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

Abstract

Background and purposeRhabdomyolysis is a medical emergency characterized by acute skeletal muscle breakdown with a sudden rise and subsequent fall of serum creatine kinase (CK) levels. Rhabdomyolysis events are provoked by exposure to external triggers, possibly in combination with an increased genetic susceptibility. We aimed to describe comprehensively the external triggers and potentially pathogenic genetic variants possibly implicated in increased rhabdomyolysis susceptibility.MethodsWe performed a retrospective single‐center study, including a total of 1302 patients with an acute CK level exceeding 2000 IU/l.ResultsAnoxia 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 these patients, an unequivocal genetic defect was identified. A total of 22 genes with pathogenic variants were identified, including 52 different variants. Of those, 11 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).ConclusionThese 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.

Referral Indications for Malignant Hyperthermia Susceptibility Diagnostics in Patients without Adverse Anesthetic Events in the Era of Next-generation Sequencing

“…It is important to mention that not all patients who suffer a rhabdomyolysis and/or exertional heat stroke episode will be referred to MH units as only a limited number of patients have a genetic background associated with an increased susceptibility to rhabdomyolysis 34 or exertional heat stroke. 25,35,36 Neurologists and sport physicians only refer patients to an MH unit with signs of an increased genetic susceptibility to rhabdomyolysis and/or exertional heat stroke, resulting in a selection bias.…”

Acute rhabdomyolysis in hepatitis-associated aplastic anemia patient undergoing allogeneic hematopoietic stem-cell transplantation: case report and literature review

“…Previous reports suggest that mutations in ACADVL, ANO5, CPT2, DMD, DYSF, FKRP, HADHA, PGM1, LPIN1, PYGM, and RYR1 genes may cause rhabdomyolysis. Moreover, AGL, CAPN3, CNBP, DMPK, MAGT1, ACADM, SCN4A, SGCA, SGCG, SMPD1, and TANGO2 were found to increase the susceptibility to rhabdomyolysis [ 32 ]. The SCN4A gene is expressed in skeletal muscle and encodes a member of the sodium channel alpha subunit gene family.…”

Incidence and clinical spectrum of rhabdomyolysis in general neurology: a retrospective cohort study

“…As a biomarker for myopathies, persistently elevated sCK activities (termed hyperCKemia) should therefore path the way for further diagnostic testing as also suggested by the European Federation of Neurological Sciences (EFNS) guidelines for cases with sCK activities beyond 1.5 times the ULN [30]. Hereditary diseases were shown to underlie a significant proportion of these cases [15], and genetic testing was proposed in the presence of additional supportive criteria associated with increased genetic susceptibility [31,32].…”