boundary of the cytoplasm

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Recessive:''' the opposite of Dominant

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Signal transduction:''' internal cell signalling process

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

*'''Transmembrane:''' existing across a membrane

*'''X chromosome:''' sex chromosome, two are represent in females and only one is present in male cells.

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

Talk:2011 Group Project 10

2011-10-05T01:32:48Z

Z3332629: /* Group Discussion Week 10-12 */

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File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_10_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
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==Group Discussion Week 10-12==
Nice drawings!

Just some videos for my section, just placing them somewhere so i know where they are :)
http://www.youtube.com/watch?v=dOhMLZCvb50
http://www.youtube.com/watch?v=GWachrbiU58
--[[User:Z3332629|Ashleigh Pontifex]] 12:01, 3 October 2011 (EST)

Joanna : http://emedicine.medscape.com/article/1173204-overview#a0199
Great over view for epidemiology, perhaps a table or some stats would be great in this section :)

- http://www.ncbi.nlm.nih.gov/pubmed/19834452 -

hey guys I changed some of the stuff on history, if you think its too much info let me know!
I deleted alot of information, and I just can't bring myself to delete more because the stuff remaining now seems so relevant. But let me know what you think!
And what do you guys think about putting an image of the Duchenne dude in the history? do you reckon that'll make that section too long?
--[[User:Z3330313|Joanna Pak]] 02:56, 5 October 2011 (EST)

Hey Jo! I had a read of the history section and it sounds good. Just an idea, where you've listed Duchenne's definition of the disease, would you prefer if those were added under DIAGNOSIS- clinical or SIGNS AND SYMPTOMS? And we could add an internal link? Maybe that'll cut down your section a bit?

Just a suggested change, i just rearranged the words around a little, dont have to. =)

*'Meryon conducted several necropsies and found intact spinal cords which indicated the disease was not from the nervous system.'

Minor edit

*'Further microscopic examination of the muscle showed that the muscular fibres '''broke''' down and converted into granular, fatty matter.'
--[[User:Z3332327|Lisa Xiao]] 11:38, 5 October 2011 (EST)

Hey Jo its Ash!! It looks heaps better, more straight forward and the table inclusion is great :)
Is everyone happy with my student drawn image in the introduction? it is appropriate in this section?
Also my table in the genetics section???

And lastly, ive notice that Rhiannon has hyperlinked all glossary terms in her section, is everyone happy to carry that across all areas???
--[[User:Z3332629|z3332629]] 12:29, 5 October 2011 (EST)

Actually one last suggestion jo, maybe change the table colour to teal so that the colour schemme consistent throughout the page :)
--[[User:Z3332629|z3332629]] 12:32, 5 October 2011 (EST)

==Peer Review==

'''Peer Review'''
* The introduction is detailed but a bit “in your face.” It may even be a bit too detailed, going into the pathogenesis of the disorder.
* History is very detailed, perhaps slightly story-like but enjoyable nonetheless. Could use a picture or two. Sufficiently referenced.
* Epidemiology is very thorough and well referenced.
* The tone of Aetiology/Genetics is a bit conversational; needs to be more detached. Good use of picture, although the legend to it is not in the correct format.
* Pathogenesis could use more references, especially for the last paragraph. Could potentially use some pictures to make clearer the specific structures discussed in the text (although they are elaborated on in the glossary).
* All the signs listed in Clinical Manifestations etc are decently elaborated upon, and the section is well-referenced. Smooth Muscle has strange “&&&” signs though. Respiratory Problems needs cleaning, notably with the line “[Effects of high CO2 and the problems it can cause]”
* Diagnosis is nicely laid out, although more references are needed.
* Treatment is decently set up and clearly explains each of the treatment plans.
--[[User:Z3290689|z3290689]] 14:44, 29 September 2011 (EST)

Group 10:
This project looks fine but it seems a little short? You want to expand the content in sections.
History is well researched but it’s quite long. You can add more images (add the reference in the description) and make the dates in Bald.
There are some spelling errors and extra signs that are not related to the work such as &&&.
Some of the references are repeated and others need to be reformatted.
Overall, Great effort.

--[[User:Z3284061|z3284061]] 11:51, 29 September 2011 (EST)

'''Peer Assessment'''
*introduction is well written and descriptive. Good use of image to make it look appealing. No references in the first paragraph.
*History section is too long, text heavy and a bit boring. Try to summarize the details on a timeline. You can include an image e.g. of Dr Edward Meryon if possible.
*Epidemiology and aetiology; well written. The image in the aetiology needs to be linked with the text.
*Pathogenesis; too brief. Needs more information and explanation of the disease process. Include an image or flowchart to compliment the text.
*Signs and symptoms; needs to be expanded a bit more. I suggest using a table to present the information that just as dot points. Same goes for the diagnosis section, which also needs to be expanded. Try and use more images, tables, graphs etc to break up the texts and make the page look more appealing.
*I suggest hyperlinking words in the page with the glossary to make the page more user friendly.
*Like the use of table in the "current and future prospects". It's better to present information like this rather than in big long paragraphs.
*The glossary needs to be expanded more.
--[[User:Z3291622|Z3291622]] 11:07, 29 September 2011 (EST)

'''''Duchenne (Group 10) Peer Review:'''''

Could you include “Duchenne Muscular Dystrophy” as the first subheading so that the reader knows exactly what the disease is at first glance? Just a suggestion.

Introduction: Topic well introduced and good use of image. Image, however, is lacking a student template.

History: Very extensive. Possibly include an image to break up the text.

Epidemiology: Sound. Some sentences are not worded/ structured properly.

Aetiology – Genetics: Information is good. Impressive self-drawn image. Well done.

Pathogenesis: An image would definitely work well in this section. Information is otherwise good, however possibly have a greater focus on the genetic component?

General Signs and Symptoms of Duchenne’s Muscular Dystrophy: This section seems too brief. Elaborate further.

Clinical manifestations and complications: Information is good. Possibly more detail for the subheading “smooth muscle.” Image lacks a student template. “&&&” – what is this? Many references in this section which is good to see!

Diagnosis: Could be elaborated further.

Treatment: Current and Future Prospects: The first paragraph lacks referencing. Possibly include an image? Table is a good idea, however colours chosen are slightly off-putting.
Glossary of terms: Could be more extensive. Not complete.

Well done. --[[User:Z3290808|z3290808]] 10:50, 29 September 2011 (EST)

Duchenne Muscular Dystrophy – Group 10

* Excellent introduction and good use of image. Is there some referencing missing in the first few sentences? Some formatting should be done on the image either to make it within the intro section or more shared between the history sections. Looks a little out of place.
* History is well written but very text heavy. Use of a timeline good improve this section and make it more succinct. Also I thought an image could be good.
* Epidemiology seems to cover all necessary information and is well referenced. Maybe an image or graph here could be good.
* I like the student drawn image in the etiology section, maybe the sizing could be improved though? Also some a more detailed description of what the image shows would also be good.
* Pathogenesis section is very informative. Maybe the pathophysiology could be covered in this section as well? Image could be added.
* General signs and symptoms would perhaps look better in a table. Otherwise it is quite brief, maybe some more elaboration aswell.
* I think diagnosis looks incomplete. Not much detail is given about how the diagnosis actually works. Very little referencing. Addition of an image would improve this section.
* Treatment looks great. I like how you have included current and future prospects. Just wondering if there was room for a heading for current and future research, as Im sure there is more research being undertaken than just in the area of treatment. This could make this project more informative, and perhaps could be another heading.
* Glossary needs improving.
* Some issues with referencing such as multiple entries for the same article and some issues with web page referencing.

--[[User:Z3288196|Z3288196]] 10:48, 29 September 2011 (EST)

'''GROUP 10: Duchenne Muscular Dystrophy'''
*Title of the whole page should just be Duchenne Muscular Dystrophy, not Introduction...
*The intro is very descriptive and comprehensive
*Image in intro needs proper referencing
*consider rephrasing this sentence "In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction"
*History has good info, but could this be better formatted in a table? this section is text heavy and could maybe use an image, it also could be extended into more recent years
*Epidemiology is summarised well and contains good statistics
*I feel that Aetiology - Genetics section has good info, easy to understand and informative but maybe it could be researched a little more
*General Signs and Symptoms of Duchenne’s Muscular Dystrophy section needs a lot more work, the list of symptoms i don't feel is enough, more expansion on these is needed. An image would improve this section too
*"diarrhoea&&&." -this needs to be fixed

Overall:
*More images are needed to break up the text
*glossary needs a bit more work, consider linking glossary words to text
*I feel that the page overall needs some more work, some sections are lacking content
*Proof reading to fix grammar and sentence structure

--[[User:Z3331556|z3331556]] 10:44, 29 September 2011 (EST)

'''Peer Review'''

This wiki still feels like what Mark Hill mentioned earlier, like a backbone for content to be built upon. The foundations are there, but still very incomplete. Comparing the sections, some have done a lot of effort, others not so much, and it is very visible.

:*Should start the wiki with this code:

<wiki>=Duchenne Muscular Dystrophy (DMD)= </wiki>

then

<wiki>==Introduction == </wiki>

:*History is far too text heavy and it shouldn't be like that, as this makes it a chore to read. A timeline would be better suited and summarise into the timeline.

:*Should be more student drawn images, since there's only one. If getting pictures is hard to find, then draw your own.

:*The one student drawn image is not referenced correctly, needs the disclaimer info.

:*Diagnosis needs to be expanded. There is 300+ articles, there has to be more info or an image to be found.

:*Pathogenesis needs to be expanded, maybe an image.

:*Signs and symptoms need more referencing. Also, just leave the title as Signs and Symptons.

:*Treatment needs to be expanded on. It isn't any good just listing drugs into a table.

:*Split the Treatment to include Managment and give a separate section for Current Research.

:*Glossary is incomplete.

--[[User:Z3293267|z3293267]] 10:37, 29 September 2011 (EST)

Group 10:

Clear and conscise but still needs more work breaking up the long slabs of writing. Perhaps more subheadings esp. in the first sections.

More pics are needed to break up the work.

Treatment includes a good table.

Glossary needs a bit of work and expanding on the explanations.

References needs to be fixed as there is duplications of references.

z3332178 =]

Peer Review

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*History section would benefit by placing the information into a timeline rather than paragraphs as it is a bit hard to follow.

:*Epidemiology section could be expanded and written in more flowing way rather than long sentences.

:*Needs more images, lots of large blocks of text. And images need to be formatted into the text as formatting currently looks awkward.

:*Further Research could be added, for example papers or groups that are researching as currently it is just being referred to.

:*Glossary could be expanded.

:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed. Also perhaps research from MORE sources is necessary as there is only a few when you cut out the double references.

--[[User:Z3217043|z3217043]] 10:02, 29 September 2011 (EST)

Group 10 Peer Review

*Headings are well organised and structured
*Too much text in history section-a table or image would be good
*Information is there however images/graphs/tables would help break up large chunks of text
*Diagnosis seems brief-perhaps merge with treatment section?
*Signs and symptoms could be expanded
*Great table in treatment
*Needs to be proof read-grammar and spelling mistakes
*Double referencing
*Glossary needs to be extended
--[[User:Z3308965|Fleur McGregor]] 09:54, 29 September 2011 (EST)

Group 10

*Introduction – Great intro, well referenced apart from the first paragraph.
*History has a lot of text, a timeline could work well here and also an image if possible just to break up the text.
*Epidemiology – well referenced and structured, text could be broken up but that’s nothing major as it’s a small section.
*Aetiology – A link between the image provided and the text would work well, and also the image could be formatted on the right of the page, to add to continuity and flow as other images are located on the right.
*Signs and Symptoms – Needs to be more information here, a description of each symptom and maybe its direct causes.
*Clinical manifestations – need a link between the image and the text, other than that it is well referenced and easy to understand.
*Treatment – table formatting is great and information is helpful
*Glossary – needs to include more terms form the page.
*There’s some doubling up in the reference section that needs to be fixed, other than that good job.

--[[User:Z3331469|z3331469]] 08:25, 29 September 2011 (EST)

peer review:

*Intro: One of the very few groups to use an image of the disease in the intro, well done! Like how you have referred to Duchenne’s as DMD in brackets initial heading to avoid confusion.

*History: A lot of writing, no techniques to break it up, which will basically bore your reader. Use a timeline perhaps.

*Epidemiology: Subheading will benefit this segment.

*Aetiology: The image could use some colour, but it is still very well done. It would be worthy to refer to the drawing as your explaining the genetics, just to bring them together.

*Pathogenesis: Very brief, not very informative and lacking subheadings or an image. Hopefully this will be fixed.

*Signs and Symptoms:Poorly done. Dot-points are a good way to initiate the writing but not appropriate as a final copy. Needs more description and research.

*Clinical manifestations:
The image used is excellent but needs more explanation.

*Diagnosis:Very short, looks incomplete and there’s only one reference for the entire section.

*Treatment: Well done, I like the colour and the table structure, makes it much easier to understand.

*Glossary: Incomplete, much more terminology has been used.

*References: Double referencing is a big problem here.

*Text:image ratio: could use more images.

--[[User:Z3290270|z3290270]] 02:16, 29 September 2011 (EST)

*history should be broken up with dates on side or within a table.
*how about a short summary table to use for epidemiology
*no picture of Guillaume Benjamin Amand Duchenne?
*no copyright permission for the drawn image in genetics.
*pathogenesis seems very small for a section that is very important.
*describe how the signs and symptoms impact on patients to show the significance of the disease.
*diagnosis needs a lot of work, this section is very important. also very little references in this section.
*not enough pictures to accompany the text
*very short glossary
*multiple references of same articles
--[[User:Z3291423|Jasjit Walia]] 00:17, 29 September 2011 (EST)

'''Peer Review for Group 10'''

*The introduction was well written, however the picture in it is not referenced as instructed. Please fix that then your intro is perfect.
*In the history section, the first sentence is oddly placed, even though it’s informative, please put that somewhere where it will flow in the paragraph.
*The history is verbose, please re write so it’s easier to follow.
*Epidemiology needs to be reevaluated as some sentences are not constructed properly
*Etiology has sound information but the paragraphs are not structured so it flows. It also seems repetitive.
*The picture in the etiology can have its caption better structured
*Pathogenesis should include some component of genetics to explain how the abnormalities bring about the pathogenesis in the genetics level.
*Explanation of how the signs and symptoms comes along from the dystrophy should be explained
*The image of the spine is not completely referenced as url of the image and the page must also be given
*Information under ‘respiratory problems’ and smooth muscle needs some reviewed as it includes words there that shouldn’t be present
*The diagnosis section could be expanded upon so it includes more information on the details of how it is detected, and images should complement the tools to diagnose the condition.
*An introduction to the table should be given. Having the table there by itself doesn’t look good.
*Further explanation should be made on the type of physical activity that would be made for therapy
*Glossary should be expanded
*There is repetitive referencing; it should be reformatted to fit in the way multiple references is made.
*You need much more pics as without the pics the page looks word heavy.

--[[User:Z3291317|Z3291317]] 23:57, 28 September 2011 (EST)

'''Group 10'''

Introduction: Good introduction. The picture could be a bit bigger. Also, a picture of the chromosome would be great.

History and epidemiology: Both sections are clear and flow well. Pictures are needed to break up the text though.

Genetics: The image is great and the text is well written.

Pathogenesis: The pathogenesis is well explained. Again, pictures would be good in this section to improve it.

Clinical manifestations: Good section. Clear, easy to understand.

Diagnosis: This section might need some more detail added. You could explain how each of the diagnostic tests work

Current and future treatment: This section is worded well but looks a little bit disjointed. I think it would be better having it either all in text or all in the table. --[[User:Z3291324|z3291324]] 23:27, 28 September 2011 (EST)

'''Group 10 Peer Review'''
* Interesting introduction, with a good amount of information. The history is also quite well outlined, although as you have no doubt seen with many of the other groups by now, a timeline woud be adequate in the history section (this also helps to break the text up and help us get a "break" from large blocks of text!)
* Epidemiology section is short but sweet - all the required information is there and summarised well. Perhaps mention the rate of mortality? (although this may be obvious)
* The student-drawn image in the aetiology section doesn't have your own copyright notice, so this should be added to the description. There also might be more to write in this section, but only if you wish to seek out the information. Diagrams can be helpful in summarising excessively detailed material.
* Pathogenesis simply needs to be longer; a lot can be written on this section and there should also be the use of diagrams throughout. Explain why the pathogenesis of DMD is so destructive; it has more than just the function of securing the sarcolemma to the cytoskeleton and is also present in other parts of the body, so make sure you explore this completely! :) (for example, dystrophin which is affected also is found in different areas of the body which may help explain some of the other symptoms of DMD).
* General signs and symptoms could have a diagram to assist in the signs and symptoms.
* Clinical manifestations and complications could have more written and explaining some of the other symptoms that aren't purely based upon the muscle damage observed in DMD.
* Diagnosis needs to have more written, especially images regarding the methods of imaging and therapy.
* Treatment; and Current and Future Prospects are different sections and shouldn't be integrated. Think carefully about the implications that current and future directions of research will have on this disease - they are huge! Try to write more and make an individual section on current and future prospectives of research for DMD; as you know from your research so far, DMD is a very important disease requiring a lot of research.
* Glossary is incomplete; References have a lot of repeats, but these are problems that are common to almost all projects.
* Generally, you just need to find better ways of altering the information in your project. Try to add tables and images to help break up the information and make sure you've discussed all the sections in the guidelines for the project properly. Keep at it! :) There are also some obvious typos ('''&&&''')?
--[[User:Z3288827|Leonard Tiong]] 22:29, 28 September 2011 (EST)

'''Group 10:'''

•History might work better in a timeline, just to break up the text as the beginning of the page looks a little overwhelming with text.

•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template for all of the uploaded images.

•The different sections seem to be a little inconsistent, where a few of the sections such as diagnosis and treatment seem a little vague. These sections could be expanded on to give the reader a more comprehensive knowledge of what is involved, especially seeing as the diagnosis section only has one reference.

•Some typos in the smooth muscle section - ‘&&&’

•A lot of the references are repeated multiple times – this should be fixed up so that each reference only appears once. And also not all the references seem to be formatted correctly.

•Glossary is incomplete

•Overall, good use of subheadings though some of the sections need to be expanded and a few more images are needed to add a better balance to the page. Good work so far.

--[[User:Z3332183|z3332183]] 21:33, 28 September 2011 (EST)

'''Group 10'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main points are there. Content is decent in some places and lacking in others. Fixing up problematic areas would be good.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
Maybe include a time-line in history?'''
General Signs and Symptoms of Duchenne’s Muscular Dystrophy section is very poor. Getting information from an insurance website is not actual research. please consider re-doing this section with sources cited from a peer-reviewed paper. Signs and symptoms should go with diagnosis as it is part of making a diagnosis. why are there ampersands in Smooth muscle section?

'''*Content is correctly cited and referenced.'''
Fix up references, some are simply links and they repeat.

'''*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 is drawn well, explanation could do with a bit more work though. File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg needs proper citation, also there isn't many images. Try including more images.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Not as much information as i was expecting and references is not as extensive as other pages - but good in-text citation (with the exception of some places such as diagnosis and Respiratory problems), it shows that the information has come from somewhere. Information from an insurance website is not evidence of extensive research so try to fix it.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
No connection to embryology - try linking genetic defects to problems in the neonate, or even if there is a prenatal test.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Some evidence of developing the wiki page with the guidelines. Will benefit from changing some things.

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

'''Group 10: Peer Assessment'''
* Your page is relatively short overall and could use some more pictures, especially in the first few sections.
* You have forgotten to put a title on you page
* The introduction is good
* You have got quite a bid of text in the history section, may be you can make a bid lighter with a time line?
* Epidemiology is nice to read and relevant
* Signs and symptoms belong into the clinical manifestation section
* Diagnostics could be more in detail
* The green and blue in the table is a bid too much colour all on a sudden. May be you can have some more colour overall or do the table in just one colour?
* It would be great to have more terms in the glossary
* I would put the diagnosis section right after pathogenesis
* Overall you have got good information on your page. May be you can work on the overall structure and some references. --z3279511 17:15, 28 September 2011 (EST)

'''Group 10'''

*Introduction: well done

*History: lots of information, some parts have no references, subheadings and a time line would be advantageous

*Epidemiology: good contend

*Aetiology: the contend seems fine, but more structure would be good

*Pathogenesis: looks good

*Signs and symptoms: that’s more like a list that a section, maybe combine it with manifestations

*Manifestations: well done, except for smooth muscle- seems incomplete?

*Diagnosis: you could add more information and details

*Treatment: the heading seems inappropriate, separate treatment and research, the contend could be more explained

*Glossary: is incomplete

*More images would be nice
--[[User:Z3387190|Z3387190]] 14:28, 28 September 2011 (EST)

'''Group 10'''

*Very poor image/text ratio – you need more images to break up the text
*Good intro
*History would work better in a timeline- you also mention nothing after the 1800s, more recent findings need to be included
*An image would be nice for pathogenesis to help the reader follow
*Not sure why you have made signs and symptoms a different heading to clinical manifestation- these could be combined
*Diagnosis is very brief and needs to be extended
*Glossary needs to be added to
*Maybe add a current research heading

===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.

