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




References:

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.


Attribution:

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.

https://www.thisamericanlife.org/radio-archives/episode/577/transcript

http://www.emerydreifussmd.org/genetics.html

Elimination of Homosexuality from the DSM - An Old But Important Story

I follow Michael Blumenfield's blog Psychiatry Talk and his most recent post reminds us that homosexuality was eliminated as a diagnostic category from the DSM 40 years ago.  Incredibly he interviewed the President of the American Psychiatric Association at the time of this decision and has these interviews posted on his blog.  Many years ago, I encountered a piece done on This American Life that documented another side to the process.  In that discussion Robert Spitzer one of the main architects of the DSM was directly influenced by his attendance at a parallel meeting of gay and lesbian psychiatrists - informally self titled the GAYPA.  He was apparently struck by the fact that homosexuality did not confer any disability in terms of psychiatric careers or social functioning and advocated for eliminating it from the DSM.

Dr. Freedman's interview (especially recording 2 and 3) starts to talk about the issues raised by the Committee for Concerned Psychiatry.(paragraph 4).  The major issues of the day were opposing the Vietnam War and homosexuality as a disease.  Dr. Freedman accepted their offer to be a petition candidate to oppose the "old boy's club" approach to APA presidency.  He describes the 1972 APA Annual Meeting in Dallas where a  gay APA member gave a talk wearing a disguise about how the DSM definition had harmed him.  He received a standing ovation.

Dr. Freedman refers to Spitzer as the Chair of a Task Force to look into homosexuality.  He prepared a document that supported dropping homosexuality as a diagnosis.  At the same time the APA Board and members were strongly in favor of it.  It was debated in committees on nomenclature, research and reference committees in a process similar to the recent DSM-5 process.  The evidence to maintain the homosexuality was found to be unscientific, based on highly selected samples and it was rejected.  The decision was front page news in both the New York Times and Washington Post.  On December 16, 1999 the Washington Post selected the APA decision as one of the "stories of the century."

There was not complete consensus and two psychoanalysts insisted on a referendum at the next election and their petition was defeated by a margin of 2:1.  Dr. Freedman provided this information because of criticism that the APA Board and not the membership favored the elimination of homosexuality.  He points out in retrospect that there were other issues that he was focused on at the time including the theft of psychoanalytic records during the Watergate scandal and the reaction to that incident.  He also raised the issue of psychiatric abuse in the Soviet Union and interview detainees who had been inappropriately placed in psychiatric hospitals.  The APA contingent refused to travel to the USSR unless they would have access to patients in psychiatric hospitals and could interview them.  The Soviets sandbagged the process by presenting cases of severe chronic mental illness and not allowing interviews.  

The 81 Words piece is given primarily by Alix Spiegel, the granddaughter of John Spiegel a past President of the APA.  At the time of this decision he was President Elect of the APA.  She waxes rhetorical at times about psychiatry but I won't dwell on those details.  They are minor in comparison with a well researched human interest story about the parallel stories that factored into this decision. She also discusses a parallel story within her family based on the occurrences at the time.

At the time that Dr. Spitzer decided to eliminate homosexuality as a diagnostic category he was probably early in his career in terms of designing diagnostic criteria and extending the DSM technology. He has described that process as basically reviewing literature, talking with experts and trying to type up a notecard with the criteria for that disorder. The MPR piece described his process with regard to the homosexuality question as more complex. He first met with a gay activist and wanted to understand that viewpoint. Several months later he arranged for three gay activists to present their case to the DSM nomenclature committee. A forum was organized at the 1973 APA Convention in Honolulu with an open debate between the analysts supporting homosexuality as a diagnosis, a faction of psychiatrists who did not, and Ronald Gold, the gay activist who befriended Spitzer. The event that led to the redraft that evening was Spitzer's attendance at the GAYPA party later that evening. After stating that he did not know any gay psychiatrists, he saw many notable psychiatrists at that meeting and went back to his hotel and redrafted the DSM criteria.

I have an interest in flagging these resources for future reference.  Listen to the This American Life piece and the interviews by Dr. Blumenfield.  This is a compelling story and clearly a decision that the APA and its membership got right.  A common criticism of psychiatry is that it is unscientific or pseudoscientific and yet one of the main points in this historic decision was the rejection of psychoanalytic research that was considered unscientific.  Dr. Freedman's commentary points out that the decision went through a process that seems to be very similar to the current DSM-5 process.  Contrary to the flurry of criticisms of the DSM-5 before the recent release, this decision was precedent setting.  It preceded most state laws regulating gay marriage by nearly 40 years.  It was hailed as recently as 1999 as being a story of the century.  And yet the press image of the DSM process suggested that the organization was socially inept and could not be trusted with similar decisions without close monitoring by non-medical organizations.

If anything this decision combined with precedent setting decisions on confidentiality, commenting on public figures, and banning psychiatry from participating in torture and capital punishment suggests that psychiatry should be one of the first professional organizations consulted.  Anyone reading this blog gets the message that the APA is far from perfect, but at times they get it very right.  This is a forty year decision that has stood the test of time and is also a good example of activism within the organization as a driving force.  Activism and political tension within the organization can be as important as the science behind the position.

George Dawson, MD, DFAPA

1.  This American Life.  81 Words.  January 18, 2002.  The NPR story of how the American Psychiatric Association decided that homosexuality was no longer a mental illness.

