Desmin (DES) is a major muscle scaffolding
protein that also functions to anchor mitochondria. Pathogenic DES mutations, however, have not previously been recognized as a cause of multi-systemic
mitochondrial disease. Here, we describe a 45-year-old man who presented to The Children's Hospital of Philadelphia Mitochondrial-Genetics Diagnostic Clinic for evaluation of progressive cardiac, neuromuscular, gastrointestinal, and
mood disorders. Muscle biopsy at age 45 was remarkable for cytoplasmic bodies, as well as ragged red fibers and SDH positive/COX negative fibers that were suggestive of a
mitochondrial myopathy. Muscle also showed significant reductions in mitochondrial content (16% of control mean for
citrate synthase activity) and
mitochondrial DNA (35% of control mean). His family history was significant for
cardiac conduction defects and
myopathy in multiple maternal relatives. Multiple single gene and panel-based sequencing studies were unrevealing. Whole exome sequencing identified a known pathogenic p.S13F mutation in DES that had previously been associated with
desmin-related myopathy.
Desmin-related myopathy is an autosomal dominant disorder characterized by right ventricular
hypertrophic cardiomyopathy,
myopathy, and arrhythmias. However, neuropathy, gastrointestinal dysfunction, and depletion of both mitochondria and
mitochondrial DNA have not previously been widely recognized in this disorder. Recognition that
mitochondrial dysfunction occurs in
desmin-related myopathy clarifies the basis for the multi-systemic manifestations, as are typical of primary
mitochondrial disorders. Understanding the mitochondrial pathophysiology of
desmin-related myopathy highlights the possibility of new
therapies for this otherwise untreatable and often fatal class of disease. We postulate that
drug treatments aimed at improving mitochondrial biogenesis or reducing oxidative stress may be effective
therapies to ameliorate the effects of
desmin-related disease.