title: THAP1 mutations (DYT6) are an additional cause of early-onset dystonia.
abstract: BACKGROUND
  The clinical phenotype of DYT6 consists mainly of primary craniocervical dystonia. Recently, the THAP1 gene was identified as the cause of DYT6, where a total of 13 mutations have been identified in Amish-Mennonite and European families.
  
  
  METHODS
  We sequenced the THAP1 gene in a series of 362 British, genetically undetermined, primary dystonia patients (78 with focal, 186 with segmental, and 98 with generalized dystonia) and in 28 dystonia-manifesting DYT1 patients and 176 normal control individuals.
  
  
  RESULTS
  Nine coding mutations were identified in the THAP1 gene. Two were small deletions, 2 were nonsense, and 5 were missense. Eight mutations were heterozygous, and 1 was homozygous. The main clinical presentation of cases with THAP1 mutations was early-onset (<30 years) dystonia in the craniocervical region or the limbs (8 of 9 patients). There was phenotypic variability with laryngeal or oromandibular dystonia present in 3 cases. Four of 9 THAP1 cases developed generalized dystonia.
  
  
  CONCLUSIONS
  The number of THAP1 mutations has been significantly expanded, indicating an uncommon but important cause of dystonia. Coding mutations account for 9 of 362 dystonia cases, indicating a mutation frequency of 2.5% of dystonia cases in the population that we have screened. The majority of cases reported here with THAP1 mutations had craniocervical- or limb-onset segmental dystonia, but we also identified 1 homozygous THAP1 mutation, associated initially with writer's dystonia and then developing segmental dystonia. Three of our patients had a nonsense or frameshift THAP1 mutation and the clinical features of laryngeal or oromandibular dystonia. These data suggest that early-onset dystonia that includes the involvement of the larynx or face is frequently associated with THAP1 mutations.
authors.affiliation: University College London Institute of Neurology, Queen Square, London WC1N 3BG, England. h.houlden@ion.ucl.ac.uk
authors.forename: H
authors.initials: H
authors.lastname: Houlden
authors.forename: S A
authors.initials: SA
authors.lastname: Schneider
authors.forename: R
authors.initials: R
authors.lastname: Paudel
authors.forename: A
authors.initials: A
authors.lastname: Melchers
authors.forename: P
authors.initials: P
authors.lastname: Schwingenschuh
authors.forename: M
authors.initials: M
authors.lastname: Edwards
authors.forename: J
authors.initials: J
authors.lastname: Hardy
authors.forename: K P
authors.initials: KP
authors.lastname: Bhatia
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004421:Dystonia / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C474080:THAP1 protein, human