The limb-girdle muscular dystrophies are a heterogeneous group of muscle diseases with both dominant and recessive inheritance patterns with onset in childhood or adulthood. Typically slowly progressive weakness is seen. The Congenital muscular dystrophies typically present at birth, and are typically recessively inherited.
There are over 30 genes that cause either LGMD or CMD, and in some cases the same gene can cause both early onset (CMD) and late onset (LGMD) phenotypes (see Table for gene names and exons). For example, Fukutin-related protein (FKRP) gene has a common missense mutation in Northern European populations, and is the cause of about 10% of adult LGMD patients. The same FKRP gene can show more severe loss of function mutations in CMD babies, often with syndromic features (eye and brain involvement).
The focus of research in the Department is on:
- Novel gene discovery. Despite the >30 muscular dystrophy genes identified to date, the majority of LGMD patients in the US population remain undiagnosed. This is in part due to the challenge of sequencing all 31 genes, and also because many more genes remain to be discovered.
- Molecular pathophysiology. Department investigators have a frozen biopsy tissue bank of over 4,000 patient biopsies. These are used first for molecular diagnostics, then the remaining tissue used to query molecular pathophysiology. A series of publications have defined biochemical pathways specific to many of the specific forms of muscular dystrophy.
- Molecular diagnostics. Genomics technologies are rapidly evolving, and the Department is often an early adopter of emerging technologies, with rapid implementation in the muscular dystrophies. For example, new NextGen DNA sequencers should be able to sequence all 841 exons in a small sample of patient blood, for a low cost. These new technologies are being developed for CMD/LGMD to improve the diagnostics, including faster turn-around, more sensitive tests, and dramatically lower costs.
- Experimental therapeutics. The Department works closely with stake holder groups, such as FED, CureDuchenne, ActionDuchenne, and Muscular Dystrophy Association to accelerate potential therapies. Pre-clinical drug trials are done using the Mouse Drug Screening Core in the Department, clinical trials with the CINRG group, and novel drug development with the integrated Validus Biopharma (VBpharm) company.