GENETIC INFLUENCES ON MOVEMENT DISORDERS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 运动障碍是残疾的常见来源。最常见的运动障碍之一是肌张力障碍，法恩将其定义为“一种以持续性肌肉收缩为特征的异常运动，经常导致扭曲和重复的运动或异常姿势。”虽然肌张力障碍可能会影响身体的任何部位，但颈部肌张力障碍，也被称为痉挛性斜颈，是成年人最常见的形式。其他的例子包括眼睑痉挛和局灶性肌张力障碍，即所谓的作家痉挛。目前研究的第一阶段集中在肌张力障碍运动障碍上。 虽然肌张力障碍有时是由药物(迟发性肌张力障碍)或其他潜在的神经疾病引起的，但大多数病例的病因仍不清楚。一些罕见的病例以常染色体显性遗传方式进行遗传传播，并在这些家庭中发现了一种异常基因DYT1。然而，大多数患有肌张力障碍的成年人没有这种疾病的家族史，也不携带DYT1基因。关于这些特发性病例的其他可能的遗传因素，人们知之甚少。缺乏关于肌张力障碍发病机制的科学信息，包括其他遗传影响，阻碍了治疗方法的发展。 最近关于肌张力障碍可能发病机制的线索来自两个不同来源的汇合。第一项研究表明，特发性颈性肌张力障碍患者和携带DYT1基因的肌张力障碍患者的皮质可塑性异常增加。携带DYT1基因但没有肌张力障碍症状的人没有发现皮质可塑性异常增加。 第二个可能的线索来自加州大学克雷默博士的实验室，那就是皮质的可塑性与不同的基因有很大的不同。脑源性神经营养因子(BDNF)的基因型别强烈影响皮质的可塑性程度。在编码BDNF基因的一个或两个等位基因中有Val66Met突变的健康受试者，短期皮质可塑性降低。这种遗传变异似乎对人类大脑功能的许多方面产生了强大的影响。例如，一项研究指出，“值得注意的是，编码过程中BDNF Val66Met基因和海马体反应之间的相互作用占到了识别记忆表现总变异的25%。” 总之，这两个观察结果表明，与没有这些症状的健康受试者相比，表现出肌张力障碍症状的人具有过度活跃的皮质可塑性，因此BDNF Val66Met基因变异的发生率相对较低。目前这项研究的具体目的是比较被诊断为肌张力障碍的人与健康的非肌张力障碍对照组中BDNF Val66Met基因的频率。 作为次要目标，两组受试者还将接受DYT1基因突变的检测。假设是，在罕见的具有DYT1基因突变的肌张力障碍患者中，与携带该突变的肌张力障碍患者相比，在一个或两个等位基因中缺乏Val66Met突变将与更早的发病年龄和更严重的肌张力障碍症状水平相关。 请注意，一组控制组将是年龄匹配的健康受试者。第二组受试者将是帕金森氏症患者，这也是一种基底节疾病，但与肌张力障碍不同，帕金森氏症是由神经生成引起的，其病理生理学推测与特发性肌张力障碍不同。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Movement disorders are a common source of disability. Among the most frequently diagnosed group of movement disorders is dystonia, defined by Fahn as "an abnormal movement characterized by sustained muscle contractions frequently causing twisting and repetitive movements or abnormal postures." Although dystonia may affect any part of the body, cervical dystonia, also called spasmodic torticollis, is the most common form in adults. Other examples include blepharospasm and focal action dystonia, so called writer's cramp. The first phase of the current study is focused on dystonic movement disorders. Although dystonia is sometimes induced by medications (tardive dystonia) or caused by other, underlying neurological disease the etiology of the majority of cases remains unknown. Some rare cases are genetically transmitted in an autosomal dominant pattern, and an abnormal gene, DYT1, has been identified in these families. However, most adults with dystonia have no family history of this disorder and do not carry the DYT1 gene. Little is known about other possible genetic contributions to these idiopathic cases. The paucity of scientific information on the pathogenesis of dystonia, including other genetic influences, has hampered the development of therapies. Recent clues regarding the possible pathogenesis of dystonia comes from convergence of two separate sources. The first1 suggests that abnormally increased cortical plasticity occurs among people with idiopathic cervical dystonia and also in people with dystonia who carry the DYT1 gene. People who are carriers of the DYT1 gene but do not have symptoms of dystonia were not found to have abnormally increased cortical plasticity. A second, possible clue, from Dr. Cramer's lab at UCI, is that cortical plasticity varies strongly in relation to a different gene. One's genotype for the protein Brain Derived Neurotrophic Factor (BDNF) strongly influences extent of cortical plasticity. Healthy subjects who have a val66met mutation in one or both alleles for the gene encoding BDNF have reduced measures of short-term cortical plasticity2. This genetic variation appears to have a powerful effect on many aspects of human brain function. For example, one study 3 noted that "Remarkably, the interaction between the BDNF val66met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance." Together, these two observations suggest the hypothesis that persons who demonstrate dystonic symptoms, as compared to healthy subjects who do not have such symptoms, have overactive cortical plasticity, and thus a relatively lower incidence of the BDNF val66met genotype variant. The specific aim of the current study is to compare the frequency of the BDNF val66met genotype in persons diagnosed with dystonia to the frequency in healthy, non-dystonic controls. As a secondary aim, both subject groups will also be tested for the presence of the mutation in the DYT1 gene. The subhypothesis is that among the rare dystonic subjects who have the DYT1 gene mutation the absence of the val66met mutation in one or both alleles will be associated with an earlier age of onset and more severe level of dystonic symptoms, as compared to dystonic patients who carry this mutation. Note that one control group will be age-matched, healthy subjects. A second control group will be subjects with Parkinson's disease, also a basal ganglia disorder, but, unlike dystonia, due to neurodgeneration and with a pathophysiology presumed different than idiopathic dystonia.