Lesch-Nyhan Disease: Neuroanatomic and Biochemical Bases of the Phenotype

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DESCRIPTION (provided by applicant): Lesch-Nyhan disease (LND) is an inherited disorder of purine metabolism that is characterized by severe motor impairment, intellectual disability (mental retardation), compulsive self-injury, and hyperuricemia. There are also partial or milder phenotypes know as Lesch-Nyhan variants (LNV). The pathogenesis of both LND and LNV begins with a mutation of the Hprt gene, which encodes the enzyme hypoxanthine-guanine phosophoribosyl transferase (HGprt). This enzyme has two distinct functions: It recycles hypoxanthine (Hprt) and guanine (Gprt) into the purine pools. While the enzyme defect likely leads to neurophysiologic and neuroanatomic abnormalities that define the clinical phenotype, it is unknown whether this results from the failure to recycle hypoxanthine, guanine, or both. However, through recently-funded R21 research, we found that some mutations produce large differential effects on Hprt and Gprt recycling. Thus, a crucial next step in elucidating the pathophysiology of LND is to determine which of the two known functions of HGprt relates most directly to specific aspects of the disease phenotype. Post-mortem neurochemical and positron emission tomography studies point to a marked depletion of dopamine from the basal ganglia in LND. Neuroimaging and post-mortem neuropathological studies point to global (intracranial) and local (caudate) reductions in LND brain volumes. In this application, we bridge strengths in neurology, biochemistry, neuropsychology, neuroimaging and pathology with extensive clinical experience to elucidate relationships between the phenotype and biochemical and anatomical biomarkers across the full spectrum of HGprt deficiency. This revised proposal now includes fully integrated molecular, biochemical, behavioral, neurological, neuroimaging, and autopsy studies of a disease that has served as a prototype for a single-gene disorder with devastating neurobehavioral consequences. In addition to a these cross-sectional studies, we also propose to conduct the largest, longest, and first quantitative longitudinal follow-up study to begin determining whether or not LND is a progressive neurodegenerative disorder. This project includes fully integrated molecular, biochemical, behavioral, neurological, neuroimaging, and autopsy studies that will greatly advance our understanding of Lesch-Nyhan disease (LND) and related conditions. PUBLIC HEALTH RELEVANCE: LND is an inherited metabolic disorder that is characterized by mental retardation, compulsive self-injury, and severe neurological deficits. These studies will provide crucial information for future clinical trials.