When to think of genetic causes for rhabdomyolysis? A Brazilian single-center exploratory study

Rhabdomyolysis is a potentially life-threatening condition that can result from genetic causes. Despite that, little is known about the genetic underpinnings behind monogenic rhabdomyolysis in Brazil.

To address the frequency and predictive factors for monogenic causes of rhabdomyolysis in a Brazilian series.

Patients presenting with rhabdomyolysis at Universidade Estadual de Campinas (UNICAMP) from April 2024 to October 2025 were selected. Rhabdomyolysis was defined when (1) there was at least 1 episode of creatine kinase (CK) levels ≥ 5x upper limit of normal (ULN) not better explained by exogeneous factors and (2) at least 1 of the RHABDO criteria (R - recurrent episodes of exertional rhabdomyolysis; H - hyperCKemia persisting more than 8 weeks after event; A: accustomed physical exercise; B - blood creatine kinase (CK) > 50x ULN; D - drug ingestion/medication/supplements or other exogenous and endogenous factors cannot sufficiently explain the rhabdomyolysis severity; O - other family members affected / other exertional symptoms [e.g., cramps or myalgia]). was met. A 2-step genetic investigation was undertaken: first a 50-gene panel enriched in metabolic myopathy genes and for those with negative results, whole exome sequencing (WES). Clinical and demographic data of patients with and without gene etiology were then compared.

We identified 20 patients, 8 of whom were men, with mean age at the first episode of rhabdomyolysis of 19.5 (2-50) years old. Monogenic etiology was found in 9 of the patients. The associated genes were PYGM (most frequent), CPT II, ACADS, ACADM, ANO5, DYSF and FKTN. Creatine kinase ≥ 5x ULN persisting for more than 8 weeks after the event (p = 0.0081), myalgia (p 0.028), objective weakness (p = 0.049) and parental consanguinity (p = 0.0090) were more frequent in the group with genetic cause.

After properly exclusion of exogenous etiologies, monogenic causes accounted for nearly half of the cases of rhabdomyolysis. Genetic testing should be pursued in those patients with persistent CK elevation, presence of myalgia, objective weakness or parental consanguinity.