--Z3389806 07:04, 27 September 2011 (EST)

'''Group 10 Peer assessment'''
*Heading order needs to re-arranged and done properly with diagnosis above before signs and symptoms.
*Introduction done sort of well needs to integrate image as an example of the myofibres.
*History rather bulky with too much text and no image, image of the founder would be fine. Also no time line present of DM needs to be added
*Epidemiology seems rather empty, images would benefit this section also more stats, further expansion of sub headings would also do well for this section
*Genetics aetiology needs to be expanded where seems to be cramped, though usage of image needs to be noted
*Pathogenesis needs images and further information
*Signs and symptoms needs to be expanded and image of some signs or tables
*Clinical manifestation done well with image and further sub-headings
*Diagnosis requires more attention with further methods of detection of DM
*Treatment is well done with the usage of the table
*Glossary needs to further expanded also linked to the pages so easy to follow the page
*References are not complete with links and repeats of the references
z3332250 23:59, 26 September 2011 (EST)

'''Group 10 Critique'''

#• The introduction was very good. Good use of images to give it a little decoration!
#• History is good
#• Epidemiology is good, however if possible try and make it longer/ include more information
#• The Genetics section is a bit too short. Add more information. Good hand drawn image!
#• Pathogenesis is a little short. Needs more information
#• Signs and Symptoms is good
#• Clinical manifestations is ok
#• Diagnosis, treatment and glossary are all well written. These sections should not require any change

--[[User:Z3289991|Robert Klein]] 16:27, 26 September 2011 (EST)

Group 10 ''Duchenne Muscular Dystrophy''
*The first paragraph of the introduction has no reference.
*The paragraphs in history are quite long, often with grammar mistakes, incorrect punctuations and many of the ideas within a sentence separated by a ''-''. For example the second last paragraph within history.
*The history is too verbose, a timeline with bullet points will look better
*Aetiology is quite concise and informative however gramatical errors are a distraction. For example ''There a multiple forms of dystrophin''. It might be a good idea to proofread the page.
*Well done with the student drawn image
*'Pathogenesis' is again well written however an image might have given it a balance between the text in the section and the pictures or tables
*The future therapies table is a little confusing, you might want to add more columns and define the therapy, and then discuss what the challenges and findings are and at the end column finish off with what the implication might be if the research is to be completed successfully. At the moment you have discussed all that in one big paragraph and the way the descriptions start, it sounds like there is no background to the description, just a little abrupt.
*The glossary is very short and you should include terms like de novo mutation.
*The existing definitions are unclear and incomplete

''Duchenne Muscular Dystrophy''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topics

Group 10-
* Need more images to break up the text
* The introduction was really easy to read and had relevant information in it
* History should be in bullet point form to make it easier to access or at least have the dates in BOLD
* Does the history include dates after the 1800s? or did all research stop then?
* Epidemiology was good. Had all the relevant info
* Pathogenesis would benefit an image or a diagram
* Signs and symptoms could be put with clinical manifestations.
* What is the point of the ‘&&&’? in clinical manifestations and complications?
* Diagnosis could be expanded upon to explain how and why these methods work
* Treatment could also be expanded on. A list of drugs doesn’t explain much
* There is not current/future research section
* This is a good start to the project but more research needs to be done

'''Group 10'''
* The structure and use of headings and subheadings is good, make sure you title your page.
* Good info very informative and it gives a good overview to DMD.
* HIstory has a lot of text could you use a timeline here?
* i think a picture of the pathogenesis would improve this section.
* Has your group look at the CNS and cognitive function of DMD boys its a controversial area as many people have different attitudes towards this but Dr Stewart Head a UNSW lecture actually studies DMD and is very informative in the area and recently published a article in the journal Brain.
* The CNS is highly affected by the lack of dystrophin as well as GABA receptors. I think this area is very import to consider as it highly affects the boys at school.
* Could you add some pictures to your page or break it up with the use of more tables as it a lot of text in comparison to pictures and tables.
* Make sure your reference list is not doubled.
* Ensure all your pictures are referenced properly.
* Student image is present.
* This is a good start.

'''Group 10 Assessment'''
*The history is a bit wordy… Maybe consider consolidating the information into a table format for ease of reading. Could also use a picture to add to it.
*The Epidemiology section could also use a picture and maybe some more information, if possible.
*Point vs Frameshift mutation jpg: Good drawing, but in the last portion of the picture the product is labeled as a ‘tunicated protein product.’ Isn’t it supposed to be a ‘truncated’ product?
*The Signs and Symptoms section could use some formatting; it just looks rather dull currently. Maybe a chart or add in a picture?
*Smooth muscle section: Why are there random &&&’s?
*The top portion of the Treatment section could use some more referencing… Good chart though! Only thing I’d suggest for it is to add some pictures if possible?
*Glossary term list is rather short… Are you sure there’s nothing else that needs defining for clarification for the reader?
*It would be a good idea also to have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word 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.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. 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 #...
*Overall, good information is included, just work on referencing things and the overall structure and you should be good!
--[[User:Z3391078|Z3391078]] 17:00, 27 September 2011 (EST)

'''Peer Assessment: Group Project 10'''
*I think the section heading of introduction accompanied by the question what is muscular dystrophy, works really well.
*It might be good to include an image in the history section to break up the text, such as of someone prominently involved with the disease findings.
*The information in clinical manifestations and complications is well written. There needs to be some fix to the formatting under the smooth muscle heading where some '&'s have been repeated.
*The current and future prospects section is great. You have summarised what
*Some of the definitions of words in the glossary need to be completed e.g. atrophy and protease.
*Under the information in some of the images such as the fisrt one, 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.
*An additional section of external links might provide information for those wanting to know more.
--[[User:Z3217345|z3217345]] 10:50, 28 September 2011 (EST)

'''Peer Review'''

* struture and format done well
* easy to read

--[[User:Z3060621|z3060621]] 21:58, 28 September 2011 (EST)

*'''Intro''': Fine
*'''History''': Nicely detailed, but missing a timeline.
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.
*'''Pathogenesis''': Content seems fine, could do with a figure?
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?
*'''Clinical manifestations and complications''': Fine
*'''Diagnosis''': Clinical Diagnosis is a bit short?
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.
*'''Glossary''': Poor. More terms need explanations.
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.

==Discussion==

'''GROUP 10!'''

'''To make everything easier to follow, we have agreed to write any updates, info, discussion etc at the BOTTOM of this page, it will just stop us having to keep going up and down and wasting time trying to find the information we want.'''

----

Hey Everyone,

So Mark went through each group today during the lab and the webpages and discussed where we should be up to. By next week, he expects the subheadings & some content to be up and running. He also recommended that we should have some more research going on in our discussion page. E.g. Research articles links, interesting sites etc.

Topics have been allocated so please begin your research and typing up some content. We can further divide our headings if necessary, take a look at some other groups, they have some pretty good ideas. Mark will be checking this next week during our lab. He'll be coming around to each of us.

So hopefully see you all next week !

--[[User:Z3332327|z3332327]] 12:53, 25 August 2011 (EST)

==Subheadings for assignment==

Intro what is DMD

History/timeline

Genetic component

Why is it an abnormality - Symptoms effect

Diagnosis, future/current prospect (treatments?)

2 case studies

Glossary of terms

====Post online any preferences you may have in terms of the topics you wish to research and by Sunday we will allocate sub topics====
--[[User:Z3332629|z3332629]] 13:09, 18 August 2011 (EST)

Okay hey guys just to get the discussion going, umm I don't mind doing the first 2 on the list. And the "Why is it an abnormality - Symptoms effect" sounds pretty interesting as well.
What are your preferences?? :)

--[[User:Z3330313|z3330313]] 14:55, 23 August 2011 (EST)

Hey Everyone, Im happy to do the diagnosis/current/future prospects point and a case study.

--z3332327 15:36

Talk:2011 Group Project 10

2011-10-05T01:32:31Z

Z3332629: /* Group Discussion Week 10-12 */

[[2011_Group_Project_10|'''Group 10''']]: [[User:z3332327]] | [[User:z3332629]] | [[User:z3332824]] | [[User:z3330313]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_10_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_10_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Group Discussion Week 10-12==
Nice drawings!

Just some videos for my section, just placing them somewhere so i know where they are :)
http://www.youtube.com/watch?v=dOhMLZCvb50
http://www.youtube.com/watch?v=GWachrbiU58
--[[User:Z3332629|Ashleigh Pontifex]] 12:01, 3 October 2011 (EST)

Joanna : http://emedicine.medscape.com/article/1173204-overview#a0199
Great over view for epidemiology, perhaps a table or some stats would be great in this section :)

- http://www.ncbi.nlm.nih.gov/pubmed/19834452 -

hey guys I changed some of the stuff on history, if you think its too much info let me know!
I deleted alot of information, and I just can't bring myself to delete more because the stuff remaining now seems so relevant. But let me know what you think!
And what do you guys think about putting an image of the Duchenne dude in the history? do you reckon that'll make that section too long?
--[[User:Z3330313|Joanna Pak]] 02:56, 5 October 2011 (EST)

Hey Jo! I had a read of the history section and it sounds good. Just an idea, where you've listed Duchenne's definition of the disease, would you prefer if those were added under DIAGNOSIS- clinical or SIGNS AND SYMPTOMS? And we could add an internal link? Maybe that'll cut down your section a bit?

Just a suggested change, i just rearranged the words around a little, dont have to. =)

*'Meryon conducted several necropsies and found intact spinal cords which indicated the disease was not from the nervous system.'

Minor edit

*'Further microscopic examination of the muscle showed that the muscular fibres '''broke''' down and converted into granular, fatty matter.'
--[[User:Z3332327|Lisa Xiao]] 11:38, 5 October 2011 (EST)

Hey Jo its Ash!! It looks heaps better, more straight forward and the table inclusion is great :)
Is everyone happy with my student drawn image in the introduction? it is appropriate in this section?
Also my table in the genetics section???

And lastly, ive notice that Rhiannon has hyperlinked all glossary terms in her section, is everyone happy to carry that across all areas???
--[[User:Z3332629|z3332629]] 12:29, 5 October 2011 (EST)

Actually one last suggestion jo, maybe change the table colour to teal so that the colour schemme consistent throughout the page :)
--[[User:Z3332629|Ashleigh Pontifex]] 12:32, 5 October 2011 (EST)

==Peer Review==

'''Peer Review'''
* The introduction is detailed but a bit “in your face.” It may even be a bit too detailed, going into the pathogenesis of the disorder.
* History is very detailed, perhaps slightly story-like but enjoyable nonetheless. Could use a picture or two. Sufficiently referenced.
* Epidemiology is very thorough and well referenced.
* The tone of Aetiology/Genetics is a bit conversational; needs to be more detached. Good use of picture, although the legend to it is not in the correct format.
* Pathogenesis could use more references, especially for the last paragraph. Could potentially use some pictures to make clearer the specific structures discussed in the text (although they are elaborated on in the glossary).
* All the signs listed in Clinical Manifestations etc are decently elaborated upon, and the section is well-referenced. Smooth Muscle has strange “&&&” signs though. Respiratory Problems needs cleaning, notably with the line “[Effects of high CO2 and the problems it can cause]”
* Diagnosis is nicely laid out, although more references are needed.
* Treatment is decently set up and clearly explains each of the treatment plans.
--[[User:Z3290689|z3290689]] 14:44, 29 September 2011 (EST)

Group 10:
This project looks fine but it seems a little short? You want to expand the content in sections.
History is well researched but it’s quite long. You can add more images (add the reference in the description) and make the dates in Bald.
There are some spelling errors and extra signs that are not related to the work such as &&&.
Some of the references are repeated and others need to be reformatted.
Overall, Great effort.

--[[User:Z3284061|z3284061]] 11:51, 29 September 2011 (EST)

'''Peer Assessment'''
*introduction is well written and descriptive. Good use of image to make it look appealing. No references in the first paragraph.
*History section is too long, text heavy and a bit boring. Try to summarize the details on a timeline. You can include an image e.g. of Dr Edward Meryon if possible.
*Epidemiology and aetiology; well written. The image in the aetiology needs to be linked with the text.
*Pathogenesis; too brief. Needs more information and explanation of the disease process. Include an image or flowchart to compliment the text.
*Signs and symptoms; needs to be expanded a bit more. I suggest using a table to present the information that just as dot points. Same goes for the diagnosis section, which also needs to be expanded. Try and use more images, tables, graphs etc to break up the texts and make the page look more appealing.
*I suggest hyperlinking words in the page with the glossary to make the page more user friendly.
*Like the use of table in the "current and future prospects". It's better to present information like this rather than in big long paragraphs.
*The glossary needs to be expanded more.
--[[User:Z3291622|Z3291622]] 11:07, 29 September 2011 (EST)

'''''Duchenne (Group 10) Peer Review:'''''

Could you include “Duchenne Muscular Dystrophy” as the first subheading so that the reader knows exactly what the disease is at first glance? Just a suggestion.

Introduction: Topic well introduced and good use of image. Image, however, is lacking a student template.

History: Very extensive. Possibly include an image to break up the text.

Epidemiology: Sound. Some sentences are not worded/ structured properly.

Aetiology – Genetics: Information is good. Impressive self-drawn image. Well done.

Pathogenesis: An image would definitely work well in this section. Information is otherwise good, however possibly have a greater focus on the genetic component?

General Signs and Symptoms of Duchenne’s Muscular Dystrophy: This section seems too brief. Elaborate further.

Clinical manifestations and complications: Information is good. Possibly more detail for the subheading “smooth muscle.” Image lacks a student template. “&&&” – what is this? Many references in this section which is good to see!

Diagnosis: Could be elaborated further.

Treatment: Current and Future Prospects: The first paragraph lacks referencing. Possibly include an image? Table is a good idea, however colours chosen are slightly off-putting.
Glossary of terms: Could be more extensive. Not complete.

Well done. --[[User:Z3290808|z3290808]] 10:50, 29 September 2011 (EST)

Duchenne Muscular Dystrophy – Group 10

* Excellent introduction and good use of image. Is there some referencing missing in the first few sentences? Some formatting should be done on the image either to make it within the intro section or more shared between the history sections. Looks a little out of place.
* History is well written but very text heavy. Use of a timeline good improve this section and make it more succinct. Also I thought an image could be good.
* Epidemiology seems to cover all necessary information and is well referenced. Maybe an image or graph here could be good.
* I like the student drawn image in the etiology section, maybe the sizing could be improved though? Also some a more detailed description of what the image shows would also be good.
* Pathogenesis section is very informative. Maybe the pathophysiology could be covered in this section as well? Image could be added.
* General signs and symptoms would perhaps look better in a table. Otherwise it is quite brief, maybe some more elaboration aswell.
* I think diagnosis looks incomplete. Not much detail is given about how the diagnosis actually works. Very little referencing. Addition of an image would improve this section.
* Treatment looks great. I like how you have included current and future prospects. Just wondering if there was room for a heading for current and future research, as Im sure there is more research being undertaken than just in the area of treatment. This could make this project more informative, and perhaps could be another heading.
* Glossary needs improving.
* Some issues with referencing such as multiple entries for the same article and some issues with web page referencing.

--[[User:Z3288196|Z3288196]] 10:48, 29 September 2011 (EST)

'''GROUP 10: Duchenne Muscular Dystrophy'''
*Title of the whole page should just be Duchenne Muscular Dystrophy, not Introduction...
*The intro is very descriptive and comprehensive
*Image in intro needs proper referencing
*consider rephrasing this sentence "In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction"
*History has good info, but could this be better formatted in a table? this section is text heavy and could maybe use an image, it also could be extended into more recent years
*Epidemiology is summarised well and contains good statistics
*I feel that Aetiology - Genetics section has good info, easy to understand and informative but maybe it could be researched a little more
*General Signs and Symptoms of Duchenne’s Muscular Dystrophy section needs a lot more work, the list of symptoms i don't feel is enough, more expansion on these is needed. An image would improve this section too
*"diarrhoea&&&." -this needs to be fixed

Overall:
*More images are needed to break up the text
*glossary needs a bit more work, consider linking glossary words to text
*I feel that the page overall needs some more work, some sections are lacking content
*Proof reading to fix grammar and sentence structure

--[[User:Z3331556|z3331556]] 10:44, 29 September 2011 (EST)

'''Peer Review'''

This wiki still feels like what Mark Hill mentioned earlier, like a backbone for content to be built upon. The foundations are there, but still very incomplete. Comparing the sections, some have done a lot of effort, others not so much, and it is very visible.

:*Should start the wiki with this code:

<wiki>=Duchenne Muscular Dystrophy (DMD)= </wiki>

then

<wiki>==Introduction == </wiki>

:*History is far too text heavy and it shouldn't be like that, as this makes it a chore to read. A timeline would be better suited and summarise into the timeline.

:*Should be more student drawn images, since there's only one. If getting pictures is hard to find, then draw your own.

:*The one student drawn image is not referenced correctly, needs the disclaimer info.

:*Diagnosis needs to be expanded. There is 300+ articles, there has to be more info or an image to be found.

:*Pathogenesis needs to be expanded, maybe an image.

:*Signs and symptoms need more referencing. Also, just leave the title as Signs and Symptons.

:*Treatment needs to be expanded on. It isn't any good just listing drugs into a table.

:*Split the Treatment to include Managment and give a separate section for Current Research.

:*Glossary is incomplete.

--[[User:Z3293267|z3293267]] 10:37, 29 September 2011 (EST)

Group 10:

Clear and conscise but still needs more work breaking up the long slabs of writing. Perhaps more subheadings esp. in the first sections.

More pics are needed to break up the work.

Treatment includes a good table.

Glossary needs a bit of work and expanding on the explanations.

References needs to be fixed as there is duplications of references.

z3332178 =]

Peer Review

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*History section would benefit by placing the information into a timeline rather than paragraphs as it is a bit hard to follow.

:*Epidemiology section could be expanded and written in more flowing way rather than long sentences.

:*Needs more images, lots of large blocks of text. And images need to be formatted into the text as formatting currently looks awkward.

:*Further Research could be added, for example papers or groups that are researching as currently it is just being referred to.

:*Glossary could be expanded.

:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed. Also perhaps research from MORE sources is necessary as there is only a few when you cut out the double references.

--[[User:Z3217043|z3217043]] 10:02, 29 September 2011 (EST)

Group 10 Peer Review

*Headings are well organised and structured
*Too much text in history section-a table or image would be good
*Information is there however images/graphs/tables would help break up large chunks of text
*Diagnosis seems brief-perhaps merge with treatment section?
*Signs and symptoms could be expanded
*Great table in treatment
*Needs to be proof read-grammar and spelling mistakes
*Double referencing
*Glossary needs to be extended
--[[User:Z3308965|Fleur McGregor]] 09:54, 29 September 2011 (EST)

Group 10

*Introduction – Great intro, well referenced apart from the first paragraph.
*History has a lot of text, a timeline could work well here and also an image if possible just to break up the text.
*Epidemiology – well referenced and structured, text could be broken up but that’s nothing major as it’s a small section.
*Aetiology – A link between the image provided and the text would work well, and also the image could be formatted on the right of the page, to add to continuity and flow as other images are located on the right.
*Signs and Symptoms – Needs to be more information here, a description of each symptom and maybe its direct causes.
*Clinical manifestations – need a link between the image and the text, other than that it is well referenced and easy to understand.
*Treatment – table formatting is great and information is helpful
*Glossary – needs to include more terms form the page.
*There’s some doubling up in the reference section that needs to be fixed, other than that good job.

--[[User:Z3331469|z3331469]] 08:25, 29 September 2011 (EST)

peer review:

*Intro: One of the very few groups to use an image of the disease in the intro, well done! Like how you have referred to Duchenne’s as DMD in brackets initial heading to avoid confusion.

*History: A lot of writing, no techniques to break it up, which will basically bore your reader. Use a timeline perhaps.

*Epidemiology: Subheading will benefit this segment.

*Aetiology: The image could use some colour, but it is still very well done. It would be worthy to refer to the drawing as your explaining the genetics, just to bring them together.

*Pathogenesis: Very brief, not very informative and lacking subheadings or an image. Hopefully this will be fixed.

*Signs and Symptoms:Poorly done. Dot-points are a good way to initiate the writing but not appropriate as a final copy. Needs more description and research.

*Clinical manifestations:
The image used is excellent but needs more explanation.

*Diagnosis:Very short, looks incomplete and there’s only one reference for the entire section.

*Treatment: Well done, I like the colour and the table structure, makes it much easier to understand.

*Glossary: Incomplete, much more terminology has been used.

*References: Double referencing is a big problem here.

*Text:image ratio: could use more images.

