Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome

TY - JOUR

T1 - Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome

AU - Witting, N

AU - Laforêt, P

AU - Voermans, N C

AU - Roux-Buisson, N

AU - Bompaire, F

AU - Rendu, J

AU - Duno, M

AU - Feillet, F

AU - Kamsteeg, E-J

AU - Poulsen, N S

AU - Dahlqvist, J R

AU - Romero, N B

AU - Fauré, J

AU - Vissing, J

AU - Behin, A

N1 - © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PY - 2018/5

Y1 - 2018/5

N2 - OBJECTIVES: Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available.MATERIAL & METHODS: We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands.RESULTS: Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility.CONCLUSION: Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.

AB - OBJECTIVES: Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available.MATERIAL & METHODS: We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands.RESULTS: Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility.CONCLUSION: Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.

KW - Adolescent

KW - Adult

KW - Child

KW - Denmark

KW - Female

KW - France

KW - Genotype

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Myalgia/genetics

KW - Netherlands

KW - Phenotype

KW - Rhabdomyolysis/genetics

KW - Ryanodine Receptor Calcium Release Channel/genetics

KW - Syndrome

KW - Young Adult

U2 - 10.1111/ane.12885

DO - 10.1111/ane.12885

M3 - Journal article

C2 - 29635721

SN - 0065-1427

VL - 137

SP - 452

EP - 461

JO - Acta Neurologica Scandinavica, Supplement

JF - Acta Neurologica Scandinavica, Supplement

IS - 5

ER -