Congenital Myasthenic Syndromes

先天性肌无力综合症

• 批准号: 6623592
• 负责人: ANDREW George ENGEL
• 金额: $ 48.53万
• 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/6623592
• 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.

该提案的广泛目的是检查先天性肌关系综合征（CMS）的神经生物学。 CMS是异质性和致残性疾病，其中神经肌肉传播的安全边缘被一种或多种特定的机制损害。 CMS并不少见，但很少被正确诊断或处理。 临床，形态学和电生理学分析可以确定CMS的起源前，突触，突触后或突触后是否是终板（EP）特异性蛋白质中的缺陷，例如乙酰胆碱受体（ACHR），乙酰胆碱酶（ACHE），或胆碱乙酰乙酰基酯酶。 CMS通过：（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，每EP的ACHR数量的估计，EP的超微结构分析以及对联合折叠上ACHR的密度和分布的评估； （3）电生理评估，由EP电位和电流的常规微电极研究，量化量释放的参数的估计以及通过单通道贴片钳记录评估ACHR通道动力学的估计； （4）当前研究指向EP特异性蛋白时，突变分析； （5）使用基因工程突变体的表达研究。 （6）当在美国或国外确定的CMS患者无法进入蛋黄酱，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（S），我们确认了上述（5）中（5）中的致病性。 提出的研究对于诊断和预防CMS，研究疾病病理生理学，制定治疗策略以及对EP特异性蛋白质结构功能关系的见解至关重要。