Congenital Myasthenic Syndromes

本提案的广泛目的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-肌肉传递的安全范围受到一种或多种特定机制的损害。CMS并不罕见，但很少得到正确的诊断和治疗。临床、形态学和电生理分析可以确定CMS的起源是突触前、突触后还是突触前，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。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中AChR的数量，EP的超微结构分析，以及评估连接皱襞上AChR的密度和分布；(3)电生理评估，包括EP电位和电流的常规微电极研究，定量释放参数的估计，以及通过单通道膜片钳记录评估AChR通道动力学；(4)当上述研究指向EP特异性蛋白时进行突变分析；(5)利用基因工程突变体进行表达研究。(6)当在美国或国外中心发现的CMS患者无法来到梅奥，但可用的数据指向候选基因或分子时，我们仍在寻找突变；如果我们检测到突变，我们就像上面(5)那样确认致病性。提出的研究对CMS的诊断和预防、研究疾病病理生理、制定治疗策略以及深入了解ep特异性蛋白的结构-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.