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) 病因不明的神经退行性疾病。他们有共同的死亡 下运动神经元(LMN)导致肌肉无力，这两种疾病都是 致命的。SMA和ALS的LMN死亡机制不同。在SMA，LMN死亡可能 在有限的一段时间内发生。没有人回答是迟到了还是 持续的LMN损失。最近对SMA的遗传学研究表明， 运动神经元存活基因(SMN2)拷贝数与SMA类型之间的关系。无人应答 是拷贝数和LMN数之间的关系。在肌萎缩侧索硬化症中， LMN死亡的机制解释了已知的特征和一系列事件 最终有可能导致LMN死亡。在肌萎缩侧索硬化症中没有回答是很自然的 LMN丢失从肌肉到肌肉的进展模式。虽然肌肉 虚弱是LMN丢失的临床表现，对于这两种疾病， 强度损失的大小并不能准确反映LMN的损失率。这个 差异是由于失神经再支配的代偿作用。 从幸存的运动神经末梢发芽的侧枝纤维。同样， 常规电生理检查不能准确测量LMN的损失。无人应答 对于这两种疾病来说，是代偿过程的动态决定了 临床状态和功能水平。 运动单位数估计(MUNE)是一种特殊的电生理测试 可以直接评估支配肌肉的LMN的数量。没有数据 关于SMA的LMN丢失的自然过程，ALS的数据很少。我们建议 为了开发和完善MUNE和其他电生理学技术来研究， 并遵循LMN损失和相关的代偿性变化的过程。对于SMA， 我们将采用MUNE技术来研究婴儿和儿童。适用于较旧的SMA和 此外，我们将改进MUNE技术以优化数据收集。对于SMA，我们 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中，评估是否 LMN的损失仍在持续。对于肌萎缩侧索硬化症，我们将确定并比较 远端和近端肌肉的LMN丢失模式。在较老的SMA和ALS中， 我们将评估LMN损失与抵押品衡量标准之间的关系 神经再支配和力量。我们预计穆恩和其他人 电生理学技术将直接适用于 SMA和ALS的临床试验，因为这些技术可以用作 提供信息的终点措施。促进MUNE在临床上的应用 试验中，我们将开发和改进这些技术，使其可用于 任何参与试验的临床中心。目前，大多数MUNE技术 依靠专有软件。我们将开发基于PC的软件 计算机系统，使其可供所有实验室使用。

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.