期刊
NEUROLOGY
卷 74, 期 10, 页码 846-850出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e3181d5276d
关键词
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资金
- Medical Research Council (MRC) UK
- Michael J Fox Foundation
- Brain Research Trust (BRT)
- National Organization for Rare Disorders (NORD)
- Ataxia UK
- British Medical Association
- Novartis
- Brain Research Trust
- Austrian Science Fund FWF
- Erwin Schrdinger Grant
- MRC [G0701075, G0601943, G0802760] Funding Source: UKRI
- Medical Research Council [G0802760, G0701075, G0601943] Funding Source: researchfish
- Parkinson's UK [G-0907] Funding Source: researchfish
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. Neurology (R) 2010; 74: 846-850
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