title: Clinical features of the myasthenic syndrome arising from mutations in GMPPB.
abstract: Congenital myasthenic syndrome (CMS) due to mutations in GMPPB has recently been reported confirming the importance of glycosylation for the integrity of neuromuscular transmission.
  
  
  
  Review of case notes of patients with mutations in GMPPB to identify the associated clinical, neurophysiological, pathological and laboratory features. In addition, serum creatine kinase (CK) levels within the Oxford CMS cohort were retrospectively analysed to assess its usefulness in the differential diagnosis of this new entity.
  
  
  
  All patients had prominent limb-girdle weakness with minimal or absent craniobulbar manifestations. Presentation was delayed beyond infancy with proximal muscle weakness and most patients recall poor performance in sports during childhood. Neurophysiology showed abnormal neuromuscular transmission only in the affected muscles and myopathic changes. Muscle biopsy showed dystrophic features and reduced α-dystroglycan glycosylation. In addition, myopathic changes were present on muscle MRI. CK was significantly increased in serum compared to other CMS subtypes. Patients were responsive to pyridostigimine alone or combined with 3,4-diaminopyridine and/or salbutamol.
  
  
  
  Patients with GMPPB-CMS have phenotypic features aligned with CMS subtypes harbouring mutations within the early stages of the glycosylation pathway. Additional features shared with the dystroglycanopathies include myopathic features, raised CK levels and variable mild cognitive delay. This syndrome underlines that CMS can occur in the absence of classic myasthenic manifestations such as ptosis and ophthalmoplegia or facial weakness, and links myasthenic disorders with dystroglycanopathies. This report should facilitate the recognition of this disorder, which is likely to be underdiagnosed and can benefit from symptomatic treatment.
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Rodríguez Cruz
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Katsiaryna
authors.initials: K
authors.lastname: Belaya
authors.affiliation: Neurology Department, Neuroscience Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Keivan
authors.initials: K
authors.lastname: Basiri
authors.affiliation: Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Sedghi
authors.affiliation: Department of Neurology, Institute of Neurological Sciences, The Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Farrugia
authors.affiliation: Department of Molecular Neurosciences, UCL Institute of Neurology, London, UK MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Liu
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Maxwell
authors.affiliation: Department of Neurology, Institute of Neurological Sciences, The Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Petty
authors.affiliation: Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Walls
authors.affiliation: Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Kennett
authors.affiliation: Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pitt
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Matt
authors.initials: M
authors.lastname: Parton
authors.affiliation: Institute of Genetic Medicine, John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Dubowitz Neuromuscular Centre & MRC Centre for Neuromuscular Diseases, UCL Institute of Child Health, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Palace
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Beeson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D060825:Cognitive Dysfunction / Q000150:complications; D003402:Creatine Kinase / Q000097:blood; D049030:Dystroglycans / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009713:Nucleotidyltransferases / Q000235:genetics*; D055815:Young Adult
chemical_list: D049030:Dystroglycans; D003402:Creatine Kinase; D009713:Nucleotidyltransferases; C026917:mannose 1-phosphate guanylyltransferase