Bressman Susan B, Raymond Deborah, Fuchs Tania, Heiman Gary A, Ozelius Laurie J, Saunders-Pullman Rachel
Department of Neurology, Beth Israel Medical Center, New York, NY 10003, USA.
Lancet Neurol. 2009 May;8(5):441-6. doi: 10.1016/S1474-4422(09)70081-X. Epub 2009 Apr 1.
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.
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.
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.
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.
Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.
THAP1基因的突变最近被确定为DYT6原发性肌张力障碍的病因；在阿米什-门诺派家族中检测到一个奠基者突变，在另一个欧洲血统家族中发现了另一种不同的突变。为了更广泛地评估该基因的作用，我们对包括一名早发性、非局灶性原发性肌张力障碍家庭成员的家族进行了突变筛查。
我们确定了36个非DYT1多病例家族，其中至少有一人在22岁之前发病且有非局灶性受累。对THAP1的所有三个编码外显子进行测序，并将有突变个体的临床特征与THAP1突变阴性个体的临床特征进行比较。还评估了基因型-表型差异。
在36个家族中，9个（25%）家族成员存在THAP1突变，大多数为德国、爱尔兰或意大利血统。一个家族有阿米什-门诺派奠基者突变，而其他8个家族各有新的、可能导致截短或错义的突变。有突变家族的临床特征符合先前描述的DYT6表型；然而，发病年龄从38岁延长到了49岁。与非携带者相比，突变携带者发病年龄更小，其肌张力障碍更可能始于臂部肌肉而非颈部肌肉，随后发展为全身性，且包括言语受累。未发现基因型-表型差异。
THAP1突变是非DYT1家族中相当一部分早发性原发性肌张力障碍的病因。THAP1突变的受累个体的特征性临床特征包括肢体和颅部肌肉受累，且言语常受影响。
肌张力障碍医学研究基金会；巴赫曼-施特劳斯肌张力障碍与帕金森基金会；国家神经疾病和中风研究所；亚伦·阿罗诺夫家族基金会。
