Familial hyperCKemia with exercise-induced myalgia associated with a novel missense variant in RYR1

Abstract

Background

RYR1 (ryanodine receptor 1), which functions as a calcium release channel in the sarcoplasmic reticulum and is associated with the susceptibility to malignant hyperthermia and several myopathies. Serum creatine kinase (CK) levels are important for the diagnosis of patients with neuromuscular diseases; however, CK levels can be elevated even in individuals without obvious clinical symptoms. Recently, RYR1 was reported as one of the genes responsible for asymptomatic or paucisymptomatic hyperCKemia.

Case presentation

Here, we report the case of a family with autosomal dominant hyperCKemia. The fraternal twin sisters complained of exertional myalgia after exercise, such as playing basketball, without evidence of muscle weakness or fatigue. Serum CK levels of the twin sister patients ranged from 642 U/L to 5620 U/L and from 411 U/L to 2609 U/L, respectively. The mother had hyperCKemia (523 U/L) without any neuromuscular symptoms. Muscle biopsy from one of the twin sisters showed no necrotic fibers, several regenerating fibers, and several fibers with internal nuclei. Exome sequencing of the same patient identified a novel, possibly pathogenic variant (NM_000540.3:c.682G>A, p.Glu228Lys) in RYR1. This variant was also detected by Sanger sequencing in another sister and mother with hyperCKemia.

Conclusions

Patients with possible pathogenic variants in RYR1 are at risk for malignant hyperthermia susceptibility and rhabdomyolysis. Genetic analyses, including RYR1 for cases with asymptomatic or paucisymptomatic hyperCKemia may be useful in identifying individuals at potential risk of malignant hyperthermia susceptibility and rhabdomyolysis.