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Research paper
Clinical features of the myasthenic syndrome arising from mutations in GMPPB
  1. Pedro M Rodríguez Cruz1,2,
  2. Katsiaryna Belaya1,
  3. Keivan Basiri3,
  4. Maryam Sedghi4,
  5. Maria Elena Farrugia5,
  6. Janice L Holton6,7,
  7. Wei Wei Liu1,
  8. Susan Maxwell1,
  9. Richard Petty5,
  10. Timothy J Walls8,
  11. Robin Kennett2,
  12. Matthew Pitt9,
  13. Anna Sarkozy7,
  14. Matt Parton7,
  15. Hanns Lochmüller10,
  16. Francesco Muntoni11,
  17. Jacqueline Palace2,
  18. David Beeson1
  1. 1Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
  2. 2Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK
  3. 3Neurology Department, Neuroscience Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran
  4. 4Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
  5. 5Department of Neurology, Institute of Neurological Sciences, The Queen Elizabeth University Hospital, Glasgow, UK
  6. 6Department of Molecular Neurosciences, UCL Institute of Neurology, London, UK
  7. 7MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
  8. 8Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
  9. 9Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  10. 10Institute of Genetic Medicine, John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK
  11. 11Dubowitz Neuromuscular Centre & MRC Centre for Neuromuscular Diseases, UCL Institute of Child Health, London, UK
  1. Correspondence to Professor David Beeson, Nuffield Department of Clinical Neurosciences, Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK; david.beeson{at}ndcn.ox.ac.uk

Abstract

Background Congenital myasthenic syndrome (CMS) due to mutations in GMPPB has recently been reported confirming the importance of glycosylation for the integrity of neuromuscular transmission.

Methods 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.

Results 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.

Conclusions 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.

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