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Journal of Neurology

, Volume 257, Issue 5, pp 754–766 | Cite as

Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7

  • A. Ben Ammar
  • F. Petit
  • N. Alexandri
  • K. Gaudon
  • S. Bauché
  • A. Rouche
  • D. Gras
  • E. Fournier
  • J. Koenig
  • T. Stojkovic
  • A. Lacour
  • P. Petiot
  • F. Zagnoli
  • L. Viollet
  • N. Pellegrini
  • D. Orlikowski
  • L. Lazaro
  • X. Ferrer
  • G. Stoltenburg
  • M. Paturneau-Jouas
  • F. Hentati
  • M. Fardeau
  • D. Sternberg
  • D. Hantaï
  • P. Richard
  • B. EymardEmail author
Original Communication

Abstract

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. Mutations of DOK7 have recently been described in recessive forms of CMS. Dok-7 is a cytoplasmic post-synaptic protein co-activator of the muscle-specific receptor-tyrosine kinase (MuSK) involved in neuromuscular synaptogenesis and maintenance. We report clinical, morphological and molecular data on 15 patients with mutations in DOK7. Eleven different mutations (5 novel) were identified and all patients but one were found to carry at least the common c.1124_1127dupTGCC mutation. Patients with DOK7 mutations have a particular limb-girdle pattern, without tubular aggregates but a frequent lipidosis on the muscle biopsy. Changes in pre- and post-synaptic compartments of the neuromuscular junction were also observed in muscle biopsies: terminal axons showed defective branching which resulted in a unique terminal axon contacting en passant postsynaptic cups. Clinical features, muscle biopsy findings or response to therapy were confusing in several patients. Characterization of this distinct phenotype is essential to provide clues for targeted genetic screening and to predict the therapeutic response to anticholinesterase treatments or ephedrine as has been suggested.

Keywords

Congenital myasthenic syndrome Neuromuscular junction Mutations DOK7 Phenotype 

Notes

Acknowledgments

This work was supported by Assistance Publique-Hôpitaux de Paris (PHRC AOM 1036), Réseaux Inserm, ANR-Maladies Rares (#ANR-07-MRAR-001), Association Française contre les Myopathies (AFM), Comité Mixte Franco-Tunisien pour la Coopération Universitaire (CMCU Project #05G0809), and a Contrat d’Interface AP-HP Inserm (to DH).

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • A. Ben Ammar
    • 1
    • 2
  • F. Petit
    • 3
  • N. Alexandri
    • 2
    • 3
  • K. Gaudon
    • 4
  • S. Bauché
    • 2
  • A. Rouche
    • 2
  • D. Gras
    • 2
  • E. Fournier
    • 5
  • J. Koenig
    • 2
    • 6
  • T. Stojkovic
    • 3
  • A. Lacour
    • 7
  • P. Petiot
    • 8
  • F. Zagnoli
    • 9
  • L. Viollet
    • 10
  • N. Pellegrini
    • 11
  • D. Orlikowski
    • 11
  • L. Lazaro
    • 12
  • X. Ferrer
    • 13
  • G. Stoltenburg
    • 14
  • M. Paturneau-Jouas
    • 2
  • F. Hentati
    • 1
  • M. Fardeau
    • 14
  • D. Sternberg
    • 4
  • D. Hantaï
    • 2
    • 3
  • P. Richard
    • 4
  • B. Eymard
    • 2
    • 3
    Email author
  1. 1.Institut National de NeurologieUniversité Tunis El ManarTunisTunisia
  2. 2.Inserm, UMRS 975, UPMC, CRICM, Institut de MyologieGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  3. 3.APHP, Centre de Référence en Pathologie Neuromusculaire Paris-Est, Institut de MyologieGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  4. 4.APHP, UF Cardiogénétique et Myogénétique, Institut de MyologieGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  5. 5.APHP, Service de Neurophysiologie, Institut de MyologieGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  6. 6.Université Victor Segalen Bordeaux 2BordeauxFrance
  7. 7.CHU de LilleCentre de Référence des Maladies NeuromusculairesLilleFrance
  8. 8.Service de NeurologieHôpital de la Croix RousseLyonFrance
  9. 9.Service de NeurologieHôpital des Armées Clermont-TonnerreBrestFrance
  10. 10.Service de Pédiatrie, Réanimation InfantileHôpital Raymond PoincaréGarchesFrance
  11. 11.Service de Réanimation MédicaleHôpital Raymond PoincaréGarchesFrance
  12. 12.Service de GénétiqueCentre HospitalierRennesFrance
  13. 13.Hôpital du Haut LévêquePessacFrance
  14. 14.Unité de Morphologie Neuromusculaire, Institut de MyologieGroupe Hospitalier Pitié-SalpêtrièreParisFrance

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