--[[User:Z3290270|z3290270]] 02:16, 29 September 2011 (EST)

*history should be broken up with dates on side or within a table.
*how about a short summary table to use for epidemiology
*no picture of Guillaume Benjamin Amand Duchenne?
*no copyright permission for the drawn image in genetics.
*pathogenesis seems very small for a section that is very important.
*describe how the signs and symptoms impact on patients to show the significance of the disease.
*diagnosis needs a lot of work, this section is very important. also very little references in this section.
*not enough pictures to accompany the text
*very short glossary
*multiple references of same articles
--[[User:Z3291423|Jasjit Walia]] 00:17, 29 September 2011 (EST)

'''Peer Review for Group 10'''

*The introduction was well written, however the picture in it is not referenced as instructed. Please fix that then your intro is perfect.
*In the history section, the first sentence is oddly placed, even though it’s informative, please put that somewhere where it will flow in the paragraph.
*The history is verbose, please re write so it’s easier to follow.
*Epidemiology needs to be reevaluated as some sentences are not constructed properly
*Etiology has sound information but the paragraphs are not structured so it flows. It also seems repetitive.
*The picture in the etiology can have its caption better structured
*Pathogenesis should include some component of genetics to explain how the abnormalities bring about the pathogenesis in the genetics level.
*Explanation of how the signs and symptoms comes along from the dystrophy should be explained
*The image of the spine is not completely referenced as url of the image and the page must also be given
*Information under ‘respiratory problems’ and smooth muscle needs some reviewed as it includes words there that shouldn’t be present
*The diagnosis section could be expanded upon so it includes more information on the details of how it is detected, and images should complement the tools to diagnose the condition.
*An introduction to the table should be given. Having the table there by itself doesn’t look good.
*Further explanation should be made on the type of physical activity that would be made for therapy
*Glossary should be expanded
*There is repetitive referencing; it should be reformatted to fit in the way multiple references is made.
*You need much more pics as without the pics the page looks word heavy.

--[[User:Z3291317|Z3291317]] 23:57, 28 September 2011 (EST)

'''Group 10'''

Introduction: Good introduction. The picture could be a bit bigger. Also, a picture of the chromosome would be great.

History and epidemiology: Both sections are clear and flow well. Pictures are needed to break up the text though.

Genetics: The image is great and the text is well written.

Pathogenesis: The pathogenesis is well explained. Again, pictures would be good in this section to improve it.

Clinical manifestations: Good section. Clear, easy to understand.

Diagnosis: This section might need some more detail added. You could explain how each of the diagnostic tests work

Current and future treatment: This section is worded well but looks a little bit disjointed. I think it would be better having it either all in text or all in the table. --[[User:Z3291324|z3291324]] 23:27, 28 September 2011 (EST)

'''Group 10 Peer Review'''
* Interesting introduction, with a good amount of information. The history is also quite well outlined, although as you have no doubt seen with many of the other groups by now, a timeline woud be adequate in the history section (this also helps to break the text up and help us get a "break" from large blocks of text!)
* Epidemiology section is short but sweet - all the required information is there and summarised well. Perhaps mention the rate of mortality? (although this may be obvious)
* The student-drawn image in the aetiology section doesn't have your own copyright notice, so this should be added to the description. There also might be more to write in this section, but only if you wish to seek out the information. Diagrams can be helpful in summarising excessively detailed material.
* Pathogenesis simply needs to be longer; a lot can be written on this section and there should also be the use of diagrams throughout. Explain why the pathogenesis of DMD is so destructive; it has more than just the function of securing the sarcolemma to the cytoskeleton and is also present in other parts of the body, so make sure you explore this completely! :) (for example, dystrophin which is affected also is found in different areas of the body which may help explain some of the other symptoms of DMD).
* General signs and symptoms could have a diagram to assist in the signs and symptoms.
* Clinical manifestations and complications could have more written and explaining some of the other symptoms that aren't purely based upon the muscle damage observed in DMD.
* Diagnosis needs to have more written, especially images regarding the methods of imaging and therapy.
* Treatment; and Current and Future Prospects are different sections and shouldn't be integrated. Think carefully about the implications that current and future directions of research will have on this disease - they are huge! Try to write more and make an individual section on current and future prospectives of research for DMD; as you know from your research so far, DMD is a very important disease requiring a lot of research.
* Glossary is incomplete; References have a lot of repeats, but these are problems that are common to almost all projects.
* Generally, you just need to find better ways of altering the information in your project. Try to add tables and images to help break up the information and make sure you've discussed all the sections in the guidelines for the project properly. Keep at it! :) There are also some obvious typos ('''&&&''')?
--[[User:Z3288827|Leonard Tiong]] 22:29, 28 September 2011 (EST)

'''Group 10:'''

•History might work better in a timeline, just to break up the text as the beginning of the page looks a little overwhelming with text.

•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template for all of the uploaded images.

•The different sections seem to be a little inconsistent, where a few of the sections such as diagnosis and treatment seem a little vague. These sections could be expanded on to give the reader a more comprehensive knowledge of what is involved, especially seeing as the diagnosis section only has one reference.

•Some typos in the smooth muscle section - ‘&&&’

•A lot of the references are repeated multiple times – this should be fixed up so that each reference only appears once. And also not all the references seem to be formatted correctly.

•Glossary is incomplete

•Overall, good use of subheadings though some of the sections need to be expanded and a few more images are needed to add a better balance to the page. Good work so far.

--[[User:Z3332183|z3332183]] 21:33, 28 September 2011 (EST)

'''Group 10'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main points are there. Content is decent in some places and lacking in others. Fixing up problematic areas would be good.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
Maybe include a time-line in history?'''
General Signs and Symptoms of Duchenne’s Muscular Dystrophy section is very poor. Getting information from an insurance website is not actual research. please consider re-doing this section with sources cited from a peer-reviewed paper. Signs and symptoms should go with diagnosis as it is part of making a diagnosis. why are there ampersands in Smooth muscle section?

'''*Content is correctly cited and referenced.'''
Fix up references, some are simply links and they repeat.

'''*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 is drawn well, explanation could do with a bit more work though. File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg needs proper citation, also there isn't many images. Try including more images.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Not as much information as i was expecting and references is not as extensive as other pages - but good in-text citation (with the exception of some places such as diagnosis and Respiratory problems), it shows that the information has come from somewhere. Information from an insurance website is not evidence of extensive research so try to fix it.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
No connection to embryology - try linking genetic defects to problems in the neonate, or even if there is a prenatal test.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Some evidence of developing the wiki page with the guidelines. Will benefit from changing some things.

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

'''Group 10: Peer Assessment'''
* Your page is relatively short overall and could use some more pictures, especially in the first few sections.
* You have forgotten to put a title on you page
* The introduction is good
* You have got quite a bid of text in the history section, may be you can make a bid lighter with a time line?
* Epidemiology is nice to read and relevant
* Signs and symptoms belong into the clinical manifestation section
* Diagnostics could be more in detail
* The green and blue in the table is a bid too much colour all on a sudden. May be you can have some more colour overall or do the table in just one colour?
* It would be great to have more terms in the glossary
* I would put the diagnosis section right after pathogenesis
* Overall you have got good information on your page. May be you can work on the overall structure and some references. --z3279511 17:15, 28 September 2011 (EST)

'''Group 10'''

*Introduction: well done

*History: lots of information, some parts have no references, subheadings and a time line would be advantageous

*Epidemiology: good contend

*Aetiology: the contend seems fine, but more structure would be good

*Pathogenesis: looks good

*Signs and symptoms: that’s more like a list that a section, maybe combine it with manifestations

*Manifestations: well done, except for smooth muscle- seems incomplete?

*Diagnosis: you could add more information and details

*Treatment: the heading seems inappropriate, separate treatment and research, the contend could be more explained

*Glossary: is incomplete

*More images would be nice
--[[User:Z3387190|Z3387190]] 14:28, 28 September 2011 (EST)

'''Group 10'''

*Very poor image/text ratio – you need more images to break up the text
*Good intro
*History would work better in a timeline- you also mention nothing after the 1800s, more recent findings need to be included
*An image would be nice for pathogenesis to help the reader follow
*Not sure why you have made signs and symptoms a different heading to clinical manifestation- these could be combined
*Diagnosis is very brief and needs to be extended
*Glossary needs to be added to
*Maybe add a current research heading

===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.

--Z3389806 07:04, 27 September 2011 (EST)

'''Group 10 Peer assessment'''
*Heading order needs to re-arranged and done properly with diagnosis above before signs and symptoms.
*Introduction done sort of well needs to integrate image as an example of the myofibres.
*History rather bulky with too much text and no image, image of the founder would be fine. Also no time line present of DM needs to be added
*Epidemiology seems rather empty, images would benefit this section also more stats, further expansion of sub headings would also do well for this section
*Genetics aetiology needs to be expanded where seems to be cramped, though usage of image needs to be noted
*Pathogenesis needs images and further information
*Signs and symptoms needs to be expanded and image of some signs or tables
*Clinical manifestation done well with image and further sub-headings
*Diagnosis requires more attention with further methods of detection of DM
*Treatment is well done with the usage of the table
*Glossary needs to further expanded also linked to the pages so easy to follow the page
*References are not complete with links and repeats of the references
z3332250 23:59, 26 September 2011 (EST)

'''Group 10 Critique'''

#• The introduction was very good. Good use of images to give it a little decoration!
#• History is good
#• Epidemiology is good, however if possible try and make it longer/ include more information
#• The Genetics section is a bit too short. Add more information. Good hand drawn image!
#• Pathogenesis is a little short. Needs more information
#• Signs and Symptoms is good
#• Clinical manifestations is ok
#• Diagnosis, treatment and glossary are all well written. These sections should not require any change

--[[User:Z3289991|Robert Klein]] 16:27, 26 September 2011 (EST)

Group 10 ''Duchenne Muscular Dystrophy''
*The first paragraph of the introduction has no reference.
*The paragraphs in history are quite long, often with grammar mistakes, incorrect punctuations and many of the ideas within a sentence separated by a ''-''. For example the second last paragraph within history.
*The history is too verbose, a timeline with bullet points will look better
*Aetiology is quite concise and informative however gramatical errors are a distraction. For example ''There a multiple forms of dystrophin''. It might be a good idea to proofread the page.
*Well done with the student drawn image
*'Pathogenesis' is again well written however an image might have given it a balance between the text in the section and the pictures or tables
*The future therapies table is a little confusing, you might want to add more columns and define the therapy, and then discuss what the challenges and findings are and at the end column finish off with what the implication might be if the research is to be completed successfully. At the moment you have discussed all that in one big paragraph and the way the descriptions start, it sounds like there is no background to the description, just a little abrupt.
*The glossary is very short and you should include terms like de novo mutation.
*The existing definitions are unclear and incomplete

''Duchenne Muscular Dystrophy''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topics

Group 10-
* Need more images to break up the text
* The introduction was really easy to read and had relevant information in it
* History should be in bullet point form to make it easier to access or at least have the dates in BOLD
* Does the history include dates after the 1800s? or did all research stop then?
* Epidemiology was good. Had all the relevant info
* Pathogenesis would benefit an image or a diagram
* Signs and symptoms could be put with clinical manifestations.
* What is the point of the ‘&&&’? in clinical manifestations and complications?
* Diagnosis could be expanded upon to explain how and why these methods work
* Treatment could also be expanded on. A list of drugs doesn’t explain much
* There is not current/future research section
* This is a good start to the project but more research needs to be done

'''Group 10'''
* The structure and use of headings and subheadings is good, make sure you title your page.
* Good info very informative and it gives a good overview to DMD.
* HIstory has a lot of text could you use a timeline here?
* i think a picture of the pathogenesis would improve this section.
* Has your group look at the CNS and cognitive function of DMD boys its a controversial area as many people have different attitudes towards this but Dr Stewart Head a UNSW lecture actually studies DMD and is very informative in the area and recently published a article in the journal Brain.
* The CNS is highly affected by the lack of dystrophin as well as GABA receptors. I think this area is very import to consider as it highly affects the boys at school.
* Could you add some pictures to your page or break it up with the use of more tables as it a lot of text in comparison to pictures and tables.
* Make sure your reference list is not doubled.
* Ensure all your pictures are referenced properly.
* Student image is present.
* This is a good start.

'''Group 10 Assessment'''
*The history is a bit wordy… Maybe consider consolidating the information into a table format for ease of reading. Could also use a picture to add to it.
*The Epidemiology section could also use a picture and maybe some more information, if possible.
*Point vs Frameshift mutation jpg: Good drawing, but in the last portion of the picture the product is labeled as a ‘tunicated protein product.’ Isn’t it supposed to be a ‘truncated’ product?
*The Signs and Symptoms section could use some formatting; it just looks rather dull currently. Maybe a chart or add in a picture?
*Smooth muscle section: Why are there random &&&’s?
*The top portion of the Treatment section could use some more referencing… Good chart though! Only thing I’d suggest for it is to add some pictures if possible?
*Glossary term list is rather short… Are you sure there’s nothing else that needs defining for clarification for the reader?
*It would be a good idea also to have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word 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.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. 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 #...
*Overall, good information is included, just work on referencing things and the overall structure and you should be good!
--[[User:Z3391078|Z3391078]] 17:00, 27 September 2011 (EST)

'''Peer Assessment: Group Project 10'''
*I think the section heading of introduction accompanied by the question what is muscular dystrophy, works really well.
*It might be good to include an image in the history section to break up the text, such as of someone prominently involved with the disease findings.
*The information in clinical manifestations and complications is well written. There needs to be some fix to the formatting under the smooth muscle heading where some '&'s have been repeated.
*The current and future prospects section is great. You have summarised what
*Some of the definitions of words in the glossary need to be completed e.g. atrophy and protease.
*Under the information in some of the images such as the fisrt one, 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.
*An additional section of external links might provide information for those wanting to know more.
--[[User:Z3217345|z3217345]] 10:50, 28 September 2011 (EST)

'''Peer Review'''

* struture and format done well
* easy to read

--[[User:Z3060621|z3060621]] 21:58, 28 September 2011 (EST)

*'''Intro''': Fine
*'''History''': Nicely detailed, but missing a timeline.
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.
*'''Pathogenesis''': Content seems fine, could do with a figure?
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?
*'''Clinical manifestations and complications''': Fine
*'''Diagnosis''': Clinical Diagnosis is a bit short?
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.
*'''Glossary''': Poor. More terms need explanations.
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.

==Discussion==

'''GROUP 10!'''

'''To make everything easier to follow, we have agreed to write any updates, info, discussion etc at the BOTTOM of this page, it will just stop us having to keep going up and down and wasting time trying to find the information we want.'''

----

Hey Everyone,

So Mark went through each group today during the lab and the webpages and discussed where we should be up to. By next week, he expects the subheadings & some content to be up and running. He also recommended that we should have some more research going on in our discussion page. E.g. Research articles links, interesting sites etc.

Topics have been allocated so please begin your research and typing up some content. We can further divide our headings if necessary, take a look at some other groups, they have some pretty good ideas. Mark will be checking this next week during our lab. He'll be coming around to each of us.

So hopefully see you all next week !

--[[User:Z3332327|z3332327]] 12:53, 25 August 2011 (EST)

==Subheadings for assignment==

Intro what is DMD

History/timeline

Genetic component

Why is it an abnormality - Symptoms effect

Diagnosis, future/current prospect (treatments?)

2 case studies

Glossary of terms

====Post online any preferences you may have in terms of the topics you wish to research and by Sunday we will allocate sub topics====
--[[User:Z3332629|z3332629]] 13:09, 18 August 2011 (EST)

Okay hey guys just to get the discussion going, umm I don't mind doing the first 2 on the list. And the "Why is it an abnormality - Symptoms effect" sounds pretty interesting as well.
What are your preferences?? :)

--[[User:Z3330313|z3330313]] 14:55, 23 August 2011 (EST)

Hey Everyone, Im happy to do the diagnosis/current/future prospects point and a case study.

--z3332327 15:36

Talk:2011 Group Project 10

2011-10-05T01:30:11Z

Z3332629: /* Group Discussion Week 10-12 */

[[2011_Group_Project_10|'''Group 10''']]: [[User:z3332327]] | [[User:z3332629]] | [[User:z3332824]] | [[User:z3330313]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_10_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_10_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Group Discussion Week 10-12==
Nice drawings!

Just some videos for my section, just placing them somewhere so i know where they are :)
http://www.youtube.com/watch?v=dOhMLZCvb50
http://www.youtube.com/watch?v=GWachrbiU58
--[[User:Z3332629|Ashleigh Pontifex]] 12:01, 3 October 2011 (EST)

Joanna : http://emedicine.medscape.com/article/1173204-overview#a0199
Great over view for epidemiology, perhaps a table or some stats would be great in this section :)

- http://www.ncbi.nlm.nih.gov/pubmed/19834452 -

hey guys I changed some of the stuff on history, if you think its too much info let me know!
I deleted alot of information, and I just can't bring myself to delete more because the stuff remaining now seems so relevant. But let me know what you think!
And what do you guys think about putting an image of the Duchenne dude in the history? do you reckon that'll make that section too long?
--[[User:Z3330313|Joanna Pak]] 02:56, 5 October 2011 (EST)

Hey Jo! I had a read of the history section and it sounds good. Just an idea, where you've listed Duchenne's definition of the disease, would you prefer if those were added under DIAGNOSIS- clinical or SIGNS AND SYMPTOMS? And we could add an internal link? Maybe that'll cut down your section a bit?

Just a suggested change, i just rearranged the words around a little, dont have to. =)

*'Meryon conducted several necropsies and found intact spinal cords which indicated the disease was not from the nervous system.'

Minor edit

*'Further microscopic examination of the muscle showed that the muscular fibres '''broke''' down and converted into granular, fatty matter.'
--[[User:Z3332327|Lisa Xiao]] 11:38, 5 October 2011 (EST)

Hey Jo its Ash!! It looks heaps better, more straight forward and the table inclusion is great :)
Is everyone happy with my student drawn image in the introduction? it is appropriate in this section?
Also my table in the genetics section???

And lastly, ive notice that Rhiannon has hyperlinked all glossary terms in her section, is everyone happy to carry that across all areas???
--[[User:Z3332629|z3332629]] 12:29, 5 October 2011 (EST)

==Peer Review==

'''Peer Review'''
* The introduction is detailed but a bit “in your face.” It may even be a bit too detailed, going into the pathogenesis of the disorder.
* History is very detailed, perhaps slightly story-like but enjoyable nonetheless. Could use a picture or two. Sufficiently referenced.
* Epidemiology is very thorough and well referenced.
* The tone of Aetiology/Genetics is a bit conversational; needs to be more detached. Good use of picture, although the legend to it is not in the correct format.
* Pathogenesis could use more references, especially for the last paragraph. Could potentially use some pictures to make clearer the specific structures discussed in the text (although they are elaborated on in the glossary).
* All the signs listed in Clinical Manifestations etc are decently elaborated upon, and the section is well-referenced. Smooth Muscle has strange “&&&” signs though. Respiratory Problems needs cleaning, notably with the line “[Effects of high CO2 and the problems it can cause]”
* Diagnosis is nicely laid out, although more references are needed.
* Treatment is decently set up and clearly explains each of the treatment plans.
--[[User:Z3290689|z3290689]] 14:44, 29 September 2011 (EST)

Group 10:
This project looks fine but it seems a little short? You want to expand the content in sections.
History is well researched but it’s quite long. You can add more images (add the reference in the description) and make the dates in Bald.
There are some spelling errors and extra signs that are not related to the work such as &&&.
Some of the references are repeated and others need to be reformatted.
Overall, Great effort.

--[[User:Z3284061|z3284061]] 11:51, 29 September 2011 (EST)

'''Peer Assessment'''
*introduction is well written and descriptive. Good use of image to make it look appealing. No references in the first paragraph.
*History section is too long, text heavy and a bit boring. Try to summarize the details on a timeline. You can include an image e.g. of Dr Edward Meryon if possible.
*Epidemiology and aetiology; well written. The image in the aetiology needs to be linked with the text.
*Pathogenesis; too brief. Needs more information and explanation of the disease process. Include an image or flowchart to compliment the text.
*Signs and symptoms; needs to be expanded a bit more. I suggest using a table to present the information that just as dot points. Same goes for the diagnosis section, which also needs to be expanded. Try and use more images, tables, graphs etc to break up the texts and make the page look more appealing.
*I suggest hyperlinking words in the page with the glossary to make the page more user friendly.
*Like the use of table in the "current and future prospects". It's better to present information like this rather than in big long paragraphs.
*The glossary needs to be expanded more.
--[[User:Z3291622|Z3291622]] 11:07, 29 September 2011 (EST)

'''''Duchenne (Group 10) Peer Review:'''''

Could you include “Duchenne Muscular Dystrophy” as the first subheading so that the reader knows exactly what the disease is at first glance? Just a suggestion.

Introduction: Topic well introduced and good use of image. Image, however, is lacking a student template.

History: Very extensive. Possibly include an image to break up the text.

Epidemiology: Sound. Some sentences are not worded/ structured properly.

Aetiology – Genetics: Information is good. Impressive self-drawn image. Well done.

Pathogenesis: An image would definitely work well in this section. Information is otherwise good, however possibly have a greater focus on the genetic component?

General Signs and Symptoms of Duchenne’s Muscular Dystrophy: This section seems too brief. Elaborate further.

