The etiology of rhabdomyolysis: an interaction between genetic susceptibilities and external triggers.

OBJECTIVES Rhabdomyolysis is a medical emergency characterized by acute skeletal muscle breakdown with a sudden rise and subsequent fall of serum creatine kinase (CK) levels. Events of rhabdomyolysis are provoked by exposure to external triggers, possibly in combination with an increased genetic susceptibility. We aimed to comprehensively describe external triggers and potentially pathogenic genetic variants possibly implicated in increased rhabdomyolysis susceptibility. METHODS We performed a retrospective single-center study, including a total of 1302 patients with an acute CK level exceeding 2000 IU/L. RESULTS Anoxia was the most frequently reported trigger (40%). A subset of 193 patients were clinically suspected of an underlying genetic disorder (recurrent episodes, a positive family history, very high or persistently increased CK levels). In 72 of them, an unequivocal genetic defect was identified. A total of 22 genes with pathogenic variants were identified, including 52 different variants. Of those, eleven genes have been previously associated with rhabdomyolysis (ACADVL, ANO5, CPT2, DMD, DYSF, FKRP, HADHA, PGM1, LPIN1, PYGM, RYR1). Eleven genes are probably implicated in increased susceptibility (including AGL, CAPN3, CNBP, DMPK, MAGT1, ACADM, SCN4A, SGCA, SGCG, SMPD1, TANGO2). CONCLUSION These findings suggest that the spectrum of genetic susceptibility for rhabdomyolysis has not yet been completely clarified. With the increasing availability of next generation sequencing in a diagnostic setting, we expect that in more cases a genetic defect will be identified.