Congenital Myasthenic Syndromes

这项建议的主要目的是研究先天性肌无力综合征(CMS)的神经生物学。CMS是一种异质性和致残性疾病，其中神经肌肉传递的安全边际受到一个或多个特定机制的影响(S)。CMS并不少见，但很少被正确诊断或治疗。临床、形态和电生理分析可以确定CMS起源于突触前、突触或突触后，并指出终板(EP)特异性蛋白的缺陷，如乙酰胆碱受体(AChR)、乙酰胆碱酯酶(AChE)或胆碱乙酰转移酶。对CMS的研究包括：(1)临床评估，包括肌电图学和抗AChR抗体检测；(2)形态评估，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数目，超微结构分析，以及评估AChR在连接皱折上的密度和分布；(3)电生理学评估，包括对EP电位和电流的常规微电极研究，量化释放参数的估计，以及通过单通道膜片钳记录评估AChR通道动力学；(4)当前面的研究指向EP特异性蛋白时进行突变分析；以及(5)使用基因工程突变体的表达研究。(6)当在美国或国外的中心确诊的CMS患者不能来梅奥，但现有数据指向候选基因或分子时，我们仍然搜索突变；如果我们检测到突变(S)，我们确认致病性，如上文(5)所示。所提出的研究对于CMS的诊断和预防，对于研究疾病的病理生理学，对于开发治疗策略，以及深入了解EP特异性蛋白的结构-功能关系都是重要的。

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.