Clinical manifestations and complications: Information is good. Possibly more detail for the subheading “smooth muscle.” Image lacks a student template. “&&&” – what is this? Many references in this section which is good to see!

Diagnosis: Could be elaborated further.

Treatment: Current and Future Prospects: The first paragraph lacks referencing. Possibly include an image? Table is a good idea, however colours chosen are slightly off-putting.
Glossary of terms: Could be more extensive. Not complete.

Well done. --[[User:Z3290808|z3290808]] 10:50, 29 September 2011 (EST)

Duchenne Muscular Dystrophy – Group 10

* Excellent introduction and good use of image. Is there some referencing missing in the first few sentences? Some formatting should be done on the image either to make it within the intro section or more shared between the history sections. Looks a little out of place.
* History is well written but very text heavy. Use of a timeline good improve this section and make it more succinct. Also I thought an image could be good.
* Epidemiology seems to cover all necessary information and is well referenced. Maybe an image or graph here could be good.
* I like the student drawn image in the etiology section, maybe the sizing could be improved though? Also some a more detailed description of what the image shows would also be good.
* Pathogenesis section is very informative. Maybe the pathophysiology could be covered in this section as well? Image could be added.
* General signs and symptoms would perhaps look better in a table. Otherwise it is quite brief, maybe some more elaboration aswell.
* I think diagnosis looks incomplete. Not much detail is given about how the diagnosis actually works. Very little referencing. Addition of an image would improve this section.
* Treatment looks great. I like how you have included current and future prospects. Just wondering if there was room for a heading for current and future research, as Im sure there is more research being undertaken than just in the area of treatment. This could make this project more informative, and perhaps could be another heading.
* Glossary needs improving.
* Some issues with referencing such as multiple entries for the same article and some issues with web page referencing.

--[[User:Z3288196|Z3288196]] 10:48, 29 September 2011 (EST)

'''GROUP 10: Duchenne Muscular Dystrophy'''
*Title of the whole page should just be Duchenne Muscular Dystrophy, not Introduction...
*The intro is very descriptive and comprehensive
*Image in intro needs proper referencing
*consider rephrasing this sentence "In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction"
*History has good info, but could this be better formatted in a table? this section is text heavy and could maybe use an image, it also could be extended into more recent years
*Epidemiology is summarised well and contains good statistics
*I feel that Aetiology - Genetics section has good info, easy to understand and informative but maybe it could be researched a little more
*General Signs and Symptoms of Duchenne’s Muscular Dystrophy section needs a lot more work, the list of symptoms i don't feel is enough, more expansion on these is needed. An image would improve this section too
*"diarrhoea&&&." -this needs to be fixed

Overall:
*More images are needed to break up the text
*glossary needs a bit more work, consider linking glossary words to text
*I feel that the page overall needs some more work, some sections are lacking content
*Proof reading to fix grammar and sentence structure

--[[User:Z3331556|z3331556]] 10:44, 29 September 2011 (EST)

'''Peer Review'''

This wiki still feels like what Mark Hill mentioned earlier, like a backbone for content to be built upon. The foundations are there, but still very incomplete. Comparing the sections, some have done a lot of effort, others not so much, and it is very visible.

:*Should start the wiki with this code:

<wiki>=Duchenne Muscular Dystrophy (DMD)= </wiki>

then

<wiki>==Introduction == </wiki>

:*History is far too text heavy and it shouldn't be like that, as this makes it a chore to read. A timeline would be better suited and summarise into the timeline.

:*Should be more student drawn images, since there's only one. If getting pictures is hard to find, then draw your own.

:*The one student drawn image is not referenced correctly, needs the disclaimer info.

:*Diagnosis needs to be expanded. There is 300+ articles, there has to be more info or an image to be found.

:*Pathogenesis needs to be expanded, maybe an image.

:*Signs and symptoms need more referencing. Also, just leave the title as Signs and Symptons.

:*Treatment needs to be expanded on. It isn't any good just listing drugs into a table.

:*Split the Treatment to include Managment and give a separate section for Current Research.

:*Glossary is incomplete.

--[[User:Z3293267|z3293267]] 10:37, 29 September 2011 (EST)

Group 10:

Clear and conscise but still needs more work breaking up the long slabs of writing. Perhaps more subheadings esp. in the first sections.

More pics are needed to break up the work.

Treatment includes a good table.

Glossary needs a bit of work and expanding on the explanations.

References needs to be fixed as there is duplications of references.

z3332178 =]

Peer Review

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*History section would benefit by placing the information into a timeline rather than paragraphs as it is a bit hard to follow.

:*Epidemiology section could be expanded and written in more flowing way rather than long sentences.

:*Needs more images, lots of large blocks of text. And images need to be formatted into the text as formatting currently looks awkward.

:*Further Research could be added, for example papers or groups that are researching as currently it is just being referred to.

:*Glossary could be expanded.

:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed. Also perhaps research from MORE sources is necessary as there is only a few when you cut out the double references.

--[[User:Z3217043|z3217043]] 10:02, 29 September 2011 (EST)

Group 10 Peer Review

*Headings are well organised and structured
*Too much text in history section-a table or image would be good
*Information is there however images/graphs/tables would help break up large chunks of text
*Diagnosis seems brief-perhaps merge with treatment section?
*Signs and symptoms could be expanded
*Great table in treatment
*Needs to be proof read-grammar and spelling mistakes
*Double referencing
*Glossary needs to be extended
--[[User:Z3308965|Fleur McGregor]] 09:54, 29 September 2011 (EST)

Group 10

*Introduction – Great intro, well referenced apart from the first paragraph.
*History has a lot of text, a timeline could work well here and also an image if possible just to break up the text.
*Epidemiology – well referenced and structured, text could be broken up but that’s nothing major as it’s a small section.
*Aetiology – A link between the image provided and the text would work well, and also the image could be formatted on the right of the page, to add to continuity and flow as other images are located on the right.
*Signs and Symptoms – Needs to be more information here, a description of each symptom and maybe its direct causes.
*Clinical manifestations – need a link between the image and the text, other than that it is well referenced and easy to understand.
*Treatment – table formatting is great and information is helpful
*Glossary – needs to include more terms form the page.
*There’s some doubling up in the reference section that needs to be fixed, other than that good job.

--[[User:Z3331469|z3331469]] 08:25, 29 September 2011 (EST)

peer review:

*Intro: One of the very few groups to use an image of the disease in the intro, well done! Like how you have referred to Duchenne’s as DMD in brackets initial heading to avoid confusion.

*History: A lot of writing, no techniques to break it up, which will basically bore your reader. Use a timeline perhaps.

*Epidemiology: Subheading will benefit this segment.

*Aetiology: The image could use some colour, but it is still very well done. It would be worthy to refer to the drawing as your explaining the genetics, just to bring them together.

*Pathogenesis: Very brief, not very informative and lacking subheadings or an image. Hopefully this will be fixed.

*Signs and Symptoms:Poorly done. Dot-points are a good way to initiate the writing but not appropriate as a final copy. Needs more description and research.

*Clinical manifestations:
The image used is excellent but needs more explanation.

*Diagnosis:Very short, looks incomplete and there’s only one reference for the entire section.

*Treatment: Well done, I like the colour and the table structure, makes it much easier to understand.

*Glossary: Incomplete, much more terminology has been used.

*References: Double referencing is a big problem here.

*Text:image ratio: could use more images.

--[[User:Z3290270|z3290270]] 02:16, 29 September 2011 (EST)

*history should be broken up with dates on side or within a table.
*how about a short summary table to use for epidemiology
*no picture of Guillaume Benjamin Amand Duchenne?
*no copyright permission for the drawn image in genetics.
*pathogenesis seems very small for a section that is very important.
*describe how the signs and symptoms impact on patients to show the significance of the disease.
*diagnosis needs a lot of work, this section is very important. also very little references in this section.
*not enough pictures to accompany the text
*very short glossary
*multiple references of same articles
--[[User:Z3291423|Jasjit Walia]] 00:17, 29 September 2011 (EST)

'''Peer Review for Group 10'''

*The introduction was well written, however the picture in it is not referenced as instructed. Please fix that then your intro is perfect.
*In the history section, the first sentence is oddly placed, even though it’s informative, please put that somewhere where it will flow in the paragraph.
*The history is verbose, please re write so it’s easier to follow.
*Epidemiology needs to be reevaluated as some sentences are not constructed properly
*Etiology has sound information but the paragraphs are not structured so it flows. It also seems repetitive.
*The picture in the etiology can have its caption better structured
*Pathogenesis should include some component of genetics to explain how the abnormalities bring about the pathogenesis in the genetics level.
*Explanation of how the signs and symptoms comes along from the dystrophy should be explained
*The image of the spine is not completely referenced as url of the image and the page must also be given
*Information under ‘respiratory problems’ and smooth muscle needs some reviewed as it includes words there that shouldn’t be present
*The diagnosis section could be expanded upon so it includes more information on the details of how it is detected, and images should complement the tools to diagnose the condition.
*An introduction to the table should be given. Having the table there by itself doesn’t look good.
*Further explanation should be made on the type of physical activity that would be made for therapy
*Glossary should be expanded
*There is repetitive referencing; it should be reformatted to fit in the way multiple references is made.
*You need much more pics as without the pics the page looks word heavy.

--[[User:Z3291317|Z3291317]] 23:57, 28 September 2011 (EST)

'''Group 10'''

Introduction: Good introduction. The picture could be a bit bigger. Also, a picture of the chromosome would be great.

History and epidemiology: Both sections are clear and flow well. Pictures are needed to break up the text though.

Genetics: The image is great and the text is well written.

Pathogenesis: The pathogenesis is well explained. Again, pictures would be good in this section to improve it.

Clinical manifestations: Good section. Clear, easy to understand.

Diagnosis: This section might need some more detail added. You could explain how each of the diagnostic tests work

Current and future treatment: This section is worded well but looks a little bit disjointed. I think it would be better having it either all in text or all in the table. --[[User:Z3291324|z3291324]] 23:27, 28 September 2011 (EST)

'''Group 10 Peer Review'''
* Interesting introduction, with a good amount of information. The history is also quite well outlined, although as you have no doubt seen with many of the other groups by now, a timeline woud be adequate in the history section (this also helps to break the text up and help us get a "break" from large blocks of text!)
* Epidemiology section is short but sweet - all the required information is there and summarised well. Perhaps mention the rate of mortality? (although this may be obvious)
* The student-drawn image in the aetiology section doesn't have your own copyright notice, so this should be added to the description. There also might be more to write in this section, but only if you wish to seek out the information. Diagrams can be helpful in summarising excessively detailed material.
* Pathogenesis simply needs to be longer; a lot can be written on this section and there should also be the use of diagrams throughout. Explain why the pathogenesis of DMD is so destructive; it has more than just the function of securing the sarcolemma to the cytoskeleton and is also present in other parts of the body, so make sure you explore this completely! :) (for example, dystrophin which is affected also is found in different areas of the body which may help explain some of the other symptoms of DMD).
* General signs and symptoms could have a diagram to assist in the signs and symptoms.
* Clinical manifestations and complications could have more written and explaining some of the other symptoms that aren't purely based upon the muscle damage observed in DMD.
* Diagnosis needs to have more written, especially images regarding the methods of imaging and therapy.
* Treatment; and Current and Future Prospects are different sections and shouldn't be integrated. Think carefully about the implications that current and future directions of research will have on this disease - they are huge! Try to write more and make an individual section on current and future prospectives of research for DMD; as you know from your research so far, DMD is a very important disease requiring a lot of research.
* Glossary is incomplete; References have a lot of repeats, but these are problems that are common to almost all projects.
* Generally, you just need to find better ways of altering the information in your project. Try to add tables and images to help break up the information and make sure you've discussed all the sections in the guidelines for the project properly. Keep at it! :) There are also some obvious typos ('''&&&''')?
--[[User:Z3288827|Leonard Tiong]] 22:29, 28 September 2011 (EST)

'''Group 10:'''

•History might work better in a timeline, just to break up the text as the beginning of the page looks a little overwhelming with text.

•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template for all of the uploaded images.

•The different sections seem to be a little inconsistent, where a few of the sections such as diagnosis and treatment seem a little vague. These sections could be expanded on to give the reader a more comprehensive knowledge of what is involved, especially seeing as the diagnosis section only has one reference.

•Some typos in the smooth muscle section - ‘&&&’

•A lot of the references are repeated multiple times – this should be fixed up so that each reference only appears once. And also not all the references seem to be formatted correctly.

•Glossary is incomplete

•Overall, good use of subheadings though some of the sections need to be expanded and a few more images are needed to add a better balance to the page. Good work so far.

--[[User:Z3332183|z3332183]] 21:33, 28 September 2011 (EST)

'''Group 10'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main points are there. Content is decent in some places and lacking in others. Fixing up problematic areas would be good.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
Maybe include a time-line in history?'''
General Signs and Symptoms of Duchenne’s Muscular Dystrophy section is very poor. Getting information from an insurance website is not actual research. please consider re-doing this section with sources cited from a peer-reviewed paper. Signs and symptoms should go with diagnosis as it is part of making a diagnosis. why are there ampersands in Smooth muscle section?

'''*Content is correctly cited and referenced.'''
Fix up references, some are simply links and they repeat.

'''*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 is drawn well, explanation could do with a bit more work though. File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg needs proper citation, also there isn't many images. Try including more images.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Not as much information as i was expecting and references is not as extensive as other pages - but good in-text citation (with the exception of some places such as diagnosis and Respiratory problems), it shows that the information has come from somewhere. Information from an insurance website is not evidence of extensive research so try to fix it.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
No connection to embryology - try linking genetic defects to problems in the neonate, or even if there is a prenatal test.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Some evidence of developing the wiki page with the guidelines. Will benefit from changing some things.

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

'''Group 10: Peer Assessment'''
* Your page is relatively short overall and could use some more pictures, especially in the first few sections.
* You have forgotten to put a title on you page
* The introduction is good
* You have got quite a bid of text in the history section, may be you can make a bid lighter with a time line?
* Epidemiology is nice to read and relevant
* Signs and symptoms belong into the clinical manifestation section
* Diagnostics could be more in detail
* The green and blue in the table is a bid too much colour all on a sudden. May be you can have some more colour overall or do the table in just one colour?
* It would be great to have more terms in the glossary
* I would put the diagnosis section right after pathogenesis
* Overall you have got good information on your page. May be you can work on the overall structure and some references. --z3279511 17:15, 28 September 2011 (EST)

'''Group 10'''

*Introduction: well done

*History: lots of information, some parts have no references, subheadings and a time line would be advantageous

*Epidemiology: good contend

*Aetiology: the contend seems fine, but more structure would be good

*Pathogenesis: looks good

*Signs and symptoms: that’s more like a list that a section, maybe combine it with manifestations

*Manifestations: well done, except for smooth muscle- seems incomplete?

*Diagnosis: you could add more information and details

*Treatment: the heading seems inappropriate, separate treatment and research, the contend could be more explained

*Glossary: is incomplete

*More images would be nice
--[[User:Z3387190|Z3387190]] 14:28, 28 September 2011 (EST)

'''Group 10'''

*Very poor image/text ratio – you need more images to break up the text
*Good intro
*History would work better in a timeline- you also mention nothing after the 1800s, more recent findings need to be included
*An image would be nice for pathogenesis to help the reader follow
*Not sure why you have made signs and symptoms a different heading to clinical manifestation- these could be combined
*Diagnosis is very brief and needs to be extended
*Glossary needs to be added to
*Maybe add a current research heading

===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.

--Z3389806 07:04, 27 September 2011 (EST)

'''Group 10 Peer assessment'''
*Heading order needs to re-arranged and done properly with diagnosis above before signs and symptoms.
*Introduction done sort of well needs to integrate image as an example of the myofibres.
*History rather bulky with too much text and no image, image of the founder would be fine. Also no time line present of DM needs to be added
*Epidemiology seems rather empty, images would benefit this section also more stats, further expansion of sub headings would also do well for this section
*Genetics aetiology needs to be expanded where seems to be cramped, though usage of image needs to be noted
*Pathogenesis needs images and further information
*Signs and symptoms needs to be expanded and image of some signs or tables
*Clinical manifestation done well with image and further sub-headings
*Diagnosis requires more attention with further methods of detection of DM
*Treatment is well done with the usage of the table
*Glossary needs to further expanded also linked to the pages so easy to follow the page
*References are not complete with links and repeats of the references
z3332250 23:59, 26 September 2011 (EST)

'''Group 10 Critique'''

#• The introduction was very good. Good use of images to give it a little decoration!
#• History is good
#• Epidemiology is good, however if possible try and make it longer/ include more information
#• The Genetics section is a bit too short. Add more information. Good hand drawn image!
#• Pathogenesis is a little short. Needs more information
#• Signs and Symptoms is good
#• Clinical manifestations is ok
#• Diagnosis, treatment and glossary are all well written. These sections should not require any change

--[[User:Z3289991|Robert Klein]] 16:27, 26 September 2011 (EST)

Group 10 ''Duchenne Muscular Dystrophy''
*The first paragraph of the introduction has no reference.
*The paragraphs in history are quite long, often with grammar mistakes, incorrect punctuations and many of the ideas within a sentence separated by a ''-''. For example the second last paragraph within history.
*The history is too verbose, a timeline with bullet points will look better
*Aetiology is quite concise and informative however gramatical errors are a distraction. For example ''There a multiple forms of dystrophin''. It might be a good idea to proofread the page.
*Well done with the student drawn image
*'Pathogenesis' is again well written however an image might have given it a balance between the text in the section and the pictures or tables
*The future therapies table is a little confusing, you might want to add more columns and define the therapy, and then discuss what the challenges and findings are and at the end column finish off with what the implication might be if the research is to be completed successfully. At the moment you have discussed all that in one big paragraph and the way the descriptions start, it sounds like there is no background to the description, just a little abrupt.
*The glossary is very short and you should include terms like de novo mutation.
*The existing definitions are unclear and incomplete

''Duchenne Muscular Dystrophy''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topics

Group 10-
* Need more images to break up the text
* The introduction was really easy to read and had relevant information in it
* History should be in bullet point form to make it easier to access or at least have the dates in BOLD
* Does the history include dates after the 1800s? or did all research stop then?
* Epidemiology was good. Had all the relevant info
* Pathogenesis would benefit an image or a diagram
* Signs and symptoms could be put with clinical manifestations.
* What is the point of the ‘&&&’? in clinical manifestations and complications?
* Diagnosis could be expanded upon to explain how and why these methods work
* Treatment could also be expanded on. A list of drugs doesn’t explain much
* There is not current/future research section
* This is a good start to the project but more research needs to be done

'''Group 10'''
* The structure and use of headings and subheadings is good, make sure you title your page.
* Good info very informative and it gives a good overview to DMD.
* HIstory has a lot of text could you use a timeline here?
* i think a picture of the pathogenesis would improve this section.
* Has your group look at the CNS and cognitive function of DMD boys its a controversial area as many people have different attitudes towards this but Dr Stewart Head a UNSW lecture actually studies DMD and is very informative in the area and recently published a article in the journal Brain.
* The CNS is highly affected by the lack of dystrophin as well as GABA receptors. I think this area is very import to consider as it highly affects the boys at school.
* Could you add some pictures to your page or break it up with the use of more tables as it a lot of text in comparison to pictures and tables.
* Make sure your reference list is not doubled.
* Ensure all your pictures are referenced properly.
* Student image is present.
* This is a good start.

'''Group 10 Assessment'''
*The history is a bit wordy… Maybe consider consolidating the information into a table format for ease of reading. Could also use a picture to add to it.
*The Epidemiology section could also use a picture and maybe some more information, if possible.
*Point vs Frameshift mutation jpg: Good drawing, but in the last portion of the picture the product is labeled as a ‘tunicated protein product.’ Isn’t it supposed to be a ‘truncated’ product?
*The Signs and Symptoms section could use some formatting; it just looks rather dull currently. Maybe a chart or add in a picture?
*Smooth muscle section: Why are there random &&&’s?
*The top portion of the Treatment section could use some more referencing… Good chart though! Only thing I’d suggest for it is to add some pictures if possible?
*Glossary term list is rather short… Are you sure there’s nothing else that needs defining for clarification for the reader?
*It would be a good idea also to have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word 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.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. 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 #...
*Overall, good information is included, just work on referencing things and the overall structure and you should be good!
--[[User:Z3391078|Z3391078]] 17:00, 27 September 2011 (EST)

'''Peer Assessment: Group Project 10'''
*I think the section heading of introduction accompanied by the question what is muscular dystrophy, works really well.
*It might be good to include an image in the history section to break up the text, such as of someone prominently involved with the disease findings.
*The information in clinical manifestations and complications is well written. There needs to be some fix to the formatting under the smooth muscle heading where some '&'s have been repeated.
*The current and future prospects section is great. You have summarised what
*Some of the definitions of words in the glossary need to be completed e.g. atrophy and protease.
*Under the information in some of the images such as the fisrt one, 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.
*An additional section of external links might provide information for those wanting to know more.
--[[User:Z3217345|z3217345]] 10:50, 28 September 2011 (EST)

'''Peer Review'''

* struture and format done well
* easy to read

--[[User:Z3060621|z3060621]] 21:58, 28 September 2011 (EST)

*'''Intro''': Fine
*'''History''': Nicely detailed, but missing a timeline.
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.
*'''Pathogenesis''': Content seems fine, could do with a figure?
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?
*'''Clinical manifestations and complications''': Fine
*'''Diagnosis''': Clinical Diagnosis is a bit short?
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.
*'''Glossary''': Poor. More terms need explanations.
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.

