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October 2005 Bethlem Myopathy/Ullrich MD conference notes

New! PT 2011
August 2008 Bethlem Myopathy/Ullrich CMD conference notes
October 2005 Bethlem Myopathy/Ullrich MD conference notes
Update 2006
Update 2005
Update 2004
Julie's Hypotonia Story
The Medical Puzzle
The Muscle Biopsy
The Diagnosis
Physical Therapy--updated in 2008!
Seating at school
Julie's Wheels
The Sleep Studies
Julie's flexible Daddy
Bethlem Myopathy--DNA and Muscles
Julie's Bethlem Myopathy Book

This October, I attended a conference for families affected by Bethlem Myopathy and Ullrich Muscular Dystrophy.  These are my notes from the conference that I shared with my pals on the yahoo myopathy list...they are NOT to be taken as medical advice and they are only as accurate as my memory.  In other words, if you are looking for reliable medical information, this isn't the place! 
The conference was put on by Dr. Carsten Bonnemann at CHOP with help from the MDA.  Dr. B is a neurologist and is both a clinician and a researcher.  It was his lab that did Julie's skin biopsy and found the collagen VI deficiency that led to her Bethlem Myopathy diagnosis.  Julie sees him briefly at her semi-annual neuro visits, but is mainly followed by Dr. Finkel.  The MDA social worker Alan was there, along with one of the two MDA PT's also named Alan (he's an equipment guru), an MDA nurse giving flu shots, and a bunch of the research team from two different labs.  In addition, there were a good 30 parents and their children.  There was also a 23 year old young man named Simon with Ullrich who spoke very eloquently about what it's been like for him growing up and coming of age.
The first speaker was Mon-Li Chu, PhD,  who is a dermatology and cutaneous biology biochemistry professor and researcher at Jefferson University which is also in Philly.  She described her her work isolating the makeup of collagen VI and then discovering the three genes that control making collagen VI.  Seems that there are 27 types of collagen and collagen is almost all tissues in the body--muscle, tendon, skin, cartilage at the very least.  Collagen VI surrounds muscle cells, surrounds bundles of muscle fibers, and is in the tendons connecting the muscle to bone.  Problems with a different collagen are at issue with EDS, Osteogenesis Imperfecta, etc.  Anyhow, having discovered all this by 1988, Dr. Chu was left with the question "is there a connective tissue disease associated with collagen VI?"
Seems that the answer came in 1996 when a Dr. Speers at Duke University contacted her about a large family with a collagen VI defect.  Speers and another researcher Jobsis each published papers identifying families with collagen VI defects related to the different genes on chromosome 21 and 2.  Around the same time, two docs in Italy, Pepe and Bertini, figured out that the scleroatonic MD described by Ullrich in 1930 was in fact one of these severe collagen VI problems.  Bethlem was described in 1976 by a doctor named Bethlem.  Now, the thinking is that Ullrich and Bethlem are not separate diseases, but rather a clinical spectrum of the same disease.  Bethlem is dominant--either you inherit it from an affected parent or you have a new mutation that is genetically dominant and has a 1 in 2 chance of being passed on to your children.  Ullrich is recessive, so either each parent is a carrier or it is also a new mutation.
What happens with the collagen VI is interesting...seems that you need three chains of proteins to make it.  In Bethlem, the amino acid glycine is replaced by a larger amino acid and it screws up the works, weakening the structure of the collagen VI.  It's there, but it doesn't work well or look right.  In Ullrich, my understanding is that the replacement of glycine is worse and the collagen VI can't form at all.
Dr. Bonnemann showed slides of muscle biopsies with normal muscle, Bethlem muscle and Ullrich muscle.  In normal muscle, the muscle cells were all the same size and the collagen VI was present in between the cells and overlapped the muscle membrane.  They don't know why the membrane and collagen VI need to overlap and interact or what kind of "messages" are passing from the muscle cells and the collagen VI.  You can just see it in the staining.  With Bethlem, the collagen VI is there, but it lies adjacent to the membrane rather than overlapping it.  The muscle cells are different sizes, too.  With Ullrich, there is no collagen VI and the muscle cells are a mess and loaded with excess connective tissue.
Since collagen VI is all through the body, there are a lot of questions with Ullrich and Bethlem and whether other systems are affects, such as the blood vessels, bladder and GI system.  There has been a lot of reporting of reflux and GI stuff in Dr. Bonnemann's experience (which, needless to say, piqued Donna's interest) and these are all clinical issues being explored by the docs.  I am curious about this with Julie who may or may not have developed some reflux this past spring.  Pepcid nightly seems to have done the trick, but we are supposed to stop using it and see how she does one of these days.
