The Jerry Lewis fundraising telethons of yore educated many people about myopathies, the most famous of which – muscular dystrophy – highlights the often-progressive and disabling muscle weakness afflicting these children. But up to 10% of myopathy cases seen by Michael Lopez, M.D., Ph.D., a Children’s of Alabama pediatric neuromuscular physician-scientist, are undiagnosable, despite comprehensive evaluation.
This dilemma has driven Lopez, also an assistant professor of pediatric neurology at the University of Alabama at Birmingham (UAB), to collaborate with colleagues to use whole genome and RNA-Seq sequencing to potentially solve such cases. Lopez has enrolled 10 patients and their families into innovative clinical research aiming to reveal the molecular basis of undiagnosed myopathies in hopes of offering affected patients a prognosis and steering them toward effective treatments.
“In a small sliver of patients, I’m convinced they have a myopathy but am unable to refine their diagnosis and give clarity on what type,” Lopez explained. “In that group of kids, in which I’m pretty sure the cause is genetic and everything else is ruled out, we end up in this diagnostic odyssey.”
To tackle this problem, Lopez joined with UAB’s Liz Worthey, Ph.D., director of the Center for Genomic Data Sciences, and Matthew Alexander, Ph.D., an assistant professor of pediatric neurology. Using simple blood draws from parents and children and next-generation gene sequencing techniques, the trio hope to identify new genes responsible for muscle disorders or previously unreported variants of uncertain significance, dubbed VUS, in genes already known to cause myopathies. These mutations can be inserted into animal models to build evidence that a specific VUS triggers the condition.
“This allows us to get a snapshot of all the mutations possible in the genome, not excluding places that turn genes on and off,” Lopez said. “Data can help us support or refute a disease-causing mechanism for the VUS.”
Lopez is well aware the project won’t produce quick answers, and participating families also understand the findings may not benefit them personally.
“But it is possible to come back with a molecular diagnosis,” he said. “If we find something that’s already well-understood, that would offer them some treatment options if they’re already available.”
Longer-term, Lopez hopes the research will point toward targeted treatments for these muscle disorders, some of which might be derived by repurposing old drugs in “off-the-shelf libraries.”
“Treatment is just one goal, a second is resolving the diagnosis and solving the case,” he said. “That’s a huge burden relieved for both family and patient. And another piece is the science – to improve our understanding of how these diseases occur and how the muscle functions.”