==Discussion==

'''GROUP 10!'''

'''To make everything easier to follow, we have agreed to write any updates, info, discussion etc at the BOTTOM of this page, it will just stop us having to keep going up and down and wasting time trying to find the information we want.'''

----

Hey Everyone,

So Mark went through each group today during the lab and the webpages and discussed where we should be up to. By next week, he expects the subheadings & some content to be up and running. He also recommended that we should have some more research going on in our discussion page. E.g. Research articles links, interesting sites etc.

Topics have been allocated so please begin your research and typing up some content. We can further divide our headings if necessary, take a look at some other groups, they have some pretty good ideas. Mark will be checking this next week during our lab. He'll be coming around to each of us.

So hopefully see you all next week !

--[[User:Z3332327|z3332327]] 12:53, 25 August 2011 (EST)

==Subheadings for assignment==

Intro what is DMD

History/timeline

Genetic component

Why is it an abnormality - Symptoms effect

Diagnosis, future/current prospect (treatments?)

2 case studies

Glossary of terms

====Post online any preferences you may have in terms of the topics you wish to research and by Sunday we will allocate sub topics====
--[[User:Z3332629|z3332629]] 13:09, 18 August 2011 (EST)

Okay hey guys just to get the discussion going, umm I don't mind doing the first 2 on the list. And the "Why is it an abnormality - Symptoms effect" sounds pretty interesting as well.
What are your preferences?? :)

--[[User:Z3330313|z3330313]] 14:55, 23 August 2011 (EST)

Hey Everyone, Im happy to do the diagnosis/current/future prospects point and a case study.

--z3332327 15:36

Talk:2011 Group Project 10

2011-10-05T01:29:50Z

Z3332629: /* Group Discussion Week 10-12 */

[[2011_Group_Project_10|'''Group 10''']]: [[User:z3332327]] | [[User:z3332629]] | [[User:z3332824]] | [[User:z3330313]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_10_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_10_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Group Discussion Week 10-12==
Nice drawings!

Just some videos for my section, just placing them somewhere so i know where they are :)
http://www.youtube.com/watch?v=dOhMLZCvb50
http://www.youtube.com/watch?v=GWachrbiU58
--[[User:Z3332629|Ashleigh Pontifex]] 12:01, 3 October 2011 (EST)

Joanna : http://emedicine.medscape.com/article/1173204-overview#a0199
Great over view for epidemiology, perhaps a table or some stats would be great in this section :)

- http://www.ncbi.nlm.nih.gov/pubmed/19834452 -

hey guys I changed some of the stuff on history, if you think its too much info let me know!
I deleted alot of information, and I just can't bring myself to delete more because the stuff remaining now seems so relevant. But let me know what you think!
And what do you guys think about putting an image of the Duchenne dude in the history? do you reckon that'll make that section too long?
--[[User:Z3330313|Joanna Pak]] 02:56, 5 October 2011 (EST)

Hey Jo! I had a read of the history section and it sounds good. Just an idea, where you've listed Duchenne's definition of the disease, would you prefer if those were added under DIAGNOSIS- clinical or SIGNS AND SYMPTOMS? And we could add an internal link? Maybe that'll cut down your section a bit?

Just a suggested change, i just rearranged the words around a little, dont have to. =)

*'Meryon conducted several necropsies and found intact spinal cords which indicated the disease was not from the nervous system.'

Minor edit

*'Further microscopic examination of the muscle showed that the muscular fibres '''broke''' down and converted into granular, fatty matter.'
--[[User:Z3332327|Lisa Xiao]] 11:38, 5 October 2011 (EST)

Hey Jo its Ash!! It looks heaps better, more straight forward and the table inclusion is great :)
Is everyone happy with my student drawn image in the introduction? it is appropriate in this section?
Also my table in the genetics section???

And lastly, ive notice that Rhiannon has hyperlinked all glossary terms in her section, is everyone happy to carry that across all areas???
--[[User:Z3332629|Ashleigh Pontifex]] 12:29, 5 October 2011 (EST)

==Peer Review==

'''Peer Review'''
* The introduction is detailed but a bit “in your face.” It may even be a bit too detailed, going into the pathogenesis of the disorder.
* History is very detailed, perhaps slightly story-like but enjoyable nonetheless. Could use a picture or two. Sufficiently referenced.
* Epidemiology is very thorough and well referenced.
* The tone of Aetiology/Genetics is a bit conversational; needs to be more detached. Good use of picture, although the legend to it is not in the correct format.
* Pathogenesis could use more references, especially for the last paragraph. Could potentially use some pictures to make clearer the specific structures discussed in the text (although they are elaborated on in the glossary).
* All the signs listed in Clinical Manifestations etc are decently elaborated upon, and the section is well-referenced. Smooth Muscle has strange “&&&” signs though. Respiratory Problems needs cleaning, notably with the line “[Effects of high CO2 and the problems it can cause]”
* Diagnosis is nicely laid out, although more references are needed.
* Treatment is decently set up and clearly explains each of the treatment plans.
--[[User:Z3290689|z3290689]] 14:44, 29 September 2011 (EST)

Group 10:
This project looks fine but it seems a little short? You want to expand the content in sections.
History is well researched but it’s quite long. You can add more images (add the reference in the description) and make the dates in Bald.
There are some spelling errors and extra signs that are not related to the work such as &&&.
Some of the references are repeated and others need to be reformatted.
Overall, Great effort.

--[[User:Z3284061|z3284061]] 11:51, 29 September 2011 (EST)

'''Peer Assessment'''
*introduction is well written and descriptive. Good use of image to make it look appealing. No references in the first paragraph.
*History section is too long, text heavy and a bit boring. Try to summarize the details on a timeline. You can include an image e.g. of Dr Edward Meryon if possible.
*Epidemiology and aetiology; well written. The image in the aetiology needs to be linked with the text.
*Pathogenesis; too brief. Needs more information and explanation of the disease process. Include an image or flowchart to compliment the text.
*Signs and symptoms; needs to be expanded a bit more. I suggest using a table to present the information that just as dot points. Same goes for the diagnosis section, which also needs to be expanded. Try and use more images, tables, graphs etc to break up the texts and make the page look more appealing.
*I suggest hyperlinking words in the page with the glossary to make the page more user friendly.
*Like the use of table in the "current and future prospects". It's better to present information like this rather than in big long paragraphs.
*The glossary needs to be expanded more.
--[[User:Z3291622|Z3291622]] 11:07, 29 September 2011 (EST)

'''''Duchenne (Group 10) Peer Review:'''''

Could you include “Duchenne Muscular Dystrophy” as the first subheading so that the reader knows exactly what the disease is at first glance? Just a suggestion.

Introduction: Topic well introduced and good use of image. Image, however, is lacking a student template.

History: Very extensive. Possibly include an image to break up the text.

Epidemiology: Sound. Some sentences are not worded/ structured properly.

Aetiology – Genetics: Information is good. Impressive self-drawn image. Well done.

Pathogenesis: An image would definitely work well in this section. Information is otherwise good, however possibly have a greater focus on the genetic component?

General Signs and Symptoms of Duchenne’s Muscular Dystrophy: This section seems too brief. Elaborate further.

Clinical manifestations and complications: Information is good. Possibly more detail for the subheading “smooth muscle.” Image lacks a student template. “&&&” – what is this? Many references in this section which is good to see!

Diagnosis: Could be elaborated further.

Treatment: Current and Future Prospects: The first paragraph lacks referencing. Possibly include an image? Table is a good idea, however colours chosen are slightly off-putting.
Glossary of terms: Could be more extensive. Not complete.

Well done. --[[User:Z3290808|z3290808]] 10:50, 29 September 2011 (EST)

Duchenne Muscular Dystrophy – Group 10

* Excellent introduction and good use of image. Is there some referencing missing in the first few sentences? Some formatting should be done on the image either to make it within the intro section or more shared between the history sections. Looks a little out of place.
* History is well written but very text heavy. Use of a timeline good improve this section and make it more succinct. Also I thought an image could be good.
* Epidemiology seems to cover all necessary information and is well referenced. Maybe an image or graph here could be good.
* I like the student drawn image in the etiology section, maybe the sizing could be improved though? Also some a more detailed description of what the image shows would also be good.
* Pathogenesis section is very informative. Maybe the pathophysiology could be covered in this section as well? Image could be added.
* General signs and symptoms would perhaps look better in a table. Otherwise it is quite brief, maybe some more elaboration aswell.
* I think diagnosis looks incomplete. Not much detail is given about how the diagnosis actually works. Very little referencing. Addition of an image would improve this section.
* Treatment looks great. I like how you have included current and future prospects. Just wondering if there was room for a heading for current and future research, as Im sure there is more research being undertaken than just in the area of treatment. This could make this project more informative, and perhaps could be another heading.
* Glossary needs improving.
* Some issues with referencing such as multiple entries for the same article and some issues with web page referencing.

--[[User:Z3288196|Z3288196]] 10:48, 29 September 2011 (EST)

'''GROUP 10: Duchenne Muscular Dystrophy'''
*Title of the whole page should just be Duchenne Muscular Dystrophy, not Introduction...
*The intro is very descriptive and comprehensive
*Image in intro needs proper referencing
*consider rephrasing this sentence "In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction"
*History has good info, but could this be better formatted in a table? this section is text heavy and could maybe use an image, it also could be extended into more recent years
*Epidemiology is summarised well and contains good statistics
*I feel that Aetiology - Genetics section has good info, easy to understand and informative but maybe it could be researched a little more
*General Signs and Symptoms of Duchenne’s Muscular Dystrophy section needs a lot more work, the list of symptoms i don't feel is enough, more expansion on these is needed. An image would improve this section too
*"diarrhoea&&&." -this needs to be fixed

Overall:
*More images are needed to break up the text
*glossary needs a bit more work, consider linking glossary words to text
*I feel that the page overall needs some more work, some sections are lacking content
*Proof reading to fix grammar and sentence structure

--[[User:Z3331556|z3331556]] 10:44, 29 September 2011 (EST)

'''Peer Review'''

This wiki still feels like what Mark Hill mentioned earlier, like a backbone for content to be built upon. The foundations are there, but still very incomplete. Comparing the sections, some have done a lot of effort, others not so much, and it is very visible.

:*Should start the wiki with this code:

<wiki>=Duchenne Muscular Dystrophy (DMD)= </wiki>

then

<wiki>==Introduction == </wiki>

:*History is far too text heavy and it shouldn't be like that, as this makes it a chore to read. A timeline would be better suited and summarise into the timeline.

:*Should be more student drawn images, since there's only one. If getting pictures is hard to find, then draw your own.

:*The one student drawn image is not referenced correctly, needs the disclaimer info.

:*Diagnosis needs to be expanded. There is 300+ articles, there has to be more info or an image to be found.

:*Pathogenesis needs to be expanded, maybe an image.

:*Signs and symptoms need more referencing. Also, just leave the title as Signs and Symptons.

:*Treatment needs to be expanded on. It isn't any good just listing drugs into a table.

:*Split the Treatment to include Managment and give a separate section for Current Research.

:*Glossary is incomplete.

--[[User:Z3293267|z3293267]] 10:37, 29 September 2011 (EST)

Group 10:

Clear and conscise but still needs more work breaking up the long slabs of writing. Perhaps more subheadings esp. in the first sections.

More pics are needed to break up the work.

Treatment includes a good table.

Glossary needs a bit of work and expanding on the explanations.

References needs to be fixed as there is duplications of references.

z3332178 =]

Peer Review

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*History section would benefit by placing the information into a timeline rather than paragraphs as it is a bit hard to follow.

:*Epidemiology section could be expanded and written in more flowing way rather than long sentences.

:*Needs more images, lots of large blocks of text. And images need to be formatted into the text as formatting currently looks awkward.

:*Further Research could be added, for example papers or groups that are researching as currently it is just being referred to.

:*Glossary could be expanded.

:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed. Also perhaps research from MORE sources is necessary as there is only a few when you cut out the double references.

--[[User:Z3217043|z3217043]] 10:02, 29 September 2011 (EST)

Group 10 Peer Review

*Headings are well organised and structured
*Too much text in history section-a table or image would be good
*Information is there however images/graphs/tables would help break up large chunks of text
*Diagnosis seems brief-perhaps merge with treatment section?
*Signs and symptoms could be expanded
*Great table in treatment
*Needs to be proof read-grammar and spelling mistakes
*Double referencing
*Glossary needs to be extended
--[[User:Z3308965|Fleur McGregor]] 09:54, 29 September 2011 (EST)

Group 10

*Introduction – Great intro, well referenced apart from the first paragraph.
*History has a lot of text, a timeline could work well here and also an image if possible just to break up the text.
*Epidemiology – well referenced and structured, text could be broken up but that’s nothing major as it’s a small section.
*Aetiology – A link between the image provided and the text would work well, and also the image could be formatted on the right of the page, to add to continuity and flow as other images are located on the right.
*Signs and Symptoms – Needs to be more information here, a description of each symptom and maybe its direct causes.
*Clinical manifestations – need a link between the image and the text, other than that it is well referenced and easy to understand.
*Treatment – table formatting is great and information is helpful
*Glossary – needs to include more terms form the page.
*There’s some doubling up in the reference section that needs to be fixed, other than that good job.

--[[User:Z3331469|z3331469]] 08:25, 29 September 2011 (EST)

peer review:

*Intro: One of the very few groups to use an image of the disease in the intro, well done! Like how you have referred to Duchenne’s as DMD in brackets initial heading to avoid confusion.

*History: A lot of writing, no techniques to break it up, which will basically bore your reader. Use a timeline perhaps.

*Epidemiology: Subheading will benefit this segment.

*Aetiology: The image could use some colour, but it is still very well done. It would be worthy to refer to the drawing as your explaining the genetics, just to bring them together.

*Pathogenesis: Very brief, not very informative and lacking subheadings or an image. Hopefully this will be fixed.

*Signs and Symptoms:Poorly done. Dot-points are a good way to initiate the writing but not appropriate as a final copy. Needs more description and research.

*Clinical manifestations:
The image used is excellent but needs more explanation.

*Diagnosis:Very short, looks incomplete and there’s only one reference for the entire section.

*Treatment: Well done, I like the colour and the table structure, makes it much easier to understand.

*Glossary: Incomplete, much more terminology has been used.

*References: Double referencing is a big problem here.

*Text:image ratio: could use more images.

--[[User:Z3290270|z3290270]] 02:16, 29 September 2011 (EST)

*history should be broken up with dates on side or within a table.
*how about a short summary table to use for epidemiology
*no picture of Guillaume Benjamin Amand Duchenne?
*no copyright permission for the drawn image in genetics.
*pathogenesis seems very small for a section that is very important.
*describe how the signs and symptoms impact on patients to show the significance of the disease.
*diagnosis needs a lot of work, this section is very important. also very little references in this section.
*not enough pictures to accompany the text
*very short glossary
*multiple references of same articles
--[[User:Z3291423|Jasjit Walia]] 00:17, 29 September 2011 (EST)

'''Peer Review for Group 10'''

*The introduction was well written, however the picture in it is not referenced as instructed. Please fix that then your intro is perfect.
*In the history section, the first sentence is oddly placed, even though it’s informative, please put that somewhere where it will flow in the paragraph.
*The history is verbose, please re write so it’s easier to follow.
*Epidemiology needs to be reevaluated as some sentences are not constructed properly
*Etiology has sound information but the paragraphs are not structured so it flows. It also seems repetitive.
*The picture in the etiology can have its caption better structured
*Pathogenesis should include some component of genetics to explain how the abnormalities bring about the pathogenesis in the genetics level.
*Explanation of how the signs and symptoms comes along from the dystrophy should be explained
*The image of the spine is not completely referenced as url of the image and the page must also be given
*Information under ‘respiratory problems’ and smooth muscle needs some reviewed as it includes words there that shouldn’t be present
*The diagnosis section could be expanded upon so it includes more information on the details of how it is detected, and images should complement the tools to diagnose the condition.
*An introduction to the table should be given. Having the table there by itself doesn’t look good.
*Further explanation should be made on the type of physical activity that would be made for therapy
*Glossary should be expanded
*There is repetitive referencing; it should be reformatted to fit in the way multiple references is made.
*You need much more pics as without the pics the page looks word heavy.

--[[User:Z3291317|Z3291317]] 23:57, 28 September 2011 (EST)

'''Group 10'''

Introduction: Good introduction. The picture could be a bit bigger. Also, a picture of the chromosome would be great.

History and epidemiology: Both sections are clear and flow well. Pictures are needed to break up the text though.

Genetics: The image is great and the text is well written.

Pathogenesis: The pathogenesis is well explained. Again, pictures would be good in this section to improve it.

Clinical manifestations: Good section. Clear, easy to understand.

Diagnosis: This section might need some more detail added. You could explain how each of the diagnostic tests work

Current and future treatment: This section is worded well but looks a little bit disjointed. I think it would be better having it either all in text or all in the table. --[[User:Z3291324|z3291324]] 23:27, 28 September 2011 (EST)

'''Group 10 Peer Review'''
* Interesting introduction, with a good amount of information. The history is also quite well outlined, although as you have no doubt seen with many of the other groups by now, a timeline woud be adequate in the history section (this also helps to break the text up and help us get a "break" from large blocks of text!)
* Epidemiology section is short but sweet - all the required information is there and summarised well. Perhaps mention the rate of mortality? (although this may be obvious)
* The student-drawn image in the aetiology section doesn't have your own copyright notice, so this should be added to the description. There also might be more to write in this section, but only if you wish to seek out the information. Diagrams can be helpful in summarising excessively detailed material.
* Pathogenesis simply needs to be longer; a lot can be written on this section and there should also be the use of diagrams throughout. Explain why the pathogenesis of DMD is so destructive; it has more than just the function of securing the sarcolemma to the cytoskeleton and is also present in other parts of the body, so make sure you explore this completely! :) (for example, dystrophin which is affected also is found in different areas of the body which may help explain some of the other symptoms of DMD).
* General signs and symptoms could have a diagram to assist in the signs and symptoms.
* Clinical manifestations and complications could have more written and explaining some of the other symptoms that aren't purely based upon the muscle damage observed in DMD.
* Diagnosis needs to have more written, especially images regarding the methods of imaging and therapy.
* Treatment; and Current and Future Prospects are different sections and shouldn't be integrated. Think carefully about the implications that current and future directions of research will have on this disease - they are huge! Try to write more and make an individual section on current and future prospectives of research for DMD; as you know from your research so far, DMD is a very important disease requiring a lot of research.
* Glossary is incomplete; References have a lot of repeats, but these are problems that are common to almost all projects.
* Generally, you just need to find better ways of altering the information in your project. Try to add tables and images to help break up the information and make sure you've discussed all the sections in the guidelines for the project properly. Keep at it! :) There are also some obvious typos ('''&&&''')?
--[[User:Z3288827|Leonard Tiong]] 22:29, 28 September 2011 (EST)

'''Group 10:'''

•History might work better in a timeline, just to break up the text as the beginning of the page looks a little overwhelming with text.

•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template for all of the uploaded images.

•The different sections seem to be a little inconsistent, where a few of the sections such as diagnosis and treatment seem a little vague. These sections could be expanded on to give the reader a more comprehensive knowledge of what is involved, especially seeing as the diagnosis section only has one reference.

•Some typos in the smooth muscle section - ‘&&&’

•A lot of the references are repeated multiple times – this should be fixed up so that each reference only appears once. And also not all the references seem to be formatted correctly.

•Glossary is incomplete

•Overall, good use of subheadings though some of the sections need to be expanded and a few more images are needed to add a better balance to the page. Good work so far.

--[[User:Z3332183|z3332183]] 21:33, 28 September 2011 (EST)

'''Group 10'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main points are there. Content is decent in some places and lacking in others. Fixing up problematic areas would be good.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
Maybe include a time-line in history?'''
General Signs and Symptoms of Duchenne’s Muscular Dystrophy section is very poor. Getting information from an insurance website is not actual research. please consider re-doing this section with sources cited from a peer-reviewed paper. Signs and symptoms should go with diagnosis as it is part of making a diagnosis. why are there ampersands in Smooth muscle section?

'''*Content is correctly cited and referenced.'''
Fix up references, some are simply links and they repeat.

'''*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 is drawn well, explanation could do with a bit more work though. File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg needs proper citation, also there isn't many images. Try including more images.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Not as much information as i was expecting and references is not as extensive as other pages - but good in-text citation (with the exception of some places such as diagnosis and Respiratory problems), it shows that the information has come from somewhere. Information from an insurance website is not evidence of extensive research so try to fix it.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
No connection to embryology - try linking genetic defects to problems in the neonate, or even if there is a prenatal test.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Some evidence of developing the wiki page with the guidelines. Will benefit from changing some things.

