title: RYR1-related congenital myopathy with fatigable weakness, responding to pyridostigimine.
abstract: The spectrum of RYR1 mutation associated disease encompasses congenital myopathies, exercise induced rhabdomyolysis, malignant hyperthermia susceptibility and King-Denborough syndrome. We report the clinical phenotype of two siblings who presented in infancy with hypotonia and striking fatigable ptosis. Their response to pyridostigimine was striking, but genetic screening for congenital myasthenic syndromes was negative, prompting further evaluation. Muscle MRI was abnormal with a selective pattern of involvement evocative of RYR1-related myopathy. This directed sequencing of the RYR1 gene, which revealed two heterozygous c.6721C>T (p.Arg2241X) nonsense mutations and novel c.8888T>C (p.Leu2963Pro) mutations in both siblings. These cases broaden the RYR1-related disease spectrum to include a myasthenic-like phenotype, including partial response to pyridostigimine. RYR1-related myopathy should be considered in the presence of fatigable weakness especially if muscle imaging demonstrates structural abnormalities. Single fibre electromyography can also be helpful in cases like this.
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Illingworth
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Main
authors.affiliation: Department of Clinical Neurophysiology, Great Ormond Street Hospital, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Pitt
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Feng
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK; Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, UK.
authors.forename: C A
authors.initials: CA
authors.lastname: Sewry
authors.affiliation: Department of Radiology, Great Ormond Street Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Gunny
authors.affiliation: Department of Paediatrics, Gloucester Royal Hospital, Gloucester, UK.
authors.forename: E
authors.initials: E
authors.lastname: Vorstman
authors.affiliation: Weatherall Institute, John Radcliffe Hospital, Oxford, UK.
authors.forename: D
authors.initials: D
authors.lastname: Beeson
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Manzur
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK. Electronic address: f.muntoni@ucl.ac.uk.
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Robb
mesh_terms: D001706:Biopsy; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D018389:Codon, Nonsense; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D018763:Muscle Fatigue / Q000187:drug effects / Q000502:physiology; D009132:Muscles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009224:Myotonia Congenita / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D011729:Pyridostigmine Bromide / Q000627:therapeutic use*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D035781:Siblings; D016896:Treatment Outcome
chemical_list: D002800:Cholinesterase Inhibitors; D018389:Codon, Nonsense; D019837:Ryanodine Receptor Calcium Release Channel; D011729:Pyridostigmine Bromide
keywords: Congenital fibre type disproportion; Electrophysiology; Fatigability; Muscle MRI; RYR1 congenital myopathy