BACKGROUND: Mutations in THAP1 were recently identified as the cause of DYT6 primary dystonia; a founder mutation was detected in Amish-Mennonite families, and a different mutation was identified in another family of European descent. To assess more broadly the role of this gene, we screened for mutations in families that included one family member who had early-onset, non-focal primary dystonia. METHODS: We identified 36 non-DYT1 multiplex families in which at least one person had non-focal involvement at an age of onset that was younger than 22 years. All three coding exons of THAP1 were sequenced, and the clinical features of individuals with mutations were compared with those of individuals who were negative for mutations in THAP1. Genotype-phenotype differences were also assessed. FINDINGS: Of 36 families, nine (25%) had members with mutations in THAP1, and most were of German, Irish, or Italian ancestry. One family had the Amish-Mennonite founder mutation, whereas the other eight families each had novel, potentially truncating or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype; however, age at onset was extended from 38 years to 49 years. Compared with non-carriers, mutation carriers were younger at onset and their dystonia was more likely to begin in brachial, rather than cervical, muscles, become generalised, and include speech involvement. Genotype-phenotype differences were not found. INTERPRETATION: Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families. The clinical features that are characteristic of affected individuals who have mutations in THAP1 include limb and cranial muscle involvement, and speech is often affected. FUNDING: Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.
BACKGROUND: Mutations in THAP1 were recently identified as the cause of DYT6primary dystonia; a founder mutation was detected in Amish-Mennonite families, and a different mutation was identified in another family of European descent. To assess more broadly the role of this gene, we screened for mutations in families that included one family member who had early-onset, non-focal primary dystonia. METHODS: We identified 36 non-DYT1 multiplex families in which at least one person had non-focal involvement at an age of onset that was younger than 22 years. All three coding exons of THAP1 were sequenced, and the clinical features of individuals with mutations were compared with those of individuals who were negative for mutations in THAP1. Genotype-phenotype differences were also assessed. FINDINGS: Of 36 families, nine (25%) had members with mutations in THAP1, and most were of German, Irish, or Italian ancestry. One family had the Amish-Mennonite founder mutation, whereas the other eight families each had novel, potentially truncating or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype; however, age at onset was extended from 38 years to 49 years. Compared with non-carriers, mutation carriers were younger at onset and their dystonia was more likely to begin in brachial, rather than cervical, muscles, become generalised, and include speech involvement. Genotype-phenotype differences were not found. INTERPRETATION: Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families. The clinical features that are characteristic of affected individuals who have mutations in THAP1 include limb and cranial muscle involvement, and speech is often affected. FUNDING: Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.
Authors: S B Bressman; D Raymond; K Wendt; R Saunders-Pullman; D De Leon; S Fahn; L Ozelius; N Risch Journal: Neurology Date: 2002-12-10 Impact factor: 9.910
Authors: S B Bressman; C Sabatti; D Raymond; D de Leon; C Klein; P L Kramer; M F Brin; S Fahn; X Breakefield; L J Ozelius; N J Risch Journal: Neurology Date: 2000-05-09 Impact factor: 9.910
Authors: E M Valente; A R Bentivoglio; E Cassetta; P H Dixon; M B Davis; A Ferraris; T Ialongo; M Frontali; N W Wood; A Albanese Journal: Ann Neurol Date: 2001-03 Impact factor: 10.422
Authors: S B Bressman; D de Leon; P L Kramer; L J Ozelius; M F Brin; P E Greene; S Fahn; X O Breakefield; N J Risch Journal: Ann Neurol Date: 1994-11 Impact factor: 10.422
Authors: P L Kramer; G A Heiman; T Gasser; L J Ozelius; D de Leon; M F Brin; R E Burke; J Hewett; A L Hunt; C Moskowitz Journal: Am J Hum Genet Date: 1994-09 Impact factor: 11.025
Authors: Mark S LeDoux; Jianfeng Xiao; Monika Rudzińska; Robert W Bastian; Zbigniew K Wszolek; Jay A Van Gerpen; Andreas Puschmann; Dragana Momčilović; Satya R Vemula; Yu Zhao Journal: Parkinsonism Relat Disord Date: 2012-02-28 Impact factor: 4.891
Authors: Fabienne Clot; David Grabli; Pierre Burbaud; Magali Aya; Pascal Derkinderen; Luc Defebvre; Philippe Damier; Pierre Krystkowiak; Pierre Pollak; Eric Leguern; Chan San; Agnès Camuzat; Emmanuel Roze; Marie Vidailhet; Alexandra Durr; Alexis Brice Journal: Neurogenetics Date: 2010-11-26 Impact factor: 2.660
Authors: Katja Lohmann; Nils Uflacker; Alev Erogullari; Thora Lohnau; Susen Winkler; Andreas Dendorfer; Susanne A Schneider; Alma Osmanovic; Marina Svetel; Andreas Ferbert; Simone Zittel; Andrea A Kühn; Alexander Schmidt; Eckart Altenmüller; Alexander Münchau; Christoph Kamm; Matthias Wittstock; Andreas Kupsch; Elena Moro; Jens Volkmann; Vladimir Kostic; Frank J Kaiser; Christine Klein; Norbert Brüggemann Journal: Eur J Hum Genet Date: 2011-08-17 Impact factor: 4.246
Authors: J Xiao; Y Zhao; R W Bastian; J S Perlmutter; B A Racette; S D Tabbal; M Karimi; R C Paniello; Z K Wszolek; R J Uitti; J A Van Gerpen; D K Simon; D Tarsy; P Hedera; D D Truong; K P Frei; S Dev Batish; A Blitzer; R F Pfeiffer; S Gong; M S LeDoux Journal: Neurology Date: 2010-01-19 Impact factor: 9.910