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CHLORPROMAZINE, IMMUNOGENETICS AND TARDIVE DYSKINESIA

氯丙嗪、免疫遗传学和迟发性运动障碍

基本信息

批准号：
3377377
负责人：
ROSA T CANOSO
金额：
$ 6.5万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-01-01 至 1989-01-31
项目状态：
已结题

项目摘要

Chronic therapy with neuroleptics is associated with development of antinuclear antibodies, an IgM-lupus anticoagulant, polyclonal elevation of IgM, and antibodies to the GM1 ganglioside. These autoantibodies are found more frequently in patients with the phenotype HLA B44 in association with tardive dyskinesia. Our preliminary data suggest that the extended-haplotype B44-DR7-FC31 carries a special risk for development of severe tardive dyskinesia in those patients with longest exposure to chlorpromazine. We propose to extend our studies on 203 patients already phenotyped and evaluated for the presence of autoantibodies and tardive dyskinesia, and on 67 patients who will be identified during the current year, to determine (1) the clinical relevance of anti-GM1 antibodies, (2) the immunogenetic markers for autoantibody production by typing these patients for the complement proteins, BF, C2, C4A, and C4B (complotypes), and establishing their extended haplotypes by performing HLA A, B, C, DR and complement phenotyping of at least 3 family members. Family members will also be tested for autoantibodies. The neuropsychiatric evaluation will include: psychiatric diagnosis by the RDC Criteria for Schizophrenia and Schizo-Affective Disorders, neuropsychiatric testing to detect impairment in cognitive function, evaluation of movement disorders by the AIMS scale, seizure activity by EEG, and brain atrophy by head computerized tomography. We postulate that there is a genetic predisposition to the production of autoantibodies regulated by the HLA marker B44 or more specifically by the extended haplotype B44-DR7-FC31. This marker is associated with the production of GM1 antibodies that are capable of inducing in humans a similar pathology to that described in experimental animal models with intracerebral and intracysternal injection of antibodies to GM1. The binding of anti-GM1 antibodies to the GM1 ganglioside present in the outer aspect of the synaptic membrane may alter neurotransmitter release leading to movement disorders, cognitive dysfunction, brain atrophy and seizure activity.

精神抑制剂的长期治疗与以下疾病的发生有关：抗核抗体，IgM-狼疮抗凝剂，多克隆升高， IgM和GM 1神经节苷脂抗体。这些自身抗体被发现在HLA B44表型患者中，迟发性运动障碍我们的初步数据表明，扩展单倍型B44-DR 7-FC 31对发展具有特殊风险，严重迟发性运动障碍，在那些患者接触最长的氯丙嗪我们建议对203名患者进行研究进行表型分析并评估自身抗体和迟发性运动障碍，以及67名患者将在目前的年，以确定（1）抗GM 1抗体的临床相关性，（2）自身抗体产生的免疫遗传标记，患者的补体蛋白BF、C2、C4 A和C4 B（补体型），并通过进行HLA A、B、C、DR 和至少3个家族成员的补体表型。家庭成员也会检测自身抗体神经精神评估将包括：精神病诊断的RDC标准精神分裂症和精神分裂情感障碍，神经精神测试，以检测认知功能障碍，运动障碍的评估 AIMS量表、EEG癫痫活动和计算机化头部脑萎缩断层扫描我们假设，有一种遗传倾向的生产，受HLA标记物B44或更具体地受HLA标记物B44调节的自身抗体。扩展单倍型B44-DR 7-FC 31。此标记与产生能够在人体内诱导与实验动物模型中描述的病理学相似，脑内和囊内注射抗GM 1抗体。的抗GM 1抗体与存在于外膜中的GM 1神经节苷脂的结合突触膜的方面可能会改变神经递质的释放，导致运动障碍认知功能障碍脑萎缩和癫痫活动