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

描述（由申请人提供）：莱施-尼汉病（LND）是一种遗传性嘌呤代谢障碍，其特征为严重运动障碍、智力残疾（精神发育迟滞）、强迫性自伤和高尿酸血症。也有部分或更温和的表型称为Lesch-Nyhan变体（LNV）。LND和LNV的发病机制都始于Hprt基因的突变，该基因编码次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HGprt）。这种酶有两种不同的功能：将次黄嘌呤（Hprt）和鸟