Clinically, Dr. Bonnemann described the Bethlem/Ullrich continuum as a congenital muscular dystrophy with a very wide range of presentation and severity.  Congenital hypotonia, distal hyperlaxity (distal means far from the trunk) and proximal contractures (proximal means close to the trunk), scoliosis, later contractures and breathing problems all seems to define Bethlem and Ullrich.  Floppiness at birth is seen with initial improvement, a plateau, and a slow progression.  I guess with Ullrich this course is in childhood, possibly very early childhood, but with Bethlem the improvement can go on through childhood and progression can be very slow and not necessarily impairing.  In a Dutch study, 50% of the patients with Bethlem needed some kind of assistance with ambulation (not necessarily a wheelchair) after age 60.  If my dh and his father are any indication, Bethlem can be a big ho-hum overall.  On the other hand, Julie is more affected at this age than they were.
My understanding was that with both Ullrich and Bethlem, after the plateau, the person does not necessarily have progressive weakness, but the contractures are progressive.  Ullrich contractures become severe and pretty intractable and that is what is most disabling.  Contractures of the rib cage can restrict breathing which is most evident at night when you are breathing with just your diaphragm and the ribcage is not expanding as it should to help.  The diaphragm is weakened at least some by this as well, hence the extra difficulty at night.  So the best way to monitor breathing is with sleep studies since daytime breathing is not affected.  Once breathing is affected, it seems that bipap/cpap does the trick and the breathing reaches a certain point of being affected and then stays there. 
There are prospects for treatment with gene therapy, stem cell transplantation and possibly meds to prevent cell death.  However, all this is a LONG way off and there are a lot of big questions still standing in the way, like what in the body actually makes the collagen VI?  They think it's the fibroblasts, but they are not positive.  What's going on in the tendon with the lack of collagen VI that it starts to get tight?  Of course, research dollars are shrinking, etc., etc.
It is also suspected that Bethlem/Ullrich is more prevalent than they thought not even a few years ago.  It is highly suspected that many people labeled with EDS actually have Bethlem or Ullrich.  I *think* the difference is the effect on the muscles....
One "aha" was the suggestion that creatine in low doses can be helpful with muscle cramps and fatigue.  You have to be careful not to overdose because it can cause kidney stones (which are NO fun) and, with all this stuff, some people respond to creatine and some do not. 
That's pretty much what I remember from my notes.  We were wrapping up with questions and I opened my social worker big mouth and asked whether the parents in the room wanted to share their top two or three concerns for their child.  For Julie, I am most concerned with her pain and fatigue, with motor delays just a bit below that.  The other parents had a variety of concerns, including GI stuff, breathing, independence, and the emotional issues.  There was a 23 year old young man there who maneuvered his power chair up to the front and talked about growing up with Ullrich and getting an engineering degree from Villanova.  He really felt that he was more concerned with typical things growing up than with his disability.  He did concede that having to use a wheelchair was a loss and that he struggled especially with having to switch to full time use of a power chair when he was in high school.  However, he views his disability as something that he has to work around but that's it.  He lived on campus in college and only had a personal assistant to help him get to bed at night and up and dressed and in his chair in the morning.  Now he lives at home and says he has the same concerns as his friends--getting a job and earning enough money to live on his own!  He drives and is very proud of his adapted van.
So what did I take away from all this?  I will run this by Dr. B and Dr. F, but I guess I am no longer doubtful about Julie's dx.  It seemed to me that without being able to say she has one of the three COL6 genes, we didn't know for CERTAIN that she has Bethlem.  But the collagen VI deficiency found in her skin biopsy seems pretty darn definitive after what I learned at this conference.  I may be mistaken or maybe the docs don't know yet, but Julie's symptoms plus this collagen VI deficiency really do add up to Bethlem--seems like they would have mentioned other possibilities if they knew of any.  I also got a better understanding of how this all works...with central core, for example, there is a defect in the muscle cells that makes those cores and messes things up.  With Bethlem, there is a defect with collagen VI which affects how the muscle cells are formed and how they group and how they work, along with possible effects on the tendons, skin and maybe more.  I think the future is likely to be reasonably ok for Julie...I'm still not certain where her plateau will be or what will happen with contractures later on, but her condition is on the milder side for Bethlem from what I can tell so that's good.  If my father-in-law is any indication, Bethlem contractures may look a little funny when you are in your 60's, but they are not disabling.  To look at my FIL, he appears to me to have elbow contractures because his arms are pretty bent when he is standing at rest.  He has finger contractures, too, by the looks of things when he puts his hands together, palm to palm.  But neither of these limits him in any way.  Yes, he is not a track star, but he is a college professor, father, grandfather, walking, driving, etc., etc.