2.  Michael Blumenfield, MD. 40th Anniversary of "Homosexuality" Being Removed from DSM.

3.  DSM-II Change - The actual DSM-II change involved the category "Sexual Deviations".  The introductory paragraph was 81 words long and "302. Homosexuality" was removed from the list.  It begins with the sentences:

"This category is for individuals whose sexual interests are directed primarily toward objects other than people of the opposite sex, toward sexual acts not usually associated with coitus, or toward coitus performed under bizarre circumstances as in....."

Adapting to a Mother with Problems

Mothers have historically held a prominent place in psychiatry.  The public often thinks that mothers are blamed for problems with their children, but the research on the matter is less clear and more subtle.  That is true even in the case of theorists who placed very little emphasis on individual psychopathology and more on problems within the family system.  The concept of "expressed emotion" evolved to describe a critical home environment that may be associated with exacerbations of schizophrenia.  Childhood adversity is the current concept that describes a number of factors that children must negotiate and that can be very problematic.  The goal of looking at these factors in childhood is an important part of any psychiatric evaluation, but not to look at someone to blame.  They are important indicators of the degree of resilience, their perspectives on important relationships and how their relationship with important childhood figures affected their personality development.  Almost everyone can recall a critical event that happened in their childhood and they can freeze it in time based on other memory associations.  I happened to hear a great example of this on the public radio show "This America Life" today.

The theme of the program today was babysitting and the piece I am interested in was the last segment called "Act Three.  Yes There is a Baby"   It is a recollection of how a son and daughter interacted with their single mother.  It is really a story of how two kids adapted to a mother who had severe problems.  It is also a story of how remote events continue to affect people over time.  One of the most surprising and consistent observations I have made in my discussions with people over time is how the relationships with parents and siblings are long lasting.  They don't seem to fade away over time.  Strong emotions and patterns of interpersonal interaction persist for decades if not an entire lifetime.  Having no contact with your parents or siblings for prolonged periods of time usually has little effect on these dimensions.  This story starts out with a teenage daughter making up a family - the McCrearys who she was babysitting for in order to escape her mother's limitations on her freedom  to move around in the 1940s.

This story interested me for a number of reasons, not the least of which is the way it echoed many themes that I have heard from people as well as my own personal experience.  The other important point is that it is a true story.  With the current constraints on the discussion of true stories by medical professionals, I think we will need to rely more and more on true stories that are openly disclosed in the media.  The eliminates any possibility of professional intervention but it allows for the emphasis of important points.  In this case I have linked to the transcript because the audio file is not available until later.  I agree with the disclaimer on the web site that you should actually listen to the audio file to get the full impact and hear the story in the voices of the people involved.

The story begins with the son Myron telling Ira Glass about how the rules about staying out from the family home were very different for him and his sister.  He enjoyed a fair amount of freedom but his mother restricted his sister to going out to church dances.   When his sister Carol is contacted, she describes a situation that is much worse.  She was followed by her mother's friends.  Her mother began calling her a whore at an age before she knew the meaning of the word.  Whenever she was employed as a babysitter, her mother needed to know the number in order to check on her.  She would also remind Carol and Myron that when their father died she got a lot of advice that she she put them both in an orphanage.  She did not and described it as the biggest mistake in her life.

In order to adapt to her mother's restrictive and abusive parenting style, Carol invented a family and would say that she was babysitting for this family when she was really sleeping out on the beach or staying with friends.   Mr.  McCreary was an FBI agent and therefore she could not give her mother their telephone number.  She was also being paid for babysitting in stocks and bonds, so there was no proof of babysitting in money.

The interesting psychiatric aspects of this story are basically threefold.  Early on Myron points out that the whole concept of "imaginary people" was something that he and his sister got directly from his mother.  She talked about seeing a lawyer, a psychiatrist ("psycholotrist"), and a doctor.  In every case the appointments with these imaginary professionals was foreboding.  She told the children that she was seeing the lawyer in order to make arrangements to put them in an orphanage.  The psychiatrist told her that her children were driving her crazy.  The doctor told her she was going to die.

Myron tells the story of coming home one day when he was ten years of age and his mother telling him that she was arranging for him to go to an orphanage with a local priest.  He decided he would go away to school at that time, even though he knew there were any number of ways he could have sabotaged it, basically because his mother had been threatening him with an orphanage "all of my life".  As a part of that process his mother wanted reassurances that he thought about her "crying my eyes out" when he was at  his "fancy school".  He decided from that point on (at age 10) that he would never ask his mother for anything or look to her for anything again.  He had that insight when he was 30 years old.

Carol lashed out at her mother when she was about 35 years old.  Her mother reacted by crying and it was the first time she had ever seen her cry.  When her mother stopped crying she said that she did the best that she could have and this lead Carol to the insight:

"And I thought, oh my god, she did. Her best was so bad. Her best was so empty. But she couldn't do any better.."

Accepting that truth and recognizing the importance that her mother had to her grandmother and aunt lead Carol to modify her emotional response to her mother.

The themes in this story are important in psychotherapy and form the basis for most psychodynamic therapies.  Although they never made it explicit Carol and Myron both had unique strategies to adapt to their mother's problems.  This is a story that has universal appeal.  Everyone has landmarks in his or her personal history when an interaction with a parent or a sibling is an organizing event in the rest of their life.  The number of possible decisions and behaviors based on that event and their complexity are are well illustrated in this family history.  The resilience of these two children and how they overcame childhood adversity is remarkable.

George Dawson, MD, DFAPA