Congenital Myasthenic Syndromes

先天性肌无力综合症

• 批准号: 7052055
• 负责人: ANDREW George ENGEL
• 金额: $ 51.08万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052055
• 关键词: acetylcholinesterase; choline acetyltransferase; cholinergic receptors; electromyography; human subject; immunocytochemistry; immunoelectron microscopy; immunoglobulin G; microelectrodes; myasthenia gravis; nerve /myelin protein; neuromuscular junction; neuromuscular transmission; neurophysiology; patient oriented research; protein structure function; receptor expression; voltage /patch clamp

The broad aim of this proposal is to examine the neurobiology of congenital myasthenic syndromes (CMS). The CMS are heterogeneous and disabling disorders in which the safety margin of neuro-muscular transmission is compromised by one or more specific mechanism(s). The CMS are not uncommon but are seldom diagnosed or treated correctly. Clinical, morphologic and electrophysiologic analysis can determine whether a CMS is presynaptic, synaptic, or postsynaptic in origin and point to a defect in an endplate (EP) specific protein, such as the acetylcholine receptor (AChR), acetylcholinesterase (AChE), or choline acetyltransferase. The CMS are investigated by: (1) Clinical assessment, including electromyography and tests for anti-AChR antibodies; (2) morphologic assessment, including immunocytochemical localization of AChR, AChE, and other EP- specific proteins, estimate of the number of AChR per EP, ultrastructural analysis of the EP, and evaluation of the density and distribution of AChR on the junctional folds; (3) electrophysiologic assessment, consisting of conventional microelectrode studies of EP potentials and currents, estimates of parameters of quantal release, and evaluation of AChR channel kinetics through single channel patch-clamp recordings; (4) mutation analysis when the preceding studies point to an EP- specific protein; and (5) expression studies using genetically engineered mutants. (6) When CMS patients identified at centers in the US or abroad cannot come to Mayo but the available data point to a candidate gene or molecule, we still search for mutations; if we detect mutation(s), we confirm pathogenicity as in (5) above. The proposed studies important for diagnosis and prevention of the CMS, for investigating disease pathophysiology, for developing strategies for therapy, and for gaining insights into structure-function relationships of EP-specific proteins.

该提案的主要目标是检查先天性肌无力综合征（CMS）的神经生物学。 CMS 是异质性和致残性疾病，其中神经肌肉传递的安全裕度受到一种或多种特定机制的损害。 CMS 并不罕见，但很少得到正确诊断或治疗。 临床、形态学和电生理学分析可以确定 CMS 起源于突触前、突触还是突触后，并指出终板 (EP) 特异性蛋白质（例如乙酰胆碱受体 (AChR)、乙酰胆碱酯酶 (AChE) 或胆碱）的缺陷乙酰转移酶。 CMS通过以下方式进行调查：（1）临床评估，包括肌电图和抗AChR抗体测试； (2)形态学评估，包括AChR、AChE和其他EP特异性蛋白的免疫细胞化学定位，估计每个EP的AChR数量，EP的超微结构分析，以及评估交界褶皱上AChR的密度和分布； (3) 电生理学评估，包括 EP 电位和电流的常规微电极研究、量子释放参数的估计以及通过单通道膜片钳记录评估 AChR 通道动力学； (4)当先前的研究指向EP特异性蛋白质时进行突变分析； (5) 使用基因工程突变体进行表达研究。 (6) 当在美国或国外的中心发现的 CMS 患者无法来梅奥但现有数据指向候选基因或分子时，我们仍然寻找突变；如果我们检测到突变，我们就确认上述（5）中的致病性。 拟议的研究对于 CMS 的诊断和预防、研究疾病病理生理学、制定治疗策略以及深入了解 EP 特异性蛋白质的结构与功能关系具有重要意义。