Genetics and Epidemiology of Essential Tremor

原发性震颤(ET)是一种以一组核心特征为特征的异质性震颤障碍。震颤综合征的特征是影响手臂和手的姿势和运动性震颤，尽管头部、声音和腿也可能受到影响。虽然经常被描述为良性疾病，但事实并非如此；许多患者在社交和身体上都有残疾，有些患者完全残疾。ET的鉴别诊断列表很广泛，包括肌张力障碍、帕金森氏症、肌阵挛、周围神经病变等。根据方法和诊断标准，患病率估计范围很大，在一般人群中从0.003%到高达2%，65岁以上人口中受影响的比例高达5%。目前尚无已知的ET生物学或诊断神经病理标志物。有阳性家族史的ET病例估计从17.4%到100%不等。最近的研究表明，高达96%的ET可能是显性遗传的。临床和遗传的异质性减缓了连锁研究的速度。到目前为止，已有三个与ET相关的基因座被连锁：1)家族性原发性震颤1(FET1)已被定位在染色体3Q13上的一系列冰岛家系中；(2)ETM在四个不相关的美国家系中被定位到染色体2p22-p25；以及(3)第三个基因座被定位在一个分离帕金森氏病和与ET一致的姿势震颤的家庭中。到目前为止，我们已经确定了12个ET和ET/PD连锁优质家系。最大的纯ET家系(DUK13001)已被排除在已知的ET基因座之外。这项建议的目的是确定并采样患有ET的大型家系，进行完整的ET基因组扫描，以建立这些家系与其他ET家系的联系，识别新的ET疾病基因座，并从DUK13001 ET家系开始分离和鉴定ET基因。

Essential Tremor (ET) is a heterogenous tremor disorder characterized by a core group of features. The tremor syndrome is characterized by postural and kinetic tremor affecting the arms and hands, although the head, voice, and legs may also be affected. Although frequently described as a benign disorder, this is not true; many patients are socially and physically handicapped, with some patients being totally disabled. The differential diagnosis list for ET is extensive including dystonia, Parkinsonism, myoclonus, peripheral neuropathy, and other conditions. Prevalence estimates range widely, depending upon methodology and diagnostic criteria, from 0.003 to as high as 2% in the general population, with as much as 5% of the population affected over the age of 65. There are no known biological or diagnostic neuropathological markers for ET. The estimates of ET cases presenting with a positive family history range from 17.4% to 100%. Recent studies indicate that up to 96% of ET may be dominantly inherited. Clinical and genetic heterogeneity have slowed linkage studies. To date three loci associated with ET have been linked: 1) Familial Essential Tremor 1 (FET1) has been mapped in a series of Icelandic families on chromosome 3q13; (2) ETM mapped, in four unrelated US families, to chromosome 2p22-p25; and (3) a third locus maps, in a family that segregates both Parkinson's disease and postural tremor consistent with ET, to Chromosome 4p. We have, to date, ascertained, twelve ET and ET/PD linkage quality families. The largest pure ET kindred (DUK13001) have been excluded from known ET loci. The aims of this proposal are to ascertain and sample large families with ET, carry out a complete ET genome scan to establish linkage for these and additional ET families, identify new ET disease loci, and isolate and characterize ET genes, beginning with DUK13001 ET family.