Friday, January 20, 2017

Emery Dreifuss Muscular Dystrophy and Lipodystrophy

Public radio is a consistent source of content about medical problems that contain lessons for everyone.  I happened to hear one last weekend.  The program was This American Life and the story was called Do These Genes Make Me Look Fatless.   The story starts out with writer David Epstein describing the public reaction to his latest book The Sports Gene.  As part of the correspondence a 39 year old woman named Jill Viles sent him an illustrated letter and it contained the heading "Olympic Medalist and Muscular Dystrophy Patient with the Same Mutation."  The side by side photos of Jill Viles and Olympic sprinter  Priscilla Lopes-Schliep are side by side on the web page and I encourage anyone reading this to take a look at the comparisons and try to figure our how Ms.  Viles came to this conclusion.  Epstein was interested and replied getting a detailed scientific brief in return.  He got a second opinion from a geneticist that he consulted in the making of his book who concluded that Ms. Viles was probably wrong about the genetics.

From there the story goes into the incredible history of Jill Viles and how she started to research her illness.  After normal early developmental milestones she started tripping and falling at the age of 4.  She was taken to the Mayo Clinic and Jill, her brother and father were all tested and showed evidence of muscle damage.  They concluded that although it looked like muscular dystrophy, girls never got it and therefore she did not have muscular dystrophy.  Over the next 8 years her arms and legs got extremely thin,  she had a burning sensation in the legs, and all of the subcutaneous fat in her extremities disappeared leaving very prominent veins.  Within a few weeks she started to fall again and was no longer able to ride a bike or roller skate.  She regained her ability to walk and then began a very unusual research program to see if she could find out what was wrong.

She started by looking at tales of the supernatural - like poltergeists.  She reasoned that the people in these books she was reading could not explain what was happening to them and she might find an answer.  Then she went to college and started to study medicine on her own.  Her project involved reading textbooks and journal articles on muscle diseases trying to find one that matched her own experience.  She was reading an article on  Emery-Dreifuss  muscular dystrophy when she noticed the description "Popeye arms" and had an immediate association to the appearance of her father's arm.  As she read the description she noticed that she had features of the illness.  She took a number of the books home on break and her father discovered that he had both the muscular and cardiac symptoms with bradycardia into the 30 beat per minute range.  His doctors told him the symptoms were from exposure to a virus.  He was re-evaluated and a pacemaker was placed.

Jill went to a neurology clinic for confirmation of the diagnosis, but the neurologist there just make a diagnosis of Muscular Dystrophy.  She got angry and would change the diagnosis by writing in the chart.  The rationale was that women do not get Emery Dreifuss Muscular Dystophy (EDMD).  She eventually located a group of researchers in Italy specializing in the disorder and sent them blood samples of her entire family.  Four years later she had confirmation that she had the gene - a single base pain mutation on the Lamin gene.  According to the Universal Mutation Database the LMNA gene has 464 known mutations and 283 variants.  Some of the diseases are more well known than others.

At this point before I get into some additional details of the illness, this is clearly an inspirational story.  Jill is clearly a very bright person.  Transitioning from an explanatory paradigm that went from the supernatural to cutting edge DNA and genetic research within a few years while dealing with a significant chronic medical problem for  which there was no clear diagnosis or treatment is astonishing.  It is a testament to her intelligence, character, and mental flexibility.  In the process she her research also made a significant difference in her father's life and the life of Olympic sprinter Lopes-Schliep.  Hearing her speak about these details in the audio file is necessary to bring some of these details to life.

Jill got a job in a lab at Johns Hopkins combing the research for any reference to the lamin gene.  In the process she came across another photo that reminded her of her own appearance.  In this case the prominent feature was a loss of subcutaneous fat called partial lipodystrophy.  She maintained that she also had this rare disorder and was met again with denials - in this case based on the likelihood of having two rare genetically determined illnesses.  This time she believed the deniers.  She also started to get increasingly anxious in reading about  EDMD and the short life expectancy.  She stopped the research completely and started teaching at a local community college.  She got married and gave birth to a son who does not have EDMD.  She had more severe weakness after the pregnancy.  Jill's father died suddenly at age 63.  In the gathering at the familiy home her sister showed her pictures of Priscilla Lopes-Schliep.  She noticed the characteristic pattern of veins and muscle fibers.  Twelve years after she stopped researching EDMD she started to research lipodystrophy.  Eventually Jill arranged a meeting and they both  submitted samples to a world expert on the condition - Dr. Abhimanyu Garg.  He confirmed they both had the same rare type of hereditary lipdystrophy.  It turns out that the partial lypodystrophy mutation and the EDMD mutation are both on the lamin A/C gene LMNA.

