Exertional rhabdomyolysis is a metabolic event characterized by the release of muscle content into the circulation due to exercise-driven breakdown of skeletal muscle. Recurrent exertional rhabdomyolysis has been associated with metabolic myopathies and mitochondrial disorders, a clinically and genetically heterogeneous group of predominantly autosomal recessive, monogenic conditions. Although genetics factors are well recognized in recurrent rhabdomyolysis, the underlying causes and mechanisms of exercise-driven muscle breakdown remain unknown in a substantial number of cases. We present clinical and genetic study results from seven adult male subjects with recurrent exertional rhabdomyolysis. In all subject, whole exome sequencing identified multiple heterozygous variants in genes associated with monogenic metabolic and/or mitochondrial disorders. These variants consisted of known pathogenic and/or new likely pathogenic variants in combination with other rare deleterious alleles. The presence of heterozygous pathogenic and rare deleterious variants in multiple genes suggests an oligogenic inheritance for exertional rhabdomyolysis etiology. Our data imply that exertional rhabdomyolysis can reflect cumulative effects or synergistic interactions of deleterious variants in multiple genes that are likely to compromise muscle metabolism under the stress of exercise.
Bibliographical noteFunding Information:
The authors are grateful to the Collaborative Health Initiative Research Program, USU, for exome sequencing and the Biomedical Instrumental Center, USU, for Sanger sequencing and oligo synthesis. We thank Drs. Georgirene Vladutiu and Kristin Heitman for critical comments and Ms. Maria Voelkel for a technical assistance. The study was supported by National Heart, Lung and Blood Institute grant HU0001-14-1-0060 to Dr. P. Deuster, and by a grant PPG-ANE-80-3397 from USU's Intramural Research Program made to Dr. F. O'Connor.
- Exertional rhabdomyolysis
- Metabolic disorders
- Mitochondrial diseases
- Multiple genetic variants
- Oligogenic inheritance
- Synergistic heterozygosity