Synergistic heterozygosities beyond energy-related metabolic pathways as the mechanism of recurrent rhabdomyolysis.

We read Sambuughin et al.'s article about patients with recurrent exertional rhabdomyolysis [1] and the correspondence by Finsterer and Mahjoub [2] with interest.

With the widespread availability of the next-generation sequencing including whole exome sequencing and multiple gene panels in recent years, more patients with rhabdomyolysis who have undergone testing are predicted to be identified with multiple variants in many genes. Beside the energy-related metabolic pathway disorders, another group of genetic disorders that may present with rhabdomyolysis is muscular dystrophy. Some patients with heterozygous variants in these genes, which generally cause autosomal recessive disorders, have mild muscular weakness [3]. We investigated four patients with rhabdomyolysis. We found that all of them carry at least two likely pathogenic (LP) or pathogenic (P) variants in energy metabolic pathways or muscular dystrophy genes [(1) FKTN, AUH, (2) DYSF, PGYM, CPT1B, (3) SYNE1, COASY, (4) FKRP, GLA].

The unidentified variants of autosomal recessive disorders could be the result of the limitation of the test. The presence of multiple LP or P variants in energy-related metabolic pathways and muscular dystrophies is, however, highly unusual occurring by chance or technical limitation alone. The investigation for subtle enzymatic functional changes [1,3] or the different amount of muscular dystrophy proteins may help elucidate the functional significance of these heterozygous variants. Biochemical analytes study such as acylcarnitine profiles [2] mentioned by one correspondence is not sensitive or specific enough to detect the effect of these heterozygous variants. Surprisingly, we identified a pathogenic variant in GLA, known to cause Fabry disease in one patient. We suggested adding this disease to a differential diagnosis of rhabdomyolysis [4].

In summary, we agreed that the presence of multiple LP/P heterozygous variants in metabolic pathways in patients with recurrent rhabdomyolysis supports the synergistic heterozygosities hypothesis [5]. We added that heterozygous variants in genes for muscular dystrophy might also contribute to the potential oligogenic mechanisms of rhabdomyolysis.

Conflict of interest

There are no conflicts of interest.

Funding

No funding was received.