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Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies

Lookup NU author(s): Dr Timothy Walls, Dr Anna Sarkozy, Dr Marta Bertoli, Dr Andrew Schaefer, Emerita Professor Katherine Bushby, Professor Hanns Lochmuller

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Congenital myasthenic syndromes are associated with impairments in neuromuscular transmission. Belaya et al. show that mutations of the glycosylation pathway enzyme GMPPB, which has previously been implicated in muscular dystrophy dystroglycanopathy, also cause a congenital myasthenic syndrome. This differential diagnosis is important to ensure that affected individuals receive appropriate medication.Congenital myasthenic syndromes are associated with impairments in neuromuscular transmission. Belaya et al. show that mutations of the glycosylation pathway enzyme GMPPB, which has previously been implicated in muscular dystrophy dystroglycanopathy, also cause a congenital myasthenic syndrome. This differential diagnosis is important to ensure that affected individuals receive appropriate medication.Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of theseGMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.


Publication metadata

Author(s): Belaya K, Cruz PMR, Liu WW, Maxwell S, McGowan S, Farrugia ME, Petty R, Walls TJ, Sedghi M, Basiri K, Yue WW, Sarkozy A, Bertoli M, Pitt M, Kennett R, Schaefer A, Bushby K, Parton M, Lochmuller H, Palace J, Muntoni F, Beeson D

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2015

Volume: 138

Pages: 2493-2504

Online publication date: 01/07/2015

Acceptance date: 04/05/2015

Date deposited: 13/11/2015

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/brain/awv185

DOI: 10.1093/brain/awv185


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Funding

Funder referenceFunder name
GOSH Biomedical Research Centre
Great Ormond Street Hospital (GOSH) Children's Charity
Medical Research Council, UK
Muscular Dystrophy Campaign
National Commissioning Group
Wellcome Trust
MRC Neuromuscular Centre
Myasthenia Gravis Association
NIHR
305121European Union
305444European Union
98482Medical Research Council UK
G1002274Medical Research Council UK

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