The Electrophysiology of Motor Neuron Diseases

描述（由申请人提供）： 脊髓性肌萎缩症（SMA）和肌萎缩侧索硬化症（ALS）是 病因不明的神经退行性疾病。他们有一个共同点， 下运动神经元（LMN）引起肌肉无力，这两种疾病都是 致命的SMA和ALS的LMN死亡机制不同。在SMA中，LMN死亡可能 在有限的时间内发生。没有答案的是，是否有迟到或 LMN持续亏损。最近的SMA遗传研究表明， 运动神经元存活基因（SMN 2）拷贝数与SMA类型的关系。没有答案 是拷贝数和LMN数之间的关系。在ALS中，没有一个 LMN死亡的机制解释了已知的特征， 最终可能导致LMN死亡。在ALS中没有答案是自然的， LMN损失从肌肉到肌肉的进展模式。虽然肌肉 虚弱是两种疾病LMN丢失的临床表现， 强度损失率并不能准确地反映陆地移动网络的损失率。的 差异是由于失神经支配的神经再支配的代偿作用， 纤维通过从幸存的运动神经末梢发芽的侧枝生长。同样地， 常规的电生理学检查不能准确测量LMN损失。没有答案 对于这两种疾病是动态的补偿过程， 临床状态和功能水平。 运动单位数目估计（MUNE）是一种特殊的电生理检查， 可以直接评估神经支配肌肉的LMN的数量。没有数据 SMA的LMN丢失的自然过程，ALS的数据很少。我们提出 开发和完善MUNE和其他电生理学技术， 并跟踪LMN丧失的过程和相关的代偿性变化。对于SMA， 我们将采用MUNE技术来研究婴儿和儿童。对于老年SMA和 ALS，我们将改进MUNE技术以优化数据收集。对于SMA，我们 将LMN丢失与临床类型和SMN2拷贝数相关。我们将开始， 在两年的赠款执行系列研究，以评估是否 存在持续的LMN损失。对于ALS，我们将确定并比较 以及远端和近端肌肉中LMN损失的模式。在老年SMA和ALS中， 我们将评估LMN损失和抵押品措施之间的关系 神经再生和力量我们预计，穆恩和其他 电生理技术将直接适用于设计 SMA和ALS的临床试验，因为这些技术可以用作 信息性终点测量。促进MUNE在临床中的使用 试验，我们将开发和完善的技术形式，可用于 参与试验的任何临床中心。目前，大多数MUNE技术 依赖专有软件。我们将开发用于基于PC的软件 计算机系统，使他们能够提供给所有实验室。

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders of unknown etiology. They have in common death of lower motor neurons (LMN) causing muscle weakness, and both disorders are fatal. Mechanisms of LMN death differ for SMA and ALS. In SMA, LMN death may occur over a limited period of time. Unanswered is whether there is late or continued LMN loss. Recent genetic studies in SMA indicate a relationship between survival motor neuron gene (SMN2) copy number and SMA type. Unanswered is the relationship between copy number and LMN number. In ALS, no single mechanism of LMN death explains known features, and a cascade of events ultimately leading to LMN death is likely. Unanswered in ALS is the natural pattern of progression of LMN loss from muscle to muscle. Although muscle weakness is the clinical manifestation of LMN loss for both disorders, the rate of loss of strength does not accurately reflect the rate of loss of LMNs. The discrepancy is due to the compensatory effects of reinnervation of denervated fibers by collateral sprouting from surviving motor nerve terminals. Similarly, routine electrophysiologic tests do not accurately measure LMN loss. Unanswered for both disorders is the dynamics of the compensatory process that determines the clinical state and level of function. Motor unit number estimation (MUNE) is a special electrophysiologic test that can directly assess the number of LMNs innervating a muscle. There are no data on the natural course of LMN loss for SMA, and little data for ALS. We propose to develop and refine MUNE and other electrophysiologic techniques to study, and follow the course of LMN loss and associated compensatory changes. For SMA, we will adapt MUNE techniques to study infants and children. For older SMA and ALS, we will refine MUNE techniques to optimize data collection. For SMA, we will correlate LMN loss with clinical type and SMN2 copy number. We will begin, in the two years of the grant-performing serial studies, to assess whether there is continued LMN loss. For ALS, we will determine and compare the rate and pattern of LMN loss in distal and proximal muscles. In older SMA and ALS, we will assess relationships between LMN loss and measures of collateral reinnervation and strength. We anticipate that MUNE and other electrophysiologic techniques will have direct applicability to the design of clinical trials for SMA and ALS, because these techniques can be used as informative end-point measures. To facilitate the use of MUNE in clinical trials, we will develop and refine the techniques in a form that can be used in any clinical center participating in trials. Currently, most MUNE techniques rely on proprietary software. We will develop software for use on PC-based computer systems, making them available to all laboratories.