Title:RYR1-Related Rhabdomyolysis: A Spectrum of Hypermetabolic States Due to
Ryanodine Receptor Dysfunction
Volume: 28
Issue: 1
Author(s): Nick Kruijt*, Luuk Van den Bersselaar, Marc Snoeck, Kees Kramers, Sheila Riazi, Coen Bongers, Susan Treves, Heinz Jungbluth and Nicol Voermans
Affiliation:
- Department of Neurology, Radboud University Medical Centre, Nijmegen,Netherlands
Keywords:
RYR1, Rhabdomyolysis, neuromuscular disorders, exertional rhabdomyolysis, exertional heat illness, malignant hyperthermia
Abstract: Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular
conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently,
a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis
events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related
rhabdomyolysis in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat
illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be
present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke
rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications,
illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not
limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental
conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in
particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients
presenting with rhabdomyolysis, genetic susceptibility is present in a proportion, with RYR1 being one of
the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis,
creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or
longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and positive family history. For
the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered,
both in the acute phase or prophylactically in patients with a history of muscle cramps and/or recurrent
rhabdomyolysis events. Aside from dantrolene, several other drugs are being investigated for their potential
therapeutic use in RYR1-related disorders. These findings offer further therapeutic perspectives for humans,
suggesting an important area for future research.
