title: Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies.
abstract: Many clinical features of autosomal centronuclear myopathies (CNM) and X-linked myotubular myopathy (XLMTM) are common to congenital myasthenic syndromes (CMS). We describe three children whose clinical and electrophysiological findings originally suggested CMS, in whom CNM was diagnosed pathologically, though not yet genetically characterised. A fourth case, with XLMTM, also showed electrophysiological features of a neuromuscular transmission defect. Three (including the XLMTM case) showed improved strength with acetylcholinesterase inhibitor treatment. We also studied neuromuscular junction structure and function in the MTM1 knockdown zebrafish model of XLMTM, demonstrating abnormal neuromuscular junction organization; anticholinesterase therapy resulted in marked clinical response. These observations suggest that a neuromuscular transmission defect may accompany CNM and contribute to muscle weakness. Muscle biopsy should be considered in infants suspected to have CMS, especially if treatment response is incomplete, or no CMS gene mutation is identified. Treatment with acetylcholinesterase inhibitors may benefit some CNM patients. This warrants further confirmation.
authors: The Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital, London, UK. robbs@gosh.nhs.uk
authors: Stephanie A
authors: SA
authors: Robb
authors: Caroline A
authors: CA
authors: Sewry
authors: James J
authors: JJ
authors: Dowling
authors: Lucy
authors: L
authors: Feng
authors: Tom
authors: T
authors: Cullup
authors: Sue
authors: S
authors: Lillis
authors: Stephen
authors: S
authors: Abbs
authors: Melissa M
authors: MM
authors: Lees
authors: Jocelyn
authors: J
authors: Laporte
authors: Adnan Y
authors: AY
authors: Manzur
authors: Ravi K
authors: RK
authors: Knight
authors: Kerry R
authors: KR
authors: Mills
authors: Michael G
authors: MG
authors: Pike
authors: Wolfram
authors: W
authors: Kress
authors: David
authors: D
authors: Beeson
authors: Heinz
authors: H
authors: Jungbluth
authors: Matthew C
authors: MC
authors: Pitt
authors: Francesco
authors: F
authors: Muntoni
mesh_terms: D000293:Adolescent; D000818:Animals; D001706:Biopsy; D002648:Child; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004576:Electromyography; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D007223:Infant; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D020914:Myopathies, Structural, Congenital / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000503:physiopathology*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D011729:Pyridostigmine Bromide / Q000494:pharmacology / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D016896:Treatment Outcome; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D002800:Cholinesterase Inhibitors; D029961:Zebrafish Proteins; C552191:MTM1 protein, zebrafish; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D011729:Pyridostigmine Bromide