G.P.49: RYR1 mutations in adults with acute rhabdomyolysis episodes

Abstract

Recurrent rhabdomyolysis episodes in adults are commonly caused by glycogenosis or fatty-acid oxidation disorders. However, in many cases the etiology remains unknown, and recently mutations in RYR1 appeared as a possible cause of exercise induced rhabdomyolysis. We studied 14 adults who presented acute rhabdomyolysis (CK above 10,000 UI/l) triggered by exercise or fever, in whom McArdle disease, fatty acid oxidation disorders, and LPIN1 mutations were excluded. All patients underwent muscle biopsy in order to screen RYR1 mutation on cDNA. Potentially pathogenic mutations in RYR1 gene were detected in 5 unrelated patients. Mutations were the following: p.Val4847Leu, p.G593R, p R3539H, Gly2434Arg, p.Gln3461Pro, p.A1352T, p.A933T and p.Ser1342Gly. Two patients presented each 2 and 3 heterozygous variants. Baseline CK levels were elevated in all cases but one (400–700 UI/l). None of them complained of myalgia or exercise intolerance. Rhabdomyolysis were triggered by weight-training in two patients, viral infection in two cases, and retinoic acid treatment in the last case. Higher recorded CK levels were between 28,000 and 94,000 UI/l, without renal failure. Three patients had a unique episode, whereas two other had several rhabdomyolysis episodes. Muscle biopsies were either normal, or showed moderate structure disorganization. Two siblings of a patient, the father of another patient, and the brother of a third patient, also presented mutations in the RYR1 gene and high baseline CK level. Per-anesthetic malignant hyperthermia was noticed in a grand-mother of one patient. Mutations in RYR1 gene should be systematically searched in patients with exercise or fever induced rhabdomyolysis episodes, after having excluded common metabolic disorders. This diagnostic implies major consequences for genetic counselling in the families, due to the potential risk of anesthetic malignant for the patients and their relatives.