CHLORPROMAZINE, IMMUNOGENETICS AND TARDIVE DYSKINESIA

慢性抗精神病药物治疗与糖尿病的发生有关 抗核抗体，一种IgM狼疮抗凝剂，多克隆升高的 免疫球蛋白和抗GM1神经节苷脂抗体。这些自身抗体被发现 更多发生在表型为HLAB44的患者中 迟发性运动障碍。我们的初步数据表明 扩展单倍型B44-DR7-FC31具有特殊的发病风险 接触时间最长的患者出现严重的迟发性运动障碍 氯丙嗪。我们建议将我们的研究扩展到203名患者。 对自身抗体和迟缓的存在进行表型和评估 运动障碍，以及67名患者，他们将在当前 年，以确定(1)抗GM1抗体的临床相关性，(2) 通过分型产生自身抗体的免疫遗传标志物 补体蛋白BF、C2、C4a和C4b(复合型)的患者， 通过执行HLAA、B、C、DR建立它们的扩展单倍型 至少3个家庭成员的补体表型。家庭成员 还将进行自身抗体检测。神经精神病学评估 将包括：根据RDC标准对精神分裂症进行的精神诊断 和精神分裂-情感障碍，神经精神测试来检测 认知功能障碍，运动障碍的评估 AIMS评分、EEG的癫痫发作活动和头部计算机控制的脑萎缩 体层摄影术。 我们假设有一种遗传易感性导致了 自身抗体受人类白细胞抗原B44或更具体地说受 扩展单倍型B44-DR7-FC31。此标记与 产生能够在人类体内诱导的GM1抗体 与实验动物模型中描述的病理相似 脑内和囊内注射抗GM1抗体。这个 抗GM1抗体与神经节苷脂结合的研究 突触膜的某些方面可能改变神经递质的释放 运动障碍、认知功能障碍、脑萎缩和癫痫 活动。

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.