title: Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes.
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.
authors: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.
authors: Juliane S
authors: JS
authors: Müller
authors: Agnes
authors: A
authors: Herczegfalvi
authors: Juan J
authors: JJ
authors: Vilchez
authors: Jaume
authors: J
authors: Colomer
authors: Linda L
authors: LL
authors: Bachinski
authors: Violeta
authors: V
authors: Mihaylova
authors: Manuela
authors: M
authors: Santos
authors: Ulrike
authors: U
authors: Schara
authors: Marcus
authors: M
authors: Deschauer
authors: Michael
authors: M
authors: Shevell
authors: Chantal
authors: C
authors: Poulin
authors: Ana
authors: A
authors: Dias
authors: Ana
authors: A
authors: Soudo
authors: Marja
authors: M
authors: Hietala
authors: Tuula
authors: T
authors: Aärimaa
authors: Ralf
authors: R
authors: Krahe
authors: Veronika
authors: V
authors: Karcagi
authors: Angela
authors: A
authors: Huebner
authors: David
authors: D
authors: Beeson
authors: Angela
authors: A
authors: Abicht
authors: Hanns
authors: H
authors: Lochmüller
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D004252:DNA Mutational Analysis / Q000379:methods; D004558:Electric Stimulation; D005260:Female; D020233:Gait Disorders, Neurologic / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D017211:Treatment Failure
chemical_list: D002800:Cholinesterase Inhibitors; C511692:DOK7 protein, human; D009124:Muscle Proteins