Jill also reached out to Etienne Lefai a researcher studying SREBP-1, transcription factors that control muscle mass through protein synthesis.  Overexpression of these same factors can lead to muscle atrophy.  Dr. Lefai credits Jill with changing the path of his research when she reached out to him.  He described her a awesome and the only example of someone outside of the research community coming in and altering his basic path of research.    

I agree completely with Dr. Lefai.  Part of the story here is how much credence you give the theories that your patients have.  For a psychiatrist it is somewhat easier.  Good psychotherapy depends on finding out underlying theories, testing them and suggesting alternate theories at times.  It can be a trying process.  Sometimes your patient really is being followed by the FBI and figuring that out is a major decision in the diagnosis and treatment plan.  I have gone to some elaborate lengths to create an experiment and conferenced in some experts from other fields like electrical engineering to test a person's theory about how the  world  works.  In the addiction field it is very common to encounter people who have never had a chemistry course in their life and now consider themselves to be experts in pharmacology and organic chemistry.  I listen to all of these theories and carefully weigh them and consider their overall meaning.  It was interesting to read why the experts rejected Jill's correct theories and how they gradually came to accept them.          

Another reason for this post is that is also allows me to highlight what I consider to be the best resource on the Internet for musculoskeletal diseases and that is the Washington University Neuromuscular Disease Center. It is essentially a free online text in neuromuscular diseases ranging from the clinical presentation to pathology to molecular biology.  It is an immediate resource for any physician treating someone with a neuromuscular disease.  In the case of Emery Dreifuss MD, there is a comprehensive page with the genetics listed right at the top.  The National Organization of Rare Diseases has a web page on congenital lipodystrophies.

I often think about what research was like when I was in medical school.  My wife and I would head to the Medical Library and I would run around pulling bound journals while she copied the articles that I needed.  That was a lot of heavy lifting that is no longer necessary thanks to the modern flow of information.

I thought about that when the story described Jill lugging heavy books home in a backpack.  That was definitely another measure of her determination.

George Dawson, MD, DFAPA


1: Dessalle K, Euthine V, Chanon S, Delarichaudy J, Fujii I, Rome S, Vidal H,Nemoz G, Simon C, Lefai E. SREBP-1 transcription factors regulate skeletal muscle cell size by controlling protein synthesis through myogenic regulatory factors. PLoS One. 2012;7(11):e50878. doi: 10.1371/journal.pone.0050878. PubMed PMID:23226416.

2: Gnocchi VF, Scharner J, Huang Z, Brady K, Lee JS, White RB, Morgan JE, Sun YB, Ellis JA, Zammit PS. Uncoordinated transcription and compromised muscle function in the lmna-null mouse model of Emery- Emery-Dreyfuss muscular dystrophy. PLoS One. 2011 Feb 22;6(2):e16651. doi: 10.1371/journal.pone.0016651. PubMed PMID: 21364987.

3: Scharner J, Brown CA, Bower M, Iannaccone ST, Khatri IA, Escolar D, Gordon E, Felice K, Crowe CA, Grosmann C, Meriggioli MN, Asamoah A, Gordon O, Gnocchi VF, Ellis JA, Mendell JR, Zammit PS. Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations. Hum Mutat. 2011 Feb;32(2):152-67. doi: 10.1002/humu.21361. PubMed PMID: 20848652. 

4: Scharner J, Gnocchi VF, Ellis JA, Zammit PS. Genotype-phenotype correlations in laminopathies: how does fate translate? Biochem Soc Trans. 2010 Feb;38(Pt 1):257-62. doi: 10.1042/BST0380257. Review. PubMed PMID: 20074070.


Figure at the top is from National Library of Medicine Genetics Home Reference page on the LMNA gene.  It is the cytogenetic location of the LMNA gene.  It was generated with the NCBI Genome Decoration Page.  The copyright is Health and Human Services and I assume this is public domain.

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