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

'''Group 10: Peer Assessment'''
* Your page is relatively short overall and could use some more pictures, especially in the first few sections.
* You have forgotten to put a title on you page
* The introduction is good
* You have got quite a bid of text in the history section, may be you can make a bid lighter with a time line?
* Epidemiology is nice to read and relevant
* Signs and symptoms belong into the clinical manifestation section
* Diagnostics could be more in detail
* The green and blue in the table is a bid too much colour all on a sudden. May be you can have some more colour overall or do the table in just one colour?
* It would be great to have more terms in the glossary
* I would put the diagnosis section right after pathogenesis
* Overall you have got good information on your page. May be you can work on the overall structure and some references. --z3279511 17:15, 28 September 2011 (EST)

'''Group 10'''

*Introduction: well done

*History: lots of information, some parts have no references, subheadings and a time line would be advantageous

*Epidemiology: good contend

*Aetiology: the contend seems fine, but more structure would be good

*Pathogenesis: looks good

*Signs and symptoms: that’s more like a list that a section, maybe combine it with manifestations

*Manifestations: well done, except for smooth muscle- seems incomplete?

*Diagnosis: you could add more information and details

*Treatment: the heading seems inappropriate, separate treatment and research, the contend could be more explained

*Glossary: is incomplete

*More images would be nice
--[[User:Z3387190|Z3387190]] 14:28, 28 September 2011 (EST)

'''Group 10'''

*Very poor image/text ratio – you need more images to break up the text
*Good intro
*History would work better in a timeline- you also mention nothing after the 1800s, more recent findings need to be included
*An image would be nice for pathogenesis to help the reader follow
*Not sure why you have made signs and symptoms a different heading to clinical manifestation- these could be combined
*Diagnosis is very brief and needs to be extended
*Glossary needs to be added to
*Maybe add a current research heading

===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.

--Z3389806 07:04, 27 September 2011 (EST)

'''Group 10 Peer assessment'''
*Heading order needs to re-arranged and done properly with diagnosis above before signs and symptoms.
*Introduction done sort of well needs to integrate image as an example of the myofibres.
*History rather bulky with too much text and no image, image of the founder would be fine. Also no time line present of DM needs to be added
*Epidemiology seems rather empty, images would benefit this section also more stats, further expansion of sub headings would also do well for this section
*Genetics aetiology needs to be expanded where seems to be cramped, though usage of image needs to be noted
*Pathogenesis needs images and further information
*Signs and symptoms needs to be expanded and image of some signs or tables
*Clinical manifestation done well with image and further sub-headings
*Diagnosis requires more attention with further methods of detection of DM
*Treatment is well done with the usage of the table
*Glossary needs to further expanded also linked to the pages so easy to follow the page
*References are not complete with links and repeats of the references
z3332250 23:59, 26 September 2011 (EST)

'''Group 10 Critique'''

#• The introduction was very good. Good use of images to give it a little decoration!
#• History is good
#• Epidemiology is good, however if possible try and make it longer/ include more information
#• The Genetics section is a bit too short. Add more information. Good hand drawn image!
#• Pathogenesis is a little short. Needs more information
#• Signs and Symptoms is good
#• Clinical manifestations is ok
#• Diagnosis, treatment and glossary are all well written. These sections should not require any change

--[[User:Z3289991|Robert Klein]] 16:27, 26 September 2011 (EST)

Group 10 ''Duchenne Muscular Dystrophy''
*The first paragraph of the introduction has no reference.
*The paragraphs in history are quite long, often with grammar mistakes, incorrect punctuations and many of the ideas within a sentence separated by a ''-''. For example the second last paragraph within history.
*The history is too verbose, a timeline with bullet points will look better
*Aetiology is quite concise and informative however gramatical errors are a distraction. For example ''There a multiple forms of dystrophin''. It might be a good idea to proofread the page.
*Well done with the student drawn image
*'Pathogenesis' is again well written however an image might have given it a balance between the text in the section and the pictures or tables
*The future therapies table is a little confusing, you might want to add more columns and define the therapy, and then discuss what the challenges and findings are and at the end column finish off with what the implication might be if the research is to be completed successfully. At the moment you have discussed all that in one big paragraph and the way the descriptions start, it sounds like there is no background to the description, just a little abrupt.
*The glossary is very short and you should include terms like de novo mutation.
*The existing definitions are unclear and incomplete

''Duchenne Muscular Dystrophy''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topics

Group 10-
* Need more images to break up the text
* The introduction was really easy to read and had relevant information in it
* History should be in bullet point form to make it easier to access or at least have the dates in BOLD
* Does the history include dates after the 1800s? or did all research stop then?
* Epidemiology was good. Had all the relevant info
* Pathogenesis would benefit an image or a diagram
* Signs and symptoms could be put with clinical manifestations.
* What is the point of the ‘&&&’? in clinical manifestations and complications?
* Diagnosis could be expanded upon to explain how and why these methods work
* Treatment could also be expanded on. A list of drugs doesn’t explain much
* There is not current/future research section
* This is a good start to the project but more research needs to be done

'''Group 10'''
* The structure and use of headings and subheadings is good, make sure you title your page.
* Good info very informative and it gives a good overview to DMD.
* HIstory has a lot of text could you use a timeline here?
* i think a picture of the pathogenesis would improve this section.
* Has your group look at the CNS and cognitive function of DMD boys its a controversial area as many people have different attitudes towards this but Dr Stewart Head a UNSW lecture actually studies DMD and is very informative in the area and recently published a article in the journal Brain.
* The CNS is highly affected by the lack of dystrophin as well as GABA receptors. I think this area is very import to consider as it highly affects the boys at school.
* Could you add some pictures to your page or break it up with the use of more tables as it a lot of text in comparison to pictures and tables.
* Make sure your reference list is not doubled.
* Ensure all your pictures are referenced properly.
* Student image is present.
* This is a good start.

'''Group 10 Assessment'''
*The history is a bit wordy… Maybe consider consolidating the information into a table format for ease of reading. Could also use a picture to add to it.
*The Epidemiology section could also use a picture and maybe some more information, if possible.
*Point vs Frameshift mutation jpg: Good drawing, but in the last portion of the picture the product is labeled as a ‘tunicated protein product.’ Isn’t it supposed to be a ‘truncated’ product?
*The Signs and Symptoms section could use some formatting; it just looks rather dull currently. Maybe a chart or add in a picture?
*Smooth muscle section: Why are there random &&&’s?
*The top portion of the Treatment section could use some more referencing… Good chart though! Only thing I’d suggest for it is to add some pictures if possible?
*Glossary term list is rather short… Are you sure there’s nothing else that needs defining for clarification for the reader?
*It would be a good idea also to have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word 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.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. 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 #...
*Overall, good information is included, just work on referencing things and the overall structure and you should be good!
--[[User:Z3391078|Z3391078]] 17:00, 27 September 2011 (EST)

'''Peer Assessment: Group Project 10'''
*I think the section heading of introduction accompanied by the question what is muscular dystrophy, works really well.
*It might be good to include an image in the history section to break up the text, such as of someone prominently involved with the disease findings.
*The information in clinical manifestations and complications is well written. There needs to be some fix to the formatting under the smooth muscle heading where some '&'s have been repeated.
*The current and future prospects section is great. You have summarised what
*Some of the definitions of words in the glossary need to be completed e.g. atrophy and protease.
*Under the information in some of the images such as the fisrt one, 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.
*An additional section of external links might provide information for those wanting to know more.
--[[User:Z3217345|z3217345]] 10:50, 28 September 2011 (EST)

'''Peer Review'''

* struture and format done well
* easy to read

--[[User:Z3060621|z3060621]] 21:58, 28 September 2011 (EST)

*'''Intro''': Fine
*'''History''': Nicely detailed, but missing a timeline.
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.
*'''Pathogenesis''': Content seems fine, could do with a figure?
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?
*'''Clinical manifestations and complications''': Fine
*'''Diagnosis''': Clinical Diagnosis is a bit short?
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.
*'''Glossary''': Poor. More terms need explanations.
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.

==Discussion==

'''GROUP 10!'''

'''To make everything easier to follow, we have agreed to write any updates, info, discussion etc at the BOTTOM of this page, it will just stop us having to keep going up and down and wasting time trying to find the information we want.'''

----

Hey Everyone,

So Mark went through each group today during the lab and the webpages and discussed where we should be up to. By next week, he expects the subheadings & some content to be up and running. He also recommended that we should have some more research going on in our discussion page. E.g. Research articles links, interesting sites etc.

Topics have been allocated so please begin your research and typing up some content. We can further divide our headings if necessary, take a look at some other groups, they have some pretty good ideas. Mark will be checking this next week during our lab. He'll be coming around to each of us.

So hopefully see you all next week !

--[[User:Z3332327|z3332327]] 12:53, 25 August 2011 (EST)

==Subheadings for assignment==

Intro what is DMD

History/timeline

Genetic component

Why is it an abnormality - Symptoms effect

Diagnosis, future/current prospect (treatments?)

2 case studies

Glossary of terms

====Post online any preferences you may have in terms of the topics you wish to research and by Sunday we will allocate sub topics====
--[[User:Z3332629|z3332629]] 13:09, 18 August 2011 (EST)

Okay hey guys just to get the discussion going, umm I don't mind doing the first 2 on the list. And the "Why is it an abnormality - Symptoms effect" sounds pretty interesting as well.
What are your preferences?? :)

--[[User:Z3330313|z3330313]] 14:55, 23 August 2011 (EST)

Hey Everyone, Im happy to do the diagnosis/current/future prospects point and a case study.

--z3332327 15:36

2011 Group Project 10

2011-10-04T00:18:48Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref name=Davies>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref name=DMD>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref name=Davies/> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref name=DMD/>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref name=Davies/>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.<ref name=Davies/>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.<ref name=Davies/>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref name=Davies/>As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Actin:''' a protein that forms the contractile units of muscle cells

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Base pair:''' two complementary bases in a nucleic acid molecule

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoplasm:''' material within a cell

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dominant:''' a trait determined by an allele that is expressed over another present allele

*'''Dystrophin:''' a protein involved in muscular contraction

*'''Dystrophin-associated protein complex (DAPC):''' a multiprotein complex that includes dystrophin and other associated proteins.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Extracellular matrix:''' network of connective tissues and fibres that provide support and exist outside the cell.

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Filamentous:''' thread-like cells

*'''Gene:''' sequence of nucleotides forming part of a chromosome

*'''Genome:''' the complete set of genetic material in a cell or organism

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Muscle contraction:''' process in which muscles shorter and are made tighter un neuronal control

*'''Muscle fiber:''' elongated contractile cell

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Nucleotides:''' compounds that form the basic structural units of nucleic acids

*'''Plasma membrane:''' composed of lipids and proteins, forms the external boundary of the cytoplasm

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Recessive:''' the opposite of Dominant

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Signal transduction:''' internal cell signalling process

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

*'''Transmembrane:''' existing across a membrane

*'''X chromosome:''' sex chromosome, two are represent in females and only one is present in male cells.

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-04T00:16:26Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref name=Davies>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref name=Davies/> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref name=Davies/>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.<ref name=Davies/>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.<ref name=Davies/>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref name=Davies/>As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Actin:''' a protein that forms the contractile units of muscle cells

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Base pair:''' two complementary bases in a nucleic acid molecule

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoplasm:''' material within a cell

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dominant:''' a trait determined by an allele that is expressed over another present allele

*'''Dystrophin:''' a protein involved in muscular contraction

*'''Dystrophin-associated protein complex (DAPC):''' a multiprotein complex that includes dystrophin and other associated proteins.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Extracellular matrix:''' network of connective tissues and fibres that provide support and exist outside the cell.

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Filamentous:''' thread-like cells

*'''Gene:''' sequence of nucleotides forming part of a chromosome

*'''Genome:''' the complete set of genetic material in a cell or organism

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Muscle contraction:''' process in which muscles shorter and are made tighter un neuronal control

*'''Muscle fiber:''' elongated contractile cell

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Nucleotides:''' compounds that form the basic structural units of nucleic acids

*'''Plasma membrane:''' composed of lipids and proteins, forms the external boundary of the cytoplasm

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Recessive:''' the opposite of Dominant

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Signal transduction:''' internal cell signalling process

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

*'''Transmembrane:''' existing across a membrane

*'''X chromosome:''' sex chromosome, two are represent in females and only one is present in male cells.

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-04T00:05:09Z

Z3332629: /* Glossary of terms */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Actin:''' a protein that forms the contractile units of muscle cells

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Base pair:''' two complementary bases in a nucleic acid molecule

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoplasm:''' material within a cell

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dominant:''' a trait determined by an allele that is expressed over another present allele

*'''Dystrophin:''' a protein involved in muscular contraction

*'''Dystrophin-associated protein complex (DAPC):''' a multiprotein complex that includes dystrophin and other associated proteins.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Extracellular matrix:''' network of connective tissues and fibres that provide support and exist outside the cell.

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Filamentous:''' thread-like cells

*'''Gene:''' sequence of nucleotides forming part of a chromosome

*'''Genome:''' the complete set of genetic material in a cell or organism

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Muscle contraction:''' process in which muscles shorter and are made tighter un neuronal control

*'''Muscle fiber:''' elongated contractile cell

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Nucleotides:''' compounds that form the basic structural units of nucleic acids

*'''Plasma membrane:''' composed of lipids and proteins, forms the external boundary of the cytoplasm

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Recessive:''' the opposite of Dominant

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Signal transduction:''' internal cell signalling process

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

*'''Transmembrane:''' existing across a membrane

*'''X chromosome:''' sex chromosome, two are represent in females and only one is present in male cells.

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-04T00:04:34Z

Z3332629: /* Glossary of terms */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Actin:''' a protein that forms the contractile units of muscle cells

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Base pair:''' two complementary bases in a nucleic acid molecule

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoplasm:''' material within a cell

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dominant:''' a trait determined by an allele that is expressed over another present allele

*'''Dystrophin:''' a protein involved in muscular contraction

*'''Dystrophin-associated protein complex (DAPC):''' a multiprotein complex that includes dystrophin and other associated proteins.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Extracellular matrix:''' network of connective tissues and fibres that provide support and exist outside the cell.

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Filamentous:''' thread-like cells

*'''Gene:''' sequence of nucleotides forming part of a chromosome

*'''Genome:''' the complete set of genetic material in a cell or organism

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Muscle contraction:''' process in which muscles shorter and are made tighter un neuronal control

*'''Muscle fiber:''' elongated contractile cell

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Plasma membrane:''' composed of lipids and proteins, forms the external boundary of the cytoplasm

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Recessive:''' the opposite of Dominant

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Signal transduction:''' internal cell signalling process

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

*'''Transmembrane:''' existing across a membrane

*'''X chromosome:''' sex chromosome, two are represent in females and only one is present in male cells.

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-04T00:01:37Z

Z3332629: /* Glossary of terms */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Actin:''' a protein that forms the contractile units of muscle cells

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Base pair:''' two complementary bases in a nucleic acid molecule

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoplasm:''' material within a cell

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophin:''' a protein involved in muscular contraction

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Gene:''' sequence of nucleotides forming part of a chromosome

*'''Genome:''' the complete set of genetic material in a cell or organism

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Muscle contraction:''' process in which muscles shorter and are made tighter un neuronal control

*'''Muscle fiber:''' elongated contractile cell

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Plasma membrane:''' composed of lipids and proteins, forms the external boundary of the cytoplasm

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

*'''X chromosome:''' sex chromosome, two are represent in females and only one is present in male cells.

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:38:37Z

Z3332629: /* Epidemiology */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:35:23Z

Z3332629: /* Duchenne Muscular Dystrophy (DMD) */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:32:00Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:27:36Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
|
*Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
|
*One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:26:20Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
| *Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
| *One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:25:46Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|250px|Dystrophin as found in the muscle fibre membrane]]

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
| *Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
| *One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Point_mutations_resulting_in_DMD.jpg|350px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:21:46Z

Z3332629: /* Duchenne Muscular Dystrophy (DMD) */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==
[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
| *Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
| *One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|300px|Dystrophin as found in the muscle fibre membrane]]
Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

[[File:Point_mutations_resulting_in_DMD.jpg|450px|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:21:17Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
| *Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
| *One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|300px|Dystrophin as found in the muscle fibre membrane]]
Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

[[File:Point_mutations_resulting_in_DMD.jpg|450px|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:20:10Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
| *Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
| *One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|300px|Dystrophin as found in the muscle fibre membrane]]
Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image based on point mutations is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

[[File:Point_mutations_resulting_in_DMD.jpg|450px|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:16:55Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
| *Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
| *One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|300px|Dystrophin as found in the muscle fibre membrane]]
Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image below is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

[[File:Point_mutations_resulting_in_DMD.jpg|450px|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T23:12:30Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

The largest gene of the human genome is called the dystrophin gene, which is localised at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres. In DMD, there is a mutation in this gene causing an absence or severe reduction in the production of dystrophin.
DMD, also known as BMD or dystrophin, is located on the short arm of the X chromosome at position 21.2. To be more specific, this particular gene is located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> This particular causitive gene was identified in 1987. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, DMD produces the protein dystrophin. There a multiple forms of dystrophin, however it is mostly common found in both skeletal and cardiac muscles. Together with other proteins, dystrophin acts to strengthen and protect muscle fibers, connecting muscle cell components and can also be involved in cell signalling. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

Muscular Dystrophy is an inherited X-linked disease caused by mutations in the DMD gene that result in abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. Two forms of muscular dystrophy exist: Duchenne and Beckers Muscular Dystrophy. As seen in image 1, the occurrence of a point deletion results in absolutely no functional dystrophin being produced, and is called Duchenne muscular dystrophy. Duchenne’s is more severe than the Beckers form, as the point mutation as opposed to deletion of the DMD gene results in some protein function being maintained in the Beckers form. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

[[File:Point_vs_frameshift_mutation_of_DMD_gene.png|500px|]]

Image 1: Point verses frameshift mutation of DMD gene

[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.

The following table summaries the 3 main roles of dystrophin in muscle fibres.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Role of dystrophin'''
|'''Brief description'''
|-style="background:"
| Structural role
| *Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
*This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Protective role
| *One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
*The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
*In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|-style="background:"
| Signalling role
| There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
*Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
*Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

|}

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|right|300px|Dystrophin as found in the muscle fibre membrane]]
Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

The image below is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

[[File:Point_mutations_resulting_in_DMD.jpg|450px|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T22:59:40Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

The largest gene of the human genome is called the dystrophin gene, which is localised at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres. In DMD, there is a mutation in this gene causing an absence or severe reduction in the production of dystrophin.
DMD, also known as BMD or dystrophin, is located on the short arm of the X chromosome at position 21.2. To be more specific, this particular gene is located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> This particular causitive gene was identified in 1987. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, DMD produces the protein dystrophin. There a multiple forms of dystrophin, however it is mostly common found in both skeletal and cardiac muscles. Together with other proteins, dystrophin acts to strengthen and protect muscle fibers, connecting muscle cell components and can also be involved in cell signalling. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

Muscular Dystrophy is an inherited X-linked disease caused by mutations in the DMD gene that result in abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. Two forms of muscular dystrophy exist: Duchenne and Beckers Muscular Dystrophy. As seen in image 1, the occurrence of a point deletion results in absolutely no functional dystrophin being produced, and is called Duchenne muscular dystrophy. Duchenne’s is more severe than the Beckers form, as the point mutation as opposed to deletion of the DMD gene results in some protein function being maintained in the Beckers form. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

[[File:Point_vs_frameshift_mutation_of_DMD_gene.png|500px|]]

Image 1: Point verses frameshift mutation of DMD gene

[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

[[File:Dystrophin_in_the_muscle_fibre_membrane.jpg|thumb|left|300px|Dystrophin as found in the muscle fibre membrane]]
The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.
Table 1: The role of dystrophin in muscle fibres. .<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

Role of dystrophin Brief description
Structural - Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
- This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction.
Protective - One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
- The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
- In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.
Signalling There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
- Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
- Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

[[File:Point_mutations_resulting_in_DMD.jpg|450px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

Image 1 is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

File:Dystrophin in the muscle fibre membrane.jpg

2011-10-03T22:58:01Z

Z3332629: This image is a visual display of the muscle fibre membrane and the location of dystrophin within the sarcolemma surrounding each muscle fibre. {{Template:2011 Student Image}}. Image creator: Ashleigh Pontifex (z3332629) Student image constructed bas

This image is a visual display of the muscle fibre membrane and the location of dystrophin within the sarcolemma surrounding each muscle fibre.

{{Template:2011 Student Image}}.

Image creator: Ashleigh Pontifex (z3332629)

Student image constructed based on the image presented on: http://www.mda.org/publications/fa-dmdbmd-what.html

Location of dystrophin within the muscle fibre membrane by Ashleigh Pontifex is licensed under a Creative Commons Attribution-NoDerivs 3.0 Unported License.
Based on a work at www.mda.org.

