MTM~CNM Family Conference

Dr. Alan Beggs: MTM and the Centronuclear myopathies: Current researchers and prospects for therapies:

Objectives of talk: Define congenitla myopathy, Genetics of CNMs. "biology" of CNMs, animal models and approache to therapy.

Definition: primary hypotonia and weakness in early onset of like and relatively non-progressive. Distinctive and specific morphological abnormalities in skeletal muscle and main pathalogical feature. 

Blood tests search for the serum creatine kinase (CK) is usually normal or either mildly elevated, CMG's come out normal. Traditionally how the muscle looks under the microscope is how specific diagnosis come about. A specifi diagnosis may lead to specific genetic testing.

Dr. Beggs had a slide that was muscle tissue with four different stains to highlight different muscle diseases. Each slide highlighted the specific "look" of the disease.

In 1996 only two genes were known to be related to congential myopaties. Now (although he says the slide is out of date), there are more than 20 known genes that cause different congenital myopathies. There are commonalities at times between the genes and the different diseases

What about centronuclear myopathies? Normal adult muscle cells are nice, large, polygonal shaped cells with nuclei on the sides. WIth Centronuclear Myopathy the nuclei are in the center. Normal child muscle cells are smaller, but the nuclei are still on the side. Children with MTM have large nuclei in the center. Comparing these affected cells with those of a fetus approximately 23 weeks in gestation look very similar. Doctors call these early gestation muscle cell "myotubes," thus the diagnosis of Myotubular Myopathy.

Elizabeth DeChene, Genetic Counselor @ The Beggs Lab:

We inherit thousands of genes from our parents that we pass along to our children. Genes control pretty much everything we have. Genes are packaged into chromosomes which are made of combinations of 4 proteins (ACTG). These letters are in a variety of orders and each specific chromosome has a specific purpose. You can uses the analogy of a library. The library is the genome, you can go to a specific section (chromosome), get a specific book, and the order that the letters are in determine the word (gene).

MTM1 gene is myotubularin protein, which is X-Linked, It was discovered in 1996 and approximately 45% of patients have this mutation. DNM2, dynamin 2 protein which is dominant inheritance discovered in 2005 and approximately 15% of patients.

There is commercial genetic testing available. Sanger Sequencing is used to look at each gene. Currently only the exon is examined (the exon is what is being expressed.). Genetic testing can be used to find an accurate diagnosis, prognosis, carrier testing, family planning, prenatal diagnosis, and development of targeted treatment or cures.

Issues with genetic testing: multiple genes (need more than one test), expense, unidentified genes, RYR1 gene which is large (over 100 segments) and has many unique mutations.

Whole Genome Testing: Genome is 3 billion exons in length, so just the individual exons are examined. Now have 20 or 30 genes to look like. This technology is far more complicated and complex and may have a higher risk for error. Even with this, the specificity of the information in invaluable. It may not quite be ready to go "live" in clinical use. The isues are difficult to interpret, indication of enrelated findings and insurance may not cover. Benefits are that it is faster, less expensive, one-stop shopping, and follow-up analysis.

Contact Elizabeth at edechene@enders.tch.harvard.edu. Her phone number is 617-919-2169.

Dr. Alan Beggs: The biology

Gene mutated (MTM1) encodes myotuburin (Laporte, 1996) One part of the story that we are unsure of the importance is the abnormal desmin accumulation in MTM1 KO Mouse muscles.  It was found the myotubularin contrils desmin intermediate filament architecture and mitochondrial dynamics in humans and mouse skeletal muscle.

I will be attaching an article regarding a treatment for Myastheia Gravis that is now showing promise in treating children with MTM-CNM. >

Therapeutic approaches to CNM: Drug development, myobalst transfer (cell replacement therapy), myostatin inhibition. Myostatin is a protein that gets turns off in certain areas for growth. Without myostatin, there isn't an "off" switch for muscle growth. In mouse models, it has been shown that without myostatin are significant increase in muscle size and strength. Mice that have MTM that are treated with the myostatin inhibitor have more strength and live longer. This is a very exciting potential treatment for children with MTM. Unfortunately, there have been two rounds of testing on children with Duchenne's, but has been halted to due some mild side affects. Compaines and researchers involved are working to modify the compound and potentially return to trials.

There is now work being done on dogs with MTM-CNM gene. These dogs are the canine equivilent to children with MTM. There is exciting work being done with these dogs!

New Articles are posted under Documents & Articles. Dr. Beggs slide show will be posted later!.

We are breaking for lunch!