Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes

Juliane S. Müller, Agnes Herczegfalvi, Juan J. Vilchez, Jaume Colomer, Linda L. Bachinski, Violeta Mihaylova, Manuela Santos, Ulrike Schara, Marcus Deschauer, Michael Shevell, Chantal Poulin, Ana Dias, Ana Soudo, Marja Hietala, Tuula Äärimaa, Ralf Krahe, V. Karcagi, Angela Huebner, David Beeson, Angela AbichtHanns Lochmüller

Research output: Contribution to journalArticle

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Abstract

Dok ('downstream-of-kinase') family of cytoplasmic proteins play a role in signalling downstream of receptor and non-receptor phosphotyrosine kinases. Recently, a skeletal muscle receptor tyrosine kinase (MuSK)-interacting cytoplasmic protein termed Dok-7 has been identified. Subsequently, we and others identified mutations in DOK7 as a cause of congenital myasthenic syndromes (CMS), providing evidence for a crucial role of Dok-7 in maintaining synaptic structure. Here we present clinical and molecular genetic data of 14 patients from 12 independent kinships with 13 different mutations in the DOK7 gene. The clinical picture of CMS with DOK7 mutations is highly variable. The age of onset may vary between birth and the third decade. However, most of the patients display a characteristic 'limb-girdle' pattern of weakness with a waddling gait and ptosis, but without ophthalmoparesis. Respiratory problems were frequent. Patients did not benefit from long-term therapy with esterase inhibitors; some of the patients even worsened. DOK7 mutations have emerged as one of the major genetic defects in CMS. The clinical picture differs significantly from CMS caused by mutations in other genes, such as the acetylcholine receptor (AChR) subunit genes. None of the patients with DOK7 mutations had tubular aggregates in the muscle biopsy, implying that 'limb-girdle myasthenia (LGM) with tubular aggregates' previously described in literature may be a pathogenic entity distinct from CMS caused by DOK7 mutations.

Original languageEnglish
Pages (from-to)1497-1506
Number of pages10
JournalBrain
Volume130
Issue number6
DOIs
Publication statusPublished - Jun 2007

Fingerprint

Congenital Myasthenic Syndromes
Mutation
Phosphotransferases
Genes
Ophthalmoplegia
Phosphotyrosine
Receptor Protein-Tyrosine Kinases
Cholinergic Receptors
Esterases
Gait
Age of Onset
Molecular Biology
Skeletal Muscle
Proteins
Extremities
Parturition
Biopsy
Muscles

Keywords

  • Congenital myasthenic syndromes
  • DOK7
  • Limb-girdle myasthenia (LGM)
  • Neuromuscular junction

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Müller, J. S., Herczegfalvi, A., Vilchez, J. J., Colomer, J., Bachinski, L. L., Mihaylova, V., ... Lochmüller, H. (2007). Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Brain, 130(6), 1497-1506. https://doi.org/10.1093/brain/awm068

Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. / Müller, Juliane S.; Herczegfalvi, Agnes; Vilchez, Juan J.; Colomer, Jaume; Bachinski, Linda L.; Mihaylova, Violeta; Santos, Manuela; Schara, Ulrike; Deschauer, Marcus; Shevell, Michael; Poulin, Chantal; Dias, Ana; Soudo, Ana; Hietala, Marja; Äärimaa, Tuula; Krahe, Ralf; Karcagi, V.; Huebner, Angela; Beeson, David; Abicht, Angela; Lochmüller, Hanns.

In: Brain, Vol. 130, No. 6, 06.2007, p. 1497-1506.

Research output: Contribution to journalArticle

Müller, JS, Herczegfalvi, A, Vilchez, JJ, Colomer, J, Bachinski, LL, Mihaylova, V, Santos, M, Schara, U, Deschauer, M, Shevell, M, Poulin, C, Dias, A, Soudo, A, Hietala, M, Äärimaa, T, Krahe, R, Karcagi, V, Huebner, A, Beeson, D, Abicht, A & Lochmüller, H 2007, 'Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes', Brain, vol. 130, no. 6, pp. 1497-1506. https://doi.org/10.1093/brain/awm068
Müller JS, Herczegfalvi A, Vilchez JJ, Colomer J, Bachinski LL, Mihaylova V et al. Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Brain. 2007 Jun;130(6):1497-1506. https://doi.org/10.1093/brain/awm068
Müller, Juliane S. ; Herczegfalvi, Agnes ; Vilchez, Juan J. ; Colomer, Jaume ; Bachinski, Linda L. ; Mihaylova, Violeta ; Santos, Manuela ; Schara, Ulrike ; Deschauer, Marcus ; Shevell, Michael ; Poulin, Chantal ; Dias, Ana ; Soudo, Ana ; Hietala, Marja ; Äärimaa, Tuula ; Krahe, Ralf ; Karcagi, V. ; Huebner, Angela ; Beeson, David ; Abicht, Angela ; Lochmüller, Hanns. / Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. In: Brain. 2007 ; Vol. 130, No. 6. pp. 1497-1506.
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AU - Äärimaa, Tuula

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