T.P.33: Clinical and genetic characterization of patients with repeated rhabdomyolysis

Abstract

In patients with repeated episodes of rhabdomyolysis, a predisposing condition should be suspected. Most inherited causes are related to metabolic myopathies and malignant hyperthermia susceptibility. However in the majority of patients with recurrent rhabdomyolysis a cause is not identified. To genetically and clinically characterize a cohort of patients with recurrent rhabdomyolysis we applied next generation sequencing methods to study a panel of 277 genes, mutations in which have been associated with neuromuscular diseases, plus Sanger sequencing of not well covered target genomic regions. Twenty-two patients were included in the study. Two were excluded for lack of clinical data available. None of them had affected relatives. Of the remaining patients six were female. Average peak CK was 61,000. Basal CK was mildly elevated in 9 and moderately in 1. No patient had fixed weakness. Seven had symptoms between episodes, predominantly aches and cramps. Rhabdomyolysis episodes were spontaneous in 5 patients. The most common trigger was exercise. Muscle biopsies showed type 2 fibre predominance in 4, cores in 3 and increased cytoplasmic lipid and glycogen in 1. Two patients had variants in RYR1, 3 in CACNA1S, 2 in SCN4A, 1 in PHKA1 and 2 were compound heterozygous for variants in HSPG2 (perlecan). Except for one of the RYR1 variants and one in HSPG2 all the rest are novel variants, with pathogenicity yet to be confirmed. In conclusion, only one of our patients had a definite diagnosis. Some other candidate genes harbour possibly pathogenic mutations, most of them in malignant hyperthermia related genes, of which SCN4A and CACNA1s have not yet been described in association with rhabdomyolysis out of the context of malignant hyperthermia. Most of the patients in the cohort remain unresolved raising the idea that rhabdomyloysis may not result from genetic susceptibility, or the responsible genes remain to be identified.