Likely genetic source of muscle weakness found in six previously undiagnosed children

Scientists at the Translational Genomics Research Institute (TGen), using state-of-the-art genetic technology, have discovered the likely cause of a child's rare type of severe muscle weakness.

The child was one of six cases in which TGen sequenced -- or decoded -- the genes of patients with Neuromuscular Disease (NMD) and was then able to identify the genetic source, or likely genetic source, of each child's symptoms, according to a study published April 8 in the journal Molecular Genetics & Genomic Medicine.

"In all six cases of myopathy, or muscle weakness, these children had undergone extensive, expensive and invasive testing -- often over many years -- without a successful diagnosis, until they enrolled in our study," said Dr. Lisa Baumbach-Reardon, an Associate Professor of TGen's Integrated Cancer Genomics Division and the study's senior author.

This is a prime example of the type of "personalized medicine" TGen uses to zero in on diagnoses for patients, and to help their physicians find the best possible treatments.

"Our results demonstrate the diagnostic value of a comprehensive approach to genetic sequencing," said Dr. Baumbach-Reardon. "This type of next-generation sequencing can greatly improve the ability to identify pathogenic, or disease-causing, genetic variants with a single, timely, affordable test."

In one of the six cases, TGen researchers found a unique disease-causing variant, or mutation, in the CACNA1S gene for a child with severe muscle weakness in addition to ophthalmoplegia, or the inability to move his eyes. Properly functioning CACNA1S is essential for muscle movement. More specifically, CACNA1S senses electrical signals from the brain and enables muscles to contract.

"To our knowledge, this is the first reported case of severe congenital myopathy with ophthalmoplegia resulting from pathogenic variants in CACNA1S," said Dr. Jesse Hunter, a TGen Senior Post-Doctoral Fellow, and the study's lead author.

Learning the specific genetic cause of symptoms is a key step in finding new therapeutic drugs that could treat the patient's disease.

In another closely related case, TGen's genetic testing found a pathogenic variant in the RYR1 gene in a case of calcium channel myopathy. When the brain sends an electrical signal, CACNA1S opens the RYR1 calcium channel flooding muscles with calcium and causing them to contract. When either partner of this duo doesn't function correctly, devastating muscle weakness results.

Five of the six cases involved patients under the care of Dr. Saunder Bernes, a neurologist at Barrow Neurological Institute at Phoenix Children's Hospital. Dr. Bernes referred all five cases to TGen for genetic sequencing in an effort to find the causes of the children's muscle weakness.