While the number of clinically defined neuromuscular diseases is relatively small, the number of genetic causes of these diseases is very large and still growing. Uncovering the genetic cause for the individual patient is the goal of the Athena Diagnostics phenotype-based Next Generation Sequencing (NGS) for neuromuscular disease.
“Phenotype-based Next Generation Sequencing provides a comprehensive, cost-effective way to find the causative variant in almost every case of neuromuscular disease,” says Joseph Higgins, MD, Medical Director for Neurology at Athena Diagnostics.
Clinicians with expertise in neuromuscular disease rarely have trouble distinguishing among the dozen or so forms of neuromuscular disease arriving at the appropriate clinical diagnosis, such as congenital myopathy, limb girdle muscular dystrophy, myotonic dystrophy, or Duchenne muscular dystrophy. “But then the question becomes why the patient has the disease—which gene is involved, and what is the nature of the mutation? That’s where the genetic test comes in,” says Dr. Higgins.
The NGS neuromuscular disease panels are clustered by phenotype, which makes test selection easy and keeps costs low. When the clinical diagnosis is limb girdle muscular dystrophy, for instance, it is appropriate to test the approximately two dozen genes that have been definitively linked to the disorder. Similarly, for a patient with periodic paralysis, testing is focused on the three ion channel genes known to cause the disease.
“We know that when we identify variants in these genes, we are going to be able to give the physician an answer,” Dr. Higgins says. In some cases, testing may also preclude the need for a muscle biopsy and its attendant morbidity.
In very rare cases, when the clinical picture doesn’t fit with any one disorder, whole exome analysis may be needed to discover the cause (which might be independent mutations in multiple genes, for example). “But that’s really for the outliers,” he says. “For the vast majority, a phenotype-based test is appropriate.”
Mutation-specific Therapy is Close to the Clinic
The value of a genetic diagnosis includes providing the patient and family with important information on heredity and prognosis. In some disorders, knowing the specific mutation may also soon be the first step in determining appropriate therapy. So-called “antisense” therapy delivers a short, mutation-specific, nucleotide-like molecule that silences the target gene before it can make mutant protein. Antisense therapy is currently in clinical development for Duchenne muscular dystrophy and myotonic dystrophy, with some promising results in clinical trials.
While the neuromuscular expert will almost always be able to choose the appropriate test on clinical grounds, Athena Diagnostics’ genetic counselors are available to consult with the physician who is less familiar with neuromuscular disease. “If the doctor describes the signs and symptoms, we can help them determine the likely classification,” Dr. Higgins says. As often as not, the best course will be to do more clinical or biochemical testing, to confirm the clinical diagnosis before moving on to the genetic test. “We try to point them in the right direction, to get the most specific clinical information possible. That will allow them to make the best test choice, and to get the most definitive diagnosis for the patient.”