NEUROLOGICAL DISEASES DUE TO INBORN ERRORS OF METABOLISM

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 理解人类新陈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新陈代谢的替代标记物进行的，比如血液测试，或者使用通过活组织检查或其他外科手术获得的样本。当需要重复测量(例如，评估治疗后的变化，或了解生长和发育)，或者面临新认识的或了解不多的人类疾病状态时，这些困难就会变得更加复杂。许多类型的儿童癫痫、智力低下、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的遗传异常的表现。这些疾病中的大多数仍未得到充分研究，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德克萨斯大学西南克莱门茨高级成像研究中心开发的新技术结合起来，通过核磁共振(核磁共振)技术测量儿童肌肉的新陈代谢，这与常规MRI研究所基于的方法相同。患有能够配合核磁共振检查的线粒体疾病的儿童将被邀请参加(与正常对照组一起)，根据DNA和其他表明线粒体疾病的测试，并将使用评分的身体和神经检查以及脑MRI进行额外评估。我们预计，这些研究将a)帮助我们更好地了解线粒体及相关能量衰竭疾病的机制，b)使我们能够在代谢流量和肌肉含量测量的基础上重新定义这些疾病，c)改进对这些疾病的诊断，包括检测高危携带者亲属，以及d)为未来临床试验的进行和评估确定潜在的可量化标记物。

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.