Journal of Neurology

, Volume 259, Issue 5, pp 838–850 | Cite as

Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations

  • Velina Guergueltcheva
  • Juliane S. Müller
  • Marina Dusl
  • Jan Senderek
  • Anders Oldfors
  • Christopher Lindbergh
  • Susan Maxwell
  • Jaume Colomer
  • Cecilia Jimenez Mallebrera
  • Andres Nascimento
  • Juan J. Vilchez
  • Nuria Muelas
  • Janbernd Kirschner
  • Shahriar Nafissi
  • Ariana Kariminejad
  • Yalda Nilipour
  • Bita Bozorgmehr
  • Hossein Najmabadi
  • Carmelo Rodolico
  • Jörn P. Sieb
  • Beate Schlotter
  • Benedikt Schoser
  • Ralf Herrmann
  • Thomas Voit
  • Ortrud K. Steinlein
  • Abdolhamid Najafi
  • Andoni Urtizberea
  • Doriette M. Soler
  • Francesco Muntoni
  • Michael G. Hanna
  • Amina Chaouch
  • Volker Straub
  • Kate Bushby
  • Jacqueline Palace
  • David Beeson
  • Angela Abicht
  • Hanns Lochmüller
Original Communication

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).

Keywords

Congenital myasthenic syndromes Limb-girdle myasthenia Tubular aggregates GFPT1 Dok-7 

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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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Velina Guergueltcheva
    • 1
    • 2
  • Juliane S. Müller
    • 3
  • Marina Dusl
    • 1
  • Jan Senderek
    • 4
    • 5
  • Anders Oldfors
    • 6
  • Christopher Lindbergh
    • 7
  • Susan Maxwell
    • 8
  • Jaume Colomer
    • 9
  • Cecilia Jimenez Mallebrera
    • 9
  • Andres Nascimento
    • 9
  • Juan J. Vilchez
    • 10
  • Nuria Muelas
    • 10
  • Janbernd Kirschner
    • 11
  • Shahriar Nafissi
    • 12
  • Ariana Kariminejad
    • 13
  • Yalda Nilipour
    • 14
  • Bita Bozorgmehr
    • 13
  • Hossein Najmabadi
    • 13
  • Carmelo Rodolico
    • 15
  • Jörn P. Sieb
    • 16
  • Beate Schlotter
    • 1
  • Benedikt Schoser
    • 1
  • Ralf Herrmann
    • 17
  • Thomas Voit
    • 18
  • Ortrud K. Steinlein
    • 19
  • Abdolhamid Najafi
    • 20
  • Andoni Urtizberea
    • 21
  • Doriette M. Soler
    • 22
  • Francesco Muntoni
    • 23
  • Michael G. Hanna
    • 24
  • Amina Chaouch
    • 3
  • Volker Straub
    • 3
  • Kate Bushby
    • 3
  • Jacqueline Palace
    • 25
  • David Beeson
    • 8
  • Angela Abicht
    • 1
  • Hanns Lochmüller
    • 3
  1. 1.Department of Neurology, Friedrich-Baur-InstitutLudwig Maximilians UniversityMunichGermany
  2. 2.Clinic of NeurologyUniversity Hospital AlexandrovskaSofiaBulgaria
  3. 3.Institute of Genetic MedicineNewcastle University, International Centre for Life, Central ParkwayNewcastle upon TyneUK
  4. 4.Institute of NeuropathologyRWTH Aachen UniversityAachenGermany
  5. 5.Institute of Human GeneticsRWTH Aachen UniversityAachenGermany
  6. 6.Department of Pathology, Institute of BiomedicineUniversity of GothenburgGothenburgSweden
  7. 7.Neuromuscular CenterSahlgrenska University HospitalGothenburgSweden
  8. 8.Neurosciences Group, Department of Clinical NeurologyWeatherall Institute of Molecular Medicine, University of OxfordOxfordUK
  9. 9.Unitat de Patologia Neuromuscular, Servei de NeurologiaHospital Sant Joan de DeuEspluguesSpain
  10. 10.Servicio de NeurologíaHospital Universitario y Politécnico La Fe and CIBER de Enfermedades Neurodegenerativas (CIBERNED)ValenciaSpain
  11. 11.Division of Neuropaediatrics and Muscle DisordersUniversity Medical CenterFreiburgGermany
  12. 12.Department of NeurologyTehran University of Medical SciencesTehranIran
  13. 13.Kariminejad-Najmabadi Pathology and Genetics CenterTehranIran
  14. 14.Neuropathology LabToos HospitalTehranIran
  15. 15.Departments of Neurosciences, Psychiatry and AnaesthesiologyA.O.U. “G. Martino”MessinaItaly
  16. 16.Department of NeurologyGeriatric Medicine and Palliative CareHanse-KlinikumGermany
  17. 17.Department of Paediatrics IUniversity Hospital EssenEssenGermany
  18. 18.Institut de Myologie, Unité Mixte de Recherche UPMC-INSERM-CNRS-AIM UM 76, U974, UMR 7215, Groupe Hospitalier Pitié-SalpêtrièreParisFrance
  19. 19.Institute of Human GeneticsLudwig Maximilians UniversityMunichGermany
  20. 20.Azad University Medical BranchTehranIran
  21. 21.Hôpital MarinHendayeFrance
  22. 22.Department of PaediatricsMater Dei HospitalMsidaMalta
  23. 23.The Dubowitz Neuromuscular CentreUCL Institute of Child HealthLondonUK
  24. 24.MRC Centre for Neuromuscular DiseasesUCL Institute of NeurologyLondonUK
  25. 25.CMS NCG Group, Department of Clinical NeurologyJohn Radcliffe HospitalOxfordUK

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