Congenital Myasthenic Syndromes

The broad aim of this proposal is to examine the neurobiology of congenital myasthenic syndromes (CMS). 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。 The CMS are not uncommon but are seldom diagnosed or treated correctly. 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（例如乙酰胆碱受体 (AChR)、乙酰胆碱酯酶 (AChE) 或胆碱乙酰转移酶）的缺陷。 The CMS are investigated by: (1) Clinical assessment, including electromyography and tests for anti-AChR antibodies; (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) mutation analysis when the preceding studies point to an EP- specific protein; and (5) expression studies using genetically engineered mutants. (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； if we detect mutation(s), we confirm pathogenicity as in (5) above. 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 特异性蛋白的结构与功能关系具有重要意义。

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.