GENETIC INFLUENCES ON MOVEMENT DISORDERS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 运动障碍是残疾的常见原因。 最常被诊断的运动障碍是肌张力障碍，Fahn将其定义为“一种以持续的肌肉收缩为特征的异常运动，经常导致扭曲和重复运动或异常姿势。虽然肌张力障碍可能影响身体的任何部位，但颈部肌张力障碍，也称为痉挛性斜颈，是成人最常见的形式。 其他例子包括眼睑痉挛和局部动作肌张力障碍，所谓的书写痉挛。 目前研究的第一阶段集中于肌张力障碍性运动障碍。 虽然肌张力障碍有时是由药物引起的（迟发性肌张力障碍）或由其他潜在的神经系统疾病引起的，但大多数病例的病因仍然未知。 一些罕见的病例是以常染色体显性遗传模式遗传的，并且在这些家庭中已经确定了异常基因DYT 1。 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DYT 1基因。 对这些特发性病例的其他可能的遗传贡献知之甚少。 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独立来源的融合。 第一个1表明，异常增加的皮质可塑性发生在患有特发性颈肌张力障碍的人和携带DYT 1基因的肌张力障碍患者中。 携带DYT 1基因但没有肌张力障碍症状的人没有发现异常增加的皮质可塑性。 第二个可能的线索来自克拉默博士在UCI的实验室，即大脑皮层的可塑性与不同的基因有很大的关系。 一个人的脑源性神经营养因子（BDNF）蛋白质基因型强烈影响皮质可塑性的程度。 在编码BDNF的基因的一个或两个等位基因中具有val 66 met突变的健康受试者具有短期皮质可塑性降低的措施2。 这种遗传变异似乎对人类大脑功能的许多方面都有强大的影响。 例如，一项研究3指出：“值得注意的是，BDNF val 66 met基因型与编码过程中海马反应之间的相互作用占识别记忆表现总变化的25%。" 总之，这两个观察结果表明，与没有这种症状的健康受试者相比，表现出张力障碍症状的人具有过度活跃的皮质可塑性，因此BDNF val 66 met基因型变异的发生率相对较低。 本研究的具体目的是比较BDNF val 66 met基因型在诊断为肌张力障碍的人群中的频率与健康非肌张力障碍对照人群中的频率。 作为次要目的，还将检测两个受试者组是否存在DYT 1基因突变。 亚假设是，在具有DYT 1基因突变的罕见肌张力障碍受试者中，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val 66 met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，一个对照组将是年龄匹配的健康受试者。 第二个对照组将是患有帕金森病的受试者，帕金森病也是一种基底神经节疾病，但与肌张力障碍不同，由于神经再生，并且假定其病理生理学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.