title: Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7.
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.
authors.affiliation: Institut National de Neurologie, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: A
authors.initials: A
authors.lastname: Ben Ammar
authors.forename: F
authors.initials: F
authors.lastname: Petit
authors.forename: N
authors.initials: N
authors.lastname: Alexandri
authors.forename: K
authors.initials: K
authors.lastname: Gaudon
authors.forename: S
authors.initials: S
authors.lastname: Bauché
authors.forename: A
authors.initials: A
authors.lastname: Rouche
authors.forename: D
authors.initials: D
authors.lastname: Gras
authors.forename: E
authors.initials: E
authors.lastname: Fournier
authors.forename: J
authors.initials: J
authors.lastname: Koenig
authors.forename: T
authors.initials: T
authors.lastname: Stojkovic
authors.forename: A
authors.initials: A
authors.lastname: Lacour
authors.forename: P
authors.initials: P
authors.lastname: Petiot
authors.forename: F
authors.initials: F
authors.lastname: Zagnoli
authors.forename: L
authors.initials: L
authors.lastname: Viollet
authors.forename: N
authors.initials: N
authors.lastname: Pellegrini
authors.forename: D
authors.initials: D
authors.lastname: Orlikowski
authors.forename: L
authors.initials: L
authors.lastname: Lazaro
authors.forename: X
authors.initials: X
authors.lastname: Ferrer
authors.forename: G
authors.initials: G
authors.lastname: Stoltenburg
authors.forename: M
authors.initials: M
authors.lastname: Paturneau-Jouas
authors.forename: F
authors.initials: F
authors.lastname: Hentati
authors.forename: M
authors.initials: M
authors.lastname: Fardeau
authors.forename: D
authors.initials: D
authors.lastname: Sternberg
authors.forename: D
authors.initials: D
authors.lastname: Hantaï
authors.forename: P
authors.initials: P
authors.lastname: Richard
authors.forename: B
authors.initials: B
authors.lastname: Eymard
mesh_terms: D001369:Axons / Q000473:pathology / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009469:Neuromuscular Junction / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D011247:Pregnancy; D014057:Tomography, X-Ray Computed
chemical_list: C511692:DOK7 protein, human; D009124:Muscle Proteins