<a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nd/3.0/88x31.png" /></a> Location of dystrophin within the muscle fibre membrane by Ashleigh Pontifex is licensed under a <a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/">Creative Commons Attribution-NoDerivs 3.0 Unported License</a>. Based on a work at <a xmlns:dct="http://purl.org/dc/terms/" href="http://www.mda.org/publications/fa-dmdbmd-what.html" rel="dct:source">www.mda.org</a>.

2011 Group Project 10

2011-10-03T22:56:19Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

The largest gene of the human genome is called the dystrophin gene, which is localised at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres. In DMD, there is a mutation in this gene causing an absence or severe reduction in the production of dystrophin.
DMD, also known as BMD or dystrophin, is located on the short arm of the X chromosome at position 21.2. To be more specific, this particular gene is located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> This particular causitive gene was identified in 1987. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, DMD produces the protein dystrophin. There a multiple forms of dystrophin, however it is mostly common found in both skeletal and cardiac muscles. Together with other proteins, dystrophin acts to strengthen and protect muscle fibers, connecting muscle cell components and can also be involved in cell signalling. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

Muscular Dystrophy is an inherited X-linked disease caused by mutations in the DMD gene that result in abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. Two forms of muscular dystrophy exist: Duchenne and Beckers Muscular Dystrophy. As seen in image 1, the occurrence of a point deletion results in absolutely no functional dystrophin being produced, and is called Duchenne muscular dystrophy. Duchenne’s is more severe than the Beckers form, as the point mutation as opposed to deletion of the DMD gene results in some protein function being maintained in the Beckers form. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

[[File:Point_vs_frameshift_mutation_of_DMD_gene.png|500px|]]

Image 1: Point verses frameshift mutation of DMD gene

[[File:X_chromosome_location_of_the_dystrophin_gene.jpg|thumb|right|200px|The location of the dystrophin gene on an X chromosome]]
The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.
Table 1: The role of dystrophin in muscle fibres. .<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

Role of dystrophin Brief description
Structural - Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
- This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction.
Protective - One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
- The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
- In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.
Signalling There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
- Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
- Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

[[File:Point_mutations_resulting_in_DMD.jpg|450px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

Image 1 is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

File:X chromosome location of the dystrophin gene.jpg

2011-10-03T22:53:55Z

Z3332629: This image is a visual display of the location of the dystrophin gene on an X chromosome. Its noted location is on the short arm of the X chromosome at position 21.2, from base pair 31,137,344 to base pair 33,357,725. {{Template:2011 Student Image}}.

This image is a visual display of the location of the dystrophin gene on an X chromosome. Its noted location is on the short arm of the X chromosome at position 21.2, from base pair 31,137,344 to base pair 33,357,725.

{{Template:2011 Student Image}}.

Image creator: Ashleigh Pontifex (z3332629)

Student image constructed based on the image presented on: http://ghr.nlm.nih.gov/gene/DMD

Location of the dystrophin gene on an X chromosome by Ashleigh Pontifex is licensed under a Creative Commons Attribution-NoDerivs 3.0 Unported License.
Based on a work at ghr.nlm.nih.gov.

<a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nd/3.0/88x31.png" /></a> Location of the dystrophin gene on an X chromosome by Ashleigh Pontifex is licensed under a <a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/">Creative Commons Attribution-NoDerivs 3.0 Unported License</a>. Based on a work at <a xmlns:dct="http://purl.org/dc/terms/" href="http://ghr.nlm.nih.gov/gene/DMD" rel="dct:source">ghr.nlm.nih.gov</a>.

2011 Group Project 10

2011-10-03T22:52:36Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

The largest gene of the human genome is called the dystrophin gene, which is localised at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres. In DMD, there is a mutation in this gene causing an absence or severe reduction in the production of dystrophin.
DMD, also known as BMD or dystrophin, is located on the short arm of the X chromosome at position 21.2. To be more specific, this particular gene is located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> This particular causitive gene was identified in 1987. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, DMD produces the protein dystrophin. There a multiple forms of dystrophin, however it is mostly common found in both skeletal and cardiac muscles. Together with other proteins, dystrophin acts to strengthen and protect muscle fibers, connecting muscle cell components and can also be involved in cell signalling. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

Muscular Dystrophy is an inherited X-linked disease caused by mutations in the DMD gene that result in abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. Two forms of muscular dystrophy exist: Duchenne and Beckers Muscular Dystrophy. As seen in image 1, the occurrence of a point deletion results in absolutely no functional dystrophin being produced, and is called Duchenne muscular dystrophy. Duchenne’s is more severe than the Beckers form, as the point mutation as opposed to deletion of the DMD gene results in some protein function being maintained in the Beckers form. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

[[File:Point_vs_frameshift_mutation_of_DMD_gene.png|500px|]]

Image 1: Point verses frameshift mutation of DMD gene

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.
Table 1: The role of dystrophin in muscle fibres. .<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

Role of dystrophin Brief description
Structural - Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
- This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction.
Protective - One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
- The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
- In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.
Signalling There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
- Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
- Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

[[File:Point_mutations_resulting_in_DMD.jpg|450px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

Image 1 is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T22:49:58Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

The largest gene of the human genome is called the dystrophin gene, which is localised at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres. In DMD, there is a mutation in this gene causing an absence or severe reduction in the production of dystrophin.
DMD, also known as BMD or dystrophin, is located on the short arm of the X chromosome at position 21.2. To be more specific, this particular gene is located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> This particular causitive gene was identified in 1987. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, DMD produces the protein dystrophin. There a multiple forms of dystrophin, however it is mostly common found in both skeletal and cardiac muscles. Together with other proteins, dystrophin acts to strengthen and protect muscle fibers, connecting muscle cell components and can also be involved in cell signalling. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

Muscular Dystrophy is an inherited X-linked disease caused by mutations in the DMD gene that result in abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. Two forms of muscular dystrophy exist: Duchenne and Beckers Muscular Dystrophy. As seen in image 1, the occurrence of a point deletion results in absolutely no functional dystrophin being produced, and is called Duchenne muscular dystrophy. Duchenne’s is more severe than the Beckers form, as the point mutation as opposed to deletion of the DMD gene results in some protein function being maintained in the Beckers form. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

[[File:Point_vs_frameshift_mutation_of_DMD_gene.png|500px|]]

Image 1: Point verses frameshift mutation of DMD gene

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.
Table 1: The role of dystrophin in muscle fibres. .<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

Role of dystrophin Brief description
Structural - Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
- This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction.
Protective - One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
- The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
- In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.
Signalling There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
- Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
- Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

[[File:Point_mutations_resulting_in_DMD.jpg|550px|thumb|right|Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy]]

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

Image 1 is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T22:48:51Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

The largest gene of the human genome is called the dystrophin gene, which is localised at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres. In DMD, there is a mutation in this gene causing an absence or severe reduction in the production of dystrophin.
DMD, also known as BMD or dystrophin, is located on the short arm of the X chromosome at position 21.2. To be more specific, this particular gene is located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> This particular causitive gene was identified in 1987. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, DMD produces the protein dystrophin. There a multiple forms of dystrophin, however it is mostly common found in both skeletal and cardiac muscles. Together with other proteins, dystrophin acts to strengthen and protect muscle fibers, connecting muscle cell components and can also be involved in cell signalling. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

Muscular Dystrophy is an inherited X-linked disease caused by mutations in the DMD gene that result in abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. Two forms of muscular dystrophy exist: Duchenne and Beckers Muscular Dystrophy. As seen in image 1, the occurrence of a point deletion results in absolutely no functional dystrophin being produced, and is called Duchenne muscular dystrophy. Duchenne’s is more severe than the Beckers form, as the point mutation as opposed to deletion of the DMD gene results in some protein function being maintained in the Beckers form. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

[[File:Point_vs_frameshift_mutation_of_DMD_gene.png|500px|]]

Image 1: Point verses frameshift mutation of DMD gene

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.
Table 1: The role of dystrophin in muscle fibres. .<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

Role of dystrophin Brief description
Structural - Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
- This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction.
Protective - One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
- The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
- In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.
Signalling There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
- Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
- Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

[[File:Point_mutations_resulting_in_DMD.jpg|550px|''Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy''|]]

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

Image 1 is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

2011 Group Project 10

2011-10-03T22:47:43Z

Z3332629: /* Aetiology - Genetics */

----

{{2011Projects}}

--[[User:S8600021|Mark Hill]] 14:52, 1 October 2011 (EST)
* History section is all text.
* Reference list still contains multiple entries for same reference. I also think that a better reference could have been used that a book published back in 1987 (Duchenne Muscular dystrophy), I know for a fact that there are a large number of review articles which could have been used here.
* Some visual way of showing Epidemiology data perhaps.
* How about some normal muscle information or dystrophic muscle sections.

--[[User:S8600021|Mark Hill]] 12:40, 8 September 2011 (EST) There is a backbone here for content to be built upon, but many sections still lack adequate work. I would have expected more by this stage in your work.
* There are no images added to the project page. I would have thought at least dystrophin gene, mutation hotspots, abnormal muscle, etc.
* History/timeline - just a single entry and nothing about the entire history of this disease.
* Epidemiology - why does it occur at this rate?
* Aetiology - Genetics - you have used a single review source for most of your information, without locating and identifying the research literature.
** If you intend to use the same reference more than once use the following format (without the wiki): <wiki><ref name="PMID21810612"><pubmed>21810612</pubmed></ref></wiki> it will then appear as a single entry in your reference list.
* Clinical manifestations and complications - fix the sub-sub-heading format, I do not like asterisks and italics, keep it simple.
* Diagnosis - you could not find a suitable illustration for this point?
* Treatment: Current and Future Prospects - Future Therapies is currently a list of terms with no adequate descriptions.
* Minor point - references should appear after the full stops.
* 2 case studies? get rid of this unless you have something to say here.
* Where is the student drawn illustration?
* Glossary - descriptions are inadequate, and in some cases just wrong.

== Duchenne Muscular Dystrophy (DMD) ==

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. In humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. However, if a male inherits the altered X-chromosome they will become a sufferer of this disease because they only have one X-chromosome.

The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate <ref>(http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)</ref> In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue during contraction. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The increase in muscle damage accompanies abnormal blood flow within the muscle which leads to progressive limb weakness, respiratory and cardiac failure and eventually premature death <ref><pubmed>21574524</pubmed></ref>.
The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.<ref>(http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)</ref>.

Pathologically, the main feature found in muscle biopsies from patients that suffer from DMD is fibrosis <ref><pubmed>20613637</pubmed></ref>, the muscle is replaced with fibro-adipose tissue and it directly causes muscle dysfunction and contributes to the lethal DMD phenotype <ref><pubmed>21263136</pubmed></ref>. Unfortunately there is no known cure for this disorder, however due to our advances in this technological era there are now many treatment methods that help delay the progress of the disease and manage the symptoms associated with it. Patients of DMD experience poor life quality and an extremely lowered life expectancy, it was only until recently procedures that delayed the progress of the disease and that help increase the quality of life have been brought about <ref><pubmed>19774532</pubmed></ref>.

== History ==

Guillaume Benjamin Amand Duchenne first described the disease in 1861. Since the early beginnings muscular dystrophy has afflicted man. Although during those times it has not been identified as a specific form of the disease, there is evidence in history of paintings depicting physical abnormalities that might just have portrayed the disease. For example, the wall paintings in Egypt dating back from the 18th Dynasty of the New Kingdom illustrate calf enlargements. <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.7</ref>. Therefore throughout history there have been cases that suggested muscular dystrophy, the first clinical descriptions of dystrophy in the English language did not appear until the 19th century due to the fact diagnosis remained speculative because of the absence of muscle pathology <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.10</ref>.

The earliest report of muscular dystrophy was from Dr Edward Meryon of St. Thomas’s Hospital, London. Born in 1809, Meryon was an English physician, a man of wide learning. He published several books concerning the nervous system and in one of his publications Meryon described eight affected boys in three families with a disease later to be identified as a form of muscular dystrophy of Duchenne’s <ref><pubmed>8326496</pubmed></ref>. His findings were reported in the following year in the Transactions of the Medical and Chirurgical Society in December 1851 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Meryon conducted several necropsies, finding intact spinal cords which he thus concluded that the disease was not of the nervous system. Instead he found muscles throughout the body were atrophied, soft and almost bloodless. Further microscopic examination of the muscle showed that the muscular fibres broken down and converted into granular, fatty matter <ref><pubmed>8326496</pubmed></ref>. Therefore Meryon named the condition “Granular degeneration of the Voluntary muscle”. These findings are closely related to the disease we know call Duchenne muscular dystrophy. Meryon concluded there was a familiar nature to the disease that was selective for males which primarily affected muscle tissue <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.12</ref>. Out of the three families he studied there were eight affected brothers and nine healthy sisters, this supported his conclusion of the disease being selective to males. Meryon’s discovery was of 10 years prior to Duchenne, characterising this specific disorder as a progressive muscle wasting disease leading to premature death in the late teens that begins in early childhood. The disease later to be referred as Duchenne muscular dystrophy.

Guillaume Benjamin Amand Duchenne is the physician that the disorder is named after. He was born in Boulogne-sur-Mer on 17 September 1806 <ref>Alan E. H. Emery, 1987, Duchenne Muscular dystrophy, Oxford Medical Publications, New York. pp.13</ref>. Duchenne was a family doctor for 11 years who was interested in the study electrical stimulation of muscle <ref><pubmed>16225184</pubmed></ref>. Duchenne first became interested in muscular dystrophy in 1858. He defined the disorder as:
- progressive weakness of movement first affecting the lower limb then later the upper
- an increase in interstitial connective tissue in affected muscles with the production of abundant fibrous and adipose tissue in the later stages
- pathologically loss of striation of muscle replaced by granular matter and fat vesicles
- a gradual increase in the size of many affected muscles
- with an onset during early childhood or early adolescence
- more prevalent in boys than girls
- can affect several children in a family <ref><pubmed>10449553</pubmed></ref>

Duchenne invented the “harpoon” which was a needle system that he utilised to obtain percutaneous sampling of muscular tissue without anesthesia <ref><pubmed>16225184</pubmed></ref>. This technique allowed study of material from the same patient at different stages of the disease.
Duchenne muscular dystrophy had its earliest contributions made by clinical neurologists and neuropathologists, in which they defined the disorder in terms of clinical presentation and muscle pathology. Later geneticists added to our understanding of the disease and today molecular biologists have increased our knowledge of the disease.

== Epidemiology ==

The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected. The most common form of muscular dystrophy found in children is Duchennes and it predominately affects males because it is an X-linked recessive disorder. Interestingly the average age of diagnosis is 5 despite the earlier onset of symptoms <ref><pubmed> 19834452</pubmed></ref>. Between 1960 to 1971, one per 5377 liveborn males or one per 5226 liveborn males surviving to five years of age had Duchenne muscular dystrophy. Of these 64% were isolated cases meaning they were the only affected member of the family and 34% were familiar cases in New South Wales and the ACT <ref><pubmed> 7205898 </pubmed></ref>.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome. Males only have one X chromosome and therefore, one altered or mutated copy of the gene is capable of causing the condition. Because of the X-linked nature of this disease in terms of its inheritance, males are more likely to develop symptoms characteristic to this disease than females. There is a high 50% chance of sons of female carriers to have the disease, with daughters having alternatively, a 50% chance of being a carrier. <ref> Medline Plus (August, 2011). “Duchenne muscular dystrophy”. Accessed via: http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm</ref> A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Although Duchennes Muscular Dystrophy is regarded as being an X-linked recessive disorder, if often still occurs in individuals without a known family history through ''de novo'' mutations.<ref>U.S. National Library of Medicine (2011). “Genes: DMD”. Author unknown, Genetics Home Reference. Accessed via http://ghr.nlm.nih.gov/gene/DMD.</ref>

== Aetiology - Genetics ==

http://www.nature.com/nrm/journal/v7/n10/full/nrm2024.html
OR Pubmed number is: 16971897

The largest gene of the human genome is called the dystrophin gene, which is localised at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres. In DMD, there is a mutation in this gene causing an absence or severe reduction in the production of dystrophin.
DMD, also known as BMD or dystrophin, is located on the short arm of the X chromosome at position 21.2. To be more specific, this particular gene is located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> This particular causitive gene was identified in 1987. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, DMD produces the protein dystrophin. There a multiple forms of dystrophin, however it is mostly common found in both skeletal and cardiac muscles. Together with other proteins, dystrophin acts to strengthen and protect muscle fibers, connecting muscle cell components and can also be involved in cell signalling. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

Muscular Dystrophy is an inherited X-linked disease caused by mutations in the DMD gene that result in abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. Two forms of muscular dystrophy exist: Duchenne and Beckers Muscular Dystrophy. As seen in image 1, the occurrence of a point deletion results in absolutely no functional dystrophin being produced, and is called Duchenne muscular dystrophy. Duchenne’s is more severe than the Beckers form, as the point mutation as opposed to deletion of the DMD gene results in some protein function being maintained in the Beckers form. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

[[File:Point_vs_frameshift_mutation_of_DMD_gene.png|500px|]]

Image 1: Point verses frameshift mutation of DMD gene

The largest gene of the human genome is called the dystrophin gene and is contained at the sacroplasmic surface of the plasma membrane (sarcolemma) of muscle fibers.<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> This particular gene codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres.

The dystrophin gene, also known as DMD, is located on the short arm of the X chromosome at position 21.2. In 1987, it was found that this particular gene was identified as being located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref> <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> In its normal functional form, this gene produces the protein dystrophin that has multiple forms, but however is found mostly commonly in skeletal and cardiac muscles. <ref>Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD</ref>

The exact function of dystrophin has not yet been well defined, however it is suggested that dystrophin plays an important structural, protective role and signalling role during muscle contraction. Table 1 gives a brief description on the role of dystrophin within muscle fibres and particular examples that support these ideas.
Table 1: The role of dystrophin in muscle fibres. .<ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref>

Role of dystrophin Brief description
Structural - Dystrophin is expressed within the sacrolemma and secures the sarcolemma to the actin cytoplasm
- This protein is said to be enriched in areas of cell-to-cell contact and is thought to be elastic and flexible hence protecting muscles from stress during contraction.
Protective - One end of dystrophin binds to the cytoskeleton through filamentous actin whilst the other binds to the dystrophin-associated protein complex (DAPC).
- The DAPC consists of cytoplasmic, transmembrane and extracellular proteins that provide a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix.
- In the absence of dystrophin, the DAPC weakens due to the loss of sarcolemmal integrity, resulting in muscle fibres being more susceptible to damage.
Signalling There are numerous examples that suggest a role of dystrophin in cell signalling. One example that will be given is the signalling role of alpha- syntrophin.
- Syntrophin links to the extracellular matrix through dystrophin and creates signal transduction complexes at the DAPC.
- Studies on mice show that in the absence of dystrophin, alpha-syntrophin is almost completely lost from the sarcolemma. This suggests that dystrophin plays an intermediate role in cell signalling pathways and especially in connecting signalling proteins to the DAPC.

Generally, muscular dystrophies can be inherited as dominant or recessive traits, or can be due to new mutations of a specific gene. <ref>Davies.K.E, Nowak. K.J (2006). "Molecular mechanisms of musclar dystrophies: old and new players." Nature Reviews. October, 2006 Volume 7, pages 763-773.</ref> As the dystrophin gene is located on the X chromosome, it can be said to be an inherited X-linked recessive condition. In the majority of affected males, the mutated gene has been inherited from the mother who is a carrier of an altered dystrophin gene, whilst a smaller minority of male cases are the result from a new mutation of this gene. In females, as they have two X chromosomes if one altered gene is expressed they are classified as carriers in that they ‘carry’ the altered gene but do not encounter any of the signs or symptoms of DMD. <ref>Genetics Home Reference. 2011. “Genetic Conditions: Duchenne and Becker muscular dystrophy.” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy</ref>

[[File:Point_mutations_resulting_in_DMD.jpg|550px|"Point mutations that result in the occurance of Becker and Duchenne Muscular Dystrophy"|]]

Mutations in the DMD gene can often result in the abnormal production or function of the protein, dystrophin. Some of these mutations include the deletion of part of the gene, abnormal duplication or alterations in the number of nucleotides. The two most common forms of muscular dystrophy are: Duchenne and Beckers Muscular Dystrophy.

Image 1 is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD). <ref>Medscape Reference (2011). Dystrophinopathies. Site author: Michelle L Mellion. Accessed via: http://emedicine.medscape.com/article/1173204-overview#a0104 </ref>

== Pathogenesis ==

[[File:Normal control muscle (a) vs. Duchennes muscular dystrophy muscle (b).jpg|200px|thumb|right|"Myofibers of normal control muscles(a)and Duchenne muscular dystrophy muscle (DMD)(b)"]]

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the [[#Glossary of terms|'''sarcolemma''']] to the actin [[#Glossary of terms| '''cytoskeleton''']] of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts<ref name= Chamberlain>Chamberlain, J. (2007),''' "Duchenne Muscular Dystrophy"''', in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).</ref>.

