NEUROLOGICAL DISEASES DUE TO INBORN ERRORS OF METABOLISM

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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.