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范围受到一种或多种特定机制的影响。 CMS并不罕见，但很少被正确诊断或治疗。 临床、形态学和电生理学分析可以确定CMS是否起源于突触前、突触或突触后，并指出终板（EP）特异性蛋白质（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。 通过以下方式研究CMS：（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AChR在连接褶皱上的密度和分布的评估;（3）电生理学评估，包括常规微电极EP电位和电流的研究，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）当前述研究指向EP特异性蛋白质时的突变分析;和（5）使用遗传工程突变体的表达研究。(6)当在美国或国外的中心鉴定的CMS患者不能来马约，但可用的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，我们确认致病性，如上文（5）所述。 这些研究对于CMS的诊断和预防、疾病病理生理学研究、治疗策略的制定以及EP特异性蛋白质结构-功能关系的深入研究具有重要意义。

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.