Recurrent Exertional Rhabdomyolysis in a Service Member with a PRKN Mutation

Purpose: Recurrent rhabdomyolysis (ER) has been identified as a risk factor for an underlying genetic muscle or mitochondrial disorder. One gene of interest, the Parkin gene (PRKN), has been implicated in mitochondrial dysregulation and the early-onset of Parkinson’s disease (PD). Heterozygous carriers of PRKN mutations might be at increased risk for developing clinical symptoms of PD including akinesia. Here we report a novel association between ER and a PRKN mutation. METHODS: Active duty service members (SM) (17- 44 y/o) diagnosed with exertional heat injury and/or rhabdomyolysis were recruited for participation in a study examining genetic risk factors for the recurrence of exertional injuries. Informed consent was obtained before enrollment and clinical history was retrieved from electronic medical records. Blood samples were collected for genotyping using next generation whole exome sequencing (WES), with muscle biopsies and clinical genetic panels performed as clinically indicated. RESULTS: A 26-year-old male SM was enrolled with a history of exercise intolerance and seven episodes of confirmed ER; a muscle biopsy was recommended. The biopsy demonstrated structurally aberrant and abnormally-distributed mitochondria with abnormal cristae and frequent paracrystalline “parking lot” inclusions, highly suggestive of a mitochondrial myopathy. WES analyses identified a PRKN p.Asn52MetfrTer29 mutation. Additionally, a next generation sequencing exercise intolerance panel identified a heterozygous variant of unknown significance in the DYSF gene. CONCLUSION: The finding of a PRKN gene mutation in a case with recurrent ER is a potential novel genetic risk factor contributing to exercise-induced muscle damage. This protein truncating mutation has been reported in the literature to cause protein aggregates and a loss of ubiquitin ligase enzyme activity of the encoded protein. While rare, this mitochondrial abnormality was previously reported in muscle biopsy of a PD patient with PRKN mutation. Although individuals who are heterozygous for the pathogenic variant are typically asymptomatic, the PRKN deficiency associated mitochondrial dysfunction during intense exercise may increase risk of ER. Supported by: The study is funded by Uniformed Services University. The authors have no financial interests or relationships to disclose.