In Duchenne Muscular Dystrophy, a mutation on the dystrophin gene causes a lack or absence of dystrophin, which causes many problems. Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated [[#Glossary of terms |'''necrosis''']] and regeneration.<ref>S Carpenter, G Karpati. '''Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired.''' Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.</ref> Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. <ref>Sarnat, H.B. (1983) '''Muscle Pathology and Histochemistry''', American Society of Clinical Pathologists, USA: 114.</ref>.

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme [[#Glossary of terms| '''protease''']], an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of [[#Glossary of terms| '''myocytes''']] and inflammation.<ref name="Spurney">Spurney, C. F. (2011), Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle & Nerve, 44: 8–19. doi: 10.1002/mus.22097</ref> In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle<ref name="Spurney"/>. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue<ref name=Chamberlain/>. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy, and causes serious complications for sufferers of DMD.

The picture on the right is a comparison of normal muscle tissue with DMD muscle. Note the absent muscle cells, the fibrous material in between the myocytes in (b) and (c), and the lack of uniformity and rigidity. These features are characteristic of DMD.

'''Signs and Symptoms of Duchenne Muscular Dystrophy'''

According to the Bupa UK health insurance website <ref>Bupa(2009). “Duchenne muscular dystrophy”. Accessed via: http://www.bupa.co.uk/individuals/health-information/directory/d/duchenne-muscular-dystrophy</ref>, the general signs and symptoms of Duchenne’s Muscular Dystrophy are not usually apparent until the child is 3 years old.

Some of the typical symptoms include:
* Delayed motor movements
* Frequent falls
* Difficulty running, jumping, and getting up from a sitting or lying down position
* Large calf muscles
* Weakness in the lower extremities
* Poor balance
* Walking on toes or waddling gait
* Difficulty raising their arms
* Abnormal curvature of the spine
* Cardiac, respiratory and cognitive impairment

Many of these symptoms are due to the instability and weakness of the body's skeletal muscles. In particular, those symptoms associated with movement such as running, jumping, keeping balance and raising oneself from the ground are particularly prominent. Other complications, such as curvature of the spine or respiratory impairment are symptoms that often arise secondarily, or at a later stage in the progression of the disease. These manifestations and complications are elaborated further below.

== Clinical Manifestations & Complications ==

====Skeletal muscle====
[[File:Spinal_problems_DMD.jpg|300px|thumb|right|Spinal deformity in DMD]]

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD <ref>http://emedicine.medscape.com/article/1173204-clinical</ref>. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11.<ref name=Chamberlain/> Other indicators of the disease include [[#Glossary of terms| '''pseudohypertrophy''']] (particularly of the calf muscles), fatigue, leg cramps and Gower's Sign<ref>http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false</ref>. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from [[#Glossary of terms|'''joint contractures''']] in the ankle, knees and hips<ref>Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)'''Occupational Therapy and Duchenne Muscular Dystrophy'''. John Wiley & Sons, England.</ref>

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or [[#Glossary of terms| '''atrophy''']], [[#Glossary of terms| '''scoliosis''']] can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis. <ref>http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf</ref> If the muscles degenerate unevenly, kyphosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/</ref> can occur - excessive ''outward'' curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/</ref> - excessive ''inward'' curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

====Cardiac muscle====
A very common and serious complication of DMD is [[#Glossary of terms| '''cardiomyopathy''']]- on average, 20% of DMD sufferers will die from cardiac failure.<ref name=Chamberlain/> Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats<ref>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref>. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however <ref>Bushby K, Muntoni F, Bourke JP. '''107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy'''. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172</ref><ref>Finsterer J, Stollberger C.''' The heart in human dystrophinopathies'''. Cardiology 2003; 99:1-19.</ref>, in the late stages of the disease, the large quantities of fibroid material in the heart can cause [[#Glossary of terms| '''systolic''']] dysfunction and ventricular [[#Glossary of terms|'''arrhythmias''']].

====Smooth muscle====
DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or [[#Glossary of terms| '''pulmonary aspiration''']]. In the most extreme cases, patients may also suffer from [[#Glossary of terms |'''acute gastric dilation''']] or intestinal [[#Glossary of terms|'''pseudo-obstruction''']], both of which can be fatal.<ref><pubmed>PMID3380114</pubmed></ref>

''(I am aware this section is not finished - I am currently researching and writing it. --[[User:Z3332824|z3332824]] 14:17, 1 October 2011 (EST))''

====Respiratory problems====
Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, especially muscles such as the diaphragm and other muscles associated with breathing. The person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. They may not be able to cough properly either.<ref name= MDFAus>http://mdaustralia.org.au/files/2011/07/002_duchenne_becker-2011.pdf.</ref> As the lungs cannot function wholly, gas exchange is compromised. From this, [[#Glossary of terms|'''hypercapnia''']] may develop and can affect energy levels, weight management, cause bad headaches and disturb sleep.<ref name=Bushby>K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. '''The multidisciplinary management of Duchenne muscular dystrophy.'''Elsevier Current Paediatrics: 2005, 15(4); 293-300.
doi:10.1016/j.cupe.2005.04.001.</ref> Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness.<ref name=Chamberlain/>

The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure.<ref name=Bushby/>

====Cognitive Impairment====

The Muscular Dystrophy Association of Australia reports that up to one third of boys will suffer from a mental disability associated with DMD. <ref name=MDFAus/><ref name=Chamberlain/> However, very few are ‘severely’ impaired. Difficulties mostly arise in terms of emotional and social interaction – more specifically, in behavioural and communication skills. They may also have problems with verbal skills, particularly when asked to repeat long or large pieces of information. <ref><pubmed>18764980</pubmed></ref>

''(I am aware this section is not complete - I am still researching and writing about it. --[[User:Z3332824|z3332824]] 18:12, 1 October 2011 (EST))''

== Diagnosis ==

* '''Clinical Diagnosis''' - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.

* '''Muscle biopsy''' - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.

* '''Genetic Testing''' - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.<ref name="genome"><http://www.genome.gov/19518854#4</http://www.genome.gov/19518854#4></ref>

[[File:Speckle_Tracking_Echocardiograph_of_a_dog_affected_with_DMD.JPG|250px|thumb|Speckle Tracking Echocardiograph]]
* '''Physical Examination''' - a variety of methods are used to assess myocardial function. These cardiac findings can provide initial clues to the presence and extent of cardiac disease.
**Electrocardiography (ECG) - is able to detect myocardial scarring commonly found in DMD patients. The scarring produces [[#Glossary of terms| '''sinus tachycardia''']].
**Holter Monitors - monitors cardiac rhythm for a longer period of time compared to ECG and therefore can provide greater detail of sporadic abnormalities.
**Echocardiography - this method is the most universal standardised assessment of cardiac function. It uses sound waves to produce a 2D image of the heart which is clearer than an X-ray image.
**Cardiac magnetic resonance (CMR) - imaging is being more frequently utilized in DMD patients, providing a sensitive and reliable non-invasive measure of cardiac function.<ref name="Spurney"/>

A combination of these components along with family history confirms the diagnosis.

==Current Treatments==

DMD is a severe neuromuscular disease affecting male children. The progressive muscle deterioration causes the patient to become wheelchair-dependent.<ref>http://www.ncbi.nlm.nih.gov/pubmed/19774532</ref>Although there is no known cure for DMD to date, there are a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments include:

{|border="1"
|-style="background:cadetblue" align="center"
|'''Type of Treatment'''
|'''Description'''
|'''Examples'''
|'''Side Effects'''
|-style="background:"align="center"
|Physical Therapy
|Targets muscle strength and function. Research has shown that long term inactivity can weaken muscles and worsen the condition.
|Regular exercise and physiotherapy sessions. Surgery may also be required in situations of severe contractures and scoliosis.
|-style="background:"align="center"
|Orthopedic appliances
|These are aimed at improving mobility and the quality of life.<ref>http://jcn.sagepub.com/content/25/9/1116</ref>
|Braces and wheelchairs.
|-style="background:"align="center"
|Medication
|A variety of steroidal drugs are administered to treat symptoms.
|
*Prednisone- is a steroidal immunosuppressant drug targeted at improving strength and function of skeletal muscle<ref name="genome"/>.

*Cyclosporine - has been used in children to treat clinical signs by targeting cardiac myocytes and consequently decreasing cardiac hypertrophy<ref> http://www.webmd.com/drugs/mono-9108-CYCLOSPORINE+CAPSULE+-+ORAL.aspx?drugid=5645&drugname=Cyclosporine+OralIt </ref>.It weakens the immune system and makes patient susceptible to cancers and other types of infections.
|
Weight gain, high blood pressure, behavioral changes, weakened bones and delayed growth<ref name="genome"/>.

Depression, peptic ulcers, muscle or joint pain, high blood presure, changes in vision, seizures and unusual bleeding or bruising. <ref>http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#side-effects</ref>.

|}

== Future Therapies ==

The following table outlines future therapies, currently being researched,that are targeted at treating and managing DMD.

{|border="1"
|-style="background:cadetblue" align="center"
|'''Future Therapies'''
|'''Description'''
|-style="background:"
|Poloxamer 188 (P188)
|P188 is a non-ionic triblock copolymer, poly(ethylene oxide)80- poly(propylene oxide)27-poly(ethylene oxide)80.
Previous studies have demonstrated the beneficial capacity of P188 in preventing and reducing cardiac damage in DMD affected animals. Based on these animal studies, P188 could become an important acute therapy in DMD. <ref name="Spurney"/P 188 is known to stabilize red blood cell membranes in sickle cell disease.<ref>Ballas SK, Files B, Luchtman-Jones L, Benjamin L, Swerdlow P, Hilliard L, Coates T, Abboud M, Wojtowicz-Praga S, Grindel JM: Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 2004, 28(2):85-102.</ref>P188 directly targets membrane instability which is known to be one of the major pathological defects in dystrophin deficient cells.<ref>http://www.biomedcentral.com/1471-2261/11/20#B11</ref>

|-style="background:"
|Losarton
|Losarton is an ATII-type1 receptor blocker which modulates ATII signaling.
Studies have shown decreased myocardial fibrosis and preservation of cardiac function in DMD mice treated with losarton over a 6 month period. Based on these findings, it is possible that losartan could decrease both skeletal and cardiac muscle fibrosis and preserve skeletal muscle strength and cardiac function in DMD patients. Clinical studies using losartan are currently in progress. <ref name="Spurney"/>
|-style="background:"
|Idebenone
|Idebenone is a synthetic analog of coenzyme Q10.
It is an antioxidant medication shown to improve mitochondrial respiratory chain function and cellular energy production. A clinical trial was recently completed studying the effects of idebenone in DMD patients with cardiac dysfunction. <ref name="Spurney"/>
|-style="background:"
|Gene Therapy
|Due to the lack of specific medical therapies for DMD at this time, gene therapy offers the promise of a cure by replacing the mutated dystrophin gene in all muscle tissues.<ref name="Spurney"/> However this type of procedure has experienced many complications in regards to the medium of replacement and the possible side effects.
|-style="background:"
|Stem Cell Transplant
|Much of the initial focus was placed on myoblast transplantation however multiple studies showed little or no success. Research was then expanded to include stem cells that were myogenic precursors. These were obtained from bone marrow, satellite cells, muscle and blood-derived stem cells. Significant further research is required before stem cell therapy becomes a viable treatment strategy. <ref name="Spurney"/>
|-style="background:"
|Utrophin
|Utrophin is an autosomal protein encoded by a gene on chromosome 6 in humans. The primary structure is very similar to that of dystrophin, being 80% identical. Current research observes the upregulation of utrophin to replace dystrophin in DMD patients. Utrophin expression is predominantly driven by two promoters: A and B. Promoter A is responsible for the skeletal muscle-specific expression of utrophin and Promoter B drives expression in endothelial cells.<ref>http://ep.physoc.org/content/early/2011/09/19/expphysiol.2010.053025.long</ref>
|}

==Current Research & Treatment Prospects==

===='''Utrophin'''====
Recent research has suggested that utrophin could be highly effective in the treatment of DMD.Utrophin is the [[#Glossary of terms|'''autosomal''']] [[#Glossary of terms|'''homologue''']] of dystrophin<ref name=Blake><pubmed>8866746</pubmed></ref>. Utrophin shares 80% similarity with dystrophin<ref name=NatUtro><pubmed>16595608</pubmed</ref>, with only small changes in the structure of the protein. The gene UTRN encodes utrophin and is located on band q24 of chromosome 6. This gene is approximately 1/3 of the size of the dystrophin gene. During human fetal development, utrophin is found at the [[#Glossary of terms|'''sarcolemma''']] until week 26, when it is replaced by dystrophin, suggesting that utrophin is a fetal isoform of dystrophin.<ref name=Blake/>Utrophin expression is not affected by the DMD gene mutation, and thus could be very important for treating ''all'' DMD patients, regardless of the type of mutation<ref name=Miura><pubmed>16443393</pubmed></ref>. Below are summaries of two important and recent papers on utrophin experiments.

*''Daily Treatment with SMTC1100, a Novel Small Molecule Utrophin Upregulator, Dramatically Reduces the Dystrophic Symptoms in the mdx Mouse''
A group of researchers from England and Italy -Tinsley and Fairclough et. al, (2011)<ref name=Tinsley><pubmed>21573153</pubmed></ref> developed a utrophin up-regulator and tested its effects in mdx mice. This journal describes the results of their experiment. The researchers developed an utrophin up-regulator called SMT C1100, which with daily dosing, significantly reduced the pathology and problems associated with dystrophin deficiency. In their experiment, mdx mice were grouped and treated as per table below: [[Image:Utrophin effects compared to control.jpg|thumb|right|Reduction in pathological features of DMD from use of utrophin up-regulation in comparison to control group]]

[[Image:Experiment groups for utrophin upregulation.JPG|650px|none|Experiment groups for utrophin upregulation in mdx mice, used by Tinsley & Fairclough et. al (2011)]]

Analysis was conducted on muscle mechanics, electrophysiology, proteins, RNA, blood and histology from each group of mice. For each variable above, the researchers described in detail the effect of utrophin on the muscle cells and how it was improved.
The results of the experiments showed that SMT C1100 had a significant impact in the treatment of DMD, especially when combined with Prednisone (PDN -type of glucocorticoid used to treat DMD). The increased levels of utrophin significantly reduced the dystrophy pathology of [[#Glossary|'''fibrosis''']] and inflammation of the muscle cells, and led to increased strength and resistance to fatigue after exercise. Other researchers<ref name=Squire><pubmed>12471059</pubmed</ref> have found similar results in experiments using utrophin therapies on mice.

Based on their results, the researchers argue that use of utrophin is very effective as it addresses the primary cause of dystrophy (i.e. it replaces the role of the missing dystrophin) and therefore can treat all mutations of Duchenne muscle dystrophies. They argue strongly the importance of retesting formulations of the utrophin up-regulator and its use in human DMD trials.

*''Naturally occuring utrophin correlates with disease severity in Duchenne muscular dystrophy''
This paper examines human DMD patients, evaluating the role of utrophin in the severity and progression of the disease. Sixteen DMD patients were investigated using muscle [[#Glossary|'''biopsies''']], muscle protein analysis, and ages at moderate disability and wheel-chair bound stage was recorded. Their results showed that DMD sufferers had up to eleven times higher levels of naturally occuring utrophin than normal adult muscle, and that utrophin expression increases with age.

Importantly, a second positive correlation was found between the quantity of utrophin at the first muscle biopsy and age at reaching wheelchair stage. From this, the authors concluded that utrophin has an ameliorating effect on muscle dystrophy and that this extended the time for which the patient could move independently.
The results of this experiment are very similar to other studies<ref name=Tinsley/> demonstrating the positive effect of utrophin in mice. In light of their results, the authors argue that utrophin is a suitable replacement for dystrophin, and is also a viable treatment for human muscle dystrophy disorders. They argue that further research and trials, particularly in humans, is needed.

==Duchenne Muscular Dystrophy Foundations and Organisations==

*'''Muscular Dystrophy Foundation Australia '''- This foundation has been set up to raise awareness of muscular dystrophy disorders and to fund research and support groups across Australia. It has offices in each state that collaborate together. They describe their values as ''innovative, passionate, determined and embracing.
Link to their website: http://mdaustralia.org.au/

*'''Muscular Dystrophy Campaign''' - This group is based in the United Kingdom and has a strong research and clinical trial programme. Similar to the Australian foundation, it also aims to raise funds and awareness of muscular dystrophy disorders.
Link to their website: http://www.muscular-dystrophy.org/

== Glossary of terms ==

*'''Acute gastric dilation:'''short, severe expansion or distension of the stomach, can cause the stomach to twist

*'''Arrhythmias:''' abnormal heart contractions/irregular heart beat.

*'''Atrophy:''' wasting away or disintegration of; decrease in size, owing to disease, misuse, injury.

*'''Autosomal:''' a non-sex chromosome

*'''Cardiomyopathy:''' heart muscle disease

*'''Cytoskeleton:''' microscopic skeleton of a cell within the cytoplasm, composed of protein

*'''Creatine kinase:''' an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.

*'''Dystrophy:''' degenerative disorder; weakens and atrophies

*'''Fibrosis:''' a repair process by the body in response to injury- damaged tissue is replaced by connective tissue and often results in a scar

*'''Homologue:''' (needs definition!!)

*'''Hypercapnia:''' abnormally high levels of CO2 in the bloodstream

*'''Joint contractures:''' stiffness of the joints, prevents movement or full extension and flexion

*'''Macrophage:''' lymphatic cell found throughout the body; clears dead cells and debris.

*'''Myocyte:''' a muscle cell

*'''Necrosis:''' cell death in a particular region of tissue

*'''Protease:''' an enzyme that breaks down proteins and peptides

*'''Pseudohypertrophy:''' enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.

*'''Pseudo-obstruction:''' when a patient expresses the symptoms of intestinal blockage, but there is no physical blockage. Can be acute or chronic.

*'''Pulmonary aspiration:''' entry of foreign material (food, drink, stomach contents like bile or vomit, pharyngeal secretions) from the oesophagus into the trachea or lower respiratory system.

*'''Sarcolemma:''' The thin membrane of striated muscle fibers.

*'''Sacroplasmic:''' (sacroplasma) The cytoplasm of striated muscle cells

*'''Scoliosis:''' abnormal curvature of the spine

*'''Sinus tachycardia:''' rhythm in which the rate of impulses arising from the SA node is elevated

*'''Systolic:''' maximum blood pressure during contraction of the heart

== References ==
<references/>

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)

File:Point mutations resulting in DMD.jpg

2011-10-03T22:44:14Z

Z3332629:

This image is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD).
{{Template:2011 Student Image}}.
Image creator: Ashleigh Pontifex (z3332629)

Student image constructed based on the image presented on: http://emedicine.medscape.com/article/1173204-overview#a0104

Point mutations resulting in Muscular Dystrophy by Ashleigh Pontifex is licensed under a Creative Commons Attribution-NoDerivs 3.0 Australia License.
Based on a work at emedicine.medscape.com.

<a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/au/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nd/3.0/au/88x31.png" /></a> Point mutations resulting in Muscular Dystrophy by Ashleigh Pontifex is licensed under a <a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/au/">Creative Commons Attribution-NoDerivs 3.0 Australia License</a>. Based on a work at <a xmlns:dct="http://purl.org/dc/terms/" href="http://emedicine.medscape.com/article/1173204-overview#a0104" rel="dct:source">emedicine.medscape.com</a>.

File:Point mutations resulting in DMD.jpg

2011-10-03T22:42:07Z

Z3332629: This image is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame tha

This image is a visual display of the different types of mutations of the dystrophin gene that result in different forms of musuclar dystrophy. The first reading frame is that of a normal dystrophin gene and can be compared to the second reading frame that reflects a point mutation in which one of the bases has been altered, resulting in an abnormal production of dystrophin. This type of mutation results in what is clinically known as Becker’s Muscular Dystrophy (BMD). The second reading frame can then be further compared to the final reading frame that has a point deletion mutation, resulting in a new reading frame for this particular gene. The end result is a truncated protein product that is known as Duchenne Muscular Dystrophy (DMD).
{{Template:2011 Student Image}}.
Image creator: Ashleigh Pontifex (z3332629)

Student image constructed based on the image presented on: http://emedicine.medscape.com/article/1173204-overview#a0104
<a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/au/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nd/3.0/au/88x31.png" /></a> Point mutations resulting in Muscular Dystrophy by Ashleigh Pontifex is licensed under a <a rel="license" href="http://creativecommons.org/licenses/by-nd/3.0/au/">Creative Commons Attribution-NoDerivs 3.0 Australia License</a>. Based on a work at <a xmlns:dct="http://purl.org/dc/terms/" href="http://emedicine.medscape.com/article/1173204-overview#a0104" rel="dct:source">emedicine.medscape.com</a>.
Point mutations resulting in Muscular Dystrophy by Ashleigh Pontifex is licensed under a Creative Commons Attribution-NoDerivs 3.0 Australia License.
Based on a work at emedicine.medscape.com.