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Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations

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Abstract

Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal. DOK7 mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene, GFPT1, in a series of DOK7-negative cases. However, detailed description of clinical features of GFPT1 patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying GFPT1 mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with GFPT1 mutations, onset of the disease occurs in the first decade of life with characteristic limb-girdle weakness and fatigue. A common feature was beneficial and sustained response to acetylcholinesterase inhibitor treatment. Most of the patients who had a muscle biopsy showed tubular aggregates in myofibers. Analysis of endplate morphology in one of the patients revealed unspecific abnormalities. Our study delineates the phenotype of CMS associated with GFPT1 mutations and expands the understanding of neuromuscular junction disorders. As tubular aggregates in context of a neuromuscular transmission defect appear to be highly indicative, we suggest calling this condition congenital myasthenic syndrome with tubular aggregates (CMS-TA).

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Abbreviations

AChE:

Acetylcholinesterase

AChR:

Acetylcholine receptor

CK:

Creatine kinase

CMAP:

Compound muscle action potential

CMS:

Congenital myasthenic syndrome

3,4-DAP:

3,4-Diaminopyridine

DOK7 :

Downstream of kinase 7 gene

EM:

Electron microscopy

EMG:

Electromyography

LG-CMS:

Limb-girdle congenital myasthenic syndrome

NMJ:

Neuromuscular junction

RNS:

Repetitive nerve stimulation

SFEMG:

Single-fiber EMG

TA:

Tubular aggregates

GFPT1/GFAT1 :

Glutamine-fructose-6-phosphate transaminase 1

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Acknowledgments

We wish to thank the patients and their families for participating in this study. The Institute of Genetic Medicine in Newcastle is part of the MRC centre for Neuromuscular Diseases. AA, JK, BS, RH, TV and HL are members of the German Muscular Dystrophy Network (MD-NET 01GM0601) funded by the German Ministry of Education and Research (BMBF, Bonn, Germany; http://www.md-net.org). Newcastle University and MD-NET are partners of TREAT-NMD (EC, 6th FP, proposal #036825; http://www.treat-nmd.eu). VG is a research fellow of the Alexander von Humboldt Foundation. JS is a Heisenberg fellow of the Deutsche Forschungsgemeinschaft. AA is supported by a grant from the Deutsche Forschungsgemeinschaft (Ab 130/2-1), DB by grants from the Medical Research Council, the Myasthenia Gravis Association and the Muscular Dystrophy Campaign. JSM receives a research fellowship by the Faculty of Medical Sciences, Newcastle University. NM received a fellowship from the Instituto de Salud Carlos III and Fundación para la Investigación del Hospital Universitario La Fe (CM06/00154). JJV and NM are members of CIBER de Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Neurology, Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany

    Velina Guergueltcheva, Marina Dusl, Beate Schlotter, Benedikt Schoser & Angela Abicht

  2. Clinic of Neurology, University Hospital Alexandrovska, Sofia, Bulgaria

    Velina Guergueltcheva

  3. Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK

    Juliane S. Müller, Amina Chaouch, Volker Straub, Kate Bushby & Hanns Lochmüller

  4. Institute of Neuropathology, RWTH Aachen University, Aachen, Germany

    Jan Senderek

  5. Institute of Human Genetics, RWTH Aachen University, Aachen, Germany

    Jan Senderek

  6. Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden

    Anders Oldfors

  7. Neuromuscular Center, Sahlgrenska University Hospital, Gothenburg, Sweden

    Christopher Lindbergh

  8. Neurosciences Group, Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Susan Maxwell & David Beeson

  9. Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Deu, Esplugues, Barcelona, Spain

    Jaume Colomer, Cecilia Jimenez Mallebrera & Andres Nascimento

  10. Servicio de Neurología, Hospital Universitario y Politécnico La Fe and CIBER de Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain

    Juan J. Vilchez & Nuria Muelas

  11. Division of Neuropaediatrics and Muscle Disorders, University Medical Center, Freiburg, Germany

    Janbernd Kirschner

  12. Department of Neurology, Tehran University of Medical Sciences, Tehran, Iran

    Shahriar Nafissi

  13. Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran

    Ariana Kariminejad, Bita Bozorgmehr & Hossein Najmabadi

  14. Neuropathology Lab, Toos Hospital, Tehran, Iran

    Yalda Nilipour

  15. Departments of Neurosciences, Psychiatry and Anaesthesiology, A.O.U. “G. Martino”, Messina, Italy

    Carmelo Rodolico

  16. Department of Neurology, Geriatric Medicine and Palliative Care, Hanse-Klinikum, Stralsund, Germany

    Jörn P. Sieb

  17. Department of Paediatrics I, University Hospital Essen, Essen, Germany

    Ralf Herrmann

  18. Institut de Myologie, Unité Mixte de Recherche UPMC-INSERM-CNRS-AIM UM 76, U974, UMR 7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Thomas Voit

  19. Institute of Human Genetics, Ludwig Maximilians University, Munich, Germany

    Ortrud K. Steinlein

  20. Azad University Medical Branch, Tehran, Iran

    Abdolhamid Najafi

  21. Hôpital Marin, Hendaye, France

    Andoni Urtizberea

  22. Department of Paediatrics, Mater Dei Hospital, Tal-Qroqq, Msida, Malta

    Doriette M. Soler

  23. The Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK

    Francesco Muntoni

  24. MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK

    Michael G. Hanna

  25. CMS NCG Group, Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK

    Jacqueline Palace

Authors
  1. Velina Guergueltcheva
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  2. Juliane S. Müller
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  3. Marina Dusl
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  4. Jan Senderek
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  6. Christopher Lindbergh
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  7. Susan Maxwell
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  9. Cecilia Jimenez Mallebrera
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  27. Andoni Urtizberea
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  28. Doriette M. Soler
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  29. Francesco Muntoni
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  30. Michael G. Hanna
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  31. Amina Chaouch
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  32. Volker Straub
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  33. Kate Bushby
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  34. Jacqueline Palace
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  35. David Beeson
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  36. Angela Abicht
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  37. Hanns Lochmüller
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Corresponding author

Correspondence to Hanns Lochmüller.

Additional information

V. Guergueltcheva and J. S. Müller contributed equally to the study.

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Guergueltcheva, V., Müller, J.S., Dusl, M. et al. Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations. J Neurol 259, 838–850 (2012). https://doi.org/10.1007/s00415-011-6262-z

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  • DOI: https://doi.org/10.1007/s00415-011-6262-z

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