NEUROLOGICAL DISEASES DUE TO INBORN ERRORS OF METABOLISM

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 了解人体代谢的一个主要挑战是缺乏直接研究活组织和器官的方法。到目前为止，大多数研究都是使用代谢的替代标志物进行的，例如血液测试，或者使用通过活检或其他外科手术获得的样本。当需要重复测量时（例如，为了评估治疗后的变化，或为了了解生长和发育），或者当面临新认识或不太了解的人类疾病状态时，这些困难会变得更加复杂。许多类型的儿童癫痫、智力迟钝、自闭症和其他常见形式的神经行为障碍现在被认为是影响大脑发育和功能的脂肪、碳水化合物和蛋白质代谢遗传异常的表现。这些疾病中的大多数仍然没有得到充分的研究，因此，治疗方法必然不能令人满意。我们建议将儿童医学中心的资源与UT西南克莱门茨高级成像研究中心开发的新技术联合收割机结合起来，通过NMR（核磁共振）技术测量儿童肌肉中的代谢，与常规MRI研究所采用的方法相同。患有线粒体疾病的儿童能够配合MRI的表现将被邀请参与（与正常对照组一起），基于DNA和其他证明线粒体疾病的测试，并将使用评分的身体和神经系统检查以及脑MRI进行额外评估。我们预计这些研究将a）帮助我们更好地理解线粒体和相关能量衰竭疾病的机制，B）允许我们基于代谢通量和肌肉含量测量重新定义这些疾病，c）改善这些疾病的诊断，包括检测高危携带者亲属，以及d）识别潜在的可量化标记物用于未来临床试验的进行和评估。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A major challenge to understanding human metabolism is posed by the absence of methods designed to investigate living tissues and organs directly. Until now, most studies have been conducted using surrogate markers of metabolism, such as blood tests, or have utilized samples obtained through biopsies or other surgical procedures. These difficulties are compounded when repeated measurements are needed (for example, to assess changes after treatment, or to understand growth and development) or when confronted with newly recognized or poorly-understood human disease states. Many types of childhood epilepsy, mental retardation, autism and other common forms of neurobehavioral disability are now thought to be manifestation of genetic abnormalities of fat, carbohydrate and protein metabolism that affect brain development and function. Most of these diseases remain understudied and, as a consequence, treatments are necessarily unsatisfactory. We propose to combine the resources of Children's Medical Center with novel technology developed at the UT Southwestern Clements Advanced Imaging Research Center to measure metabolism in the muscles of children by NMR (nuclear magnetic resonance) techniques, the same method on which routine MRI studies are based. Children afflicted by mitochondrial diseases capable of cooperating with the performance of an MRI will be invited to participate (together with a normal comparison group) on the basis of DNA and other tests demonstrative of a mitochondrial disease and will be additionally assessed using scored physical and neurological examinations and brain MRI. We anticipate that these studies will a) help us better understand the mechanisms of mitochondrial and related energy failure diseases, b) allow us to re-define these diseases on the basis of metabolic flux and muscle content measurements, c) improve the diagnosis of these disorders, including the detection of at-risk carrier relatives, and d) identify potential quantifiable markers for the conduct and evaluation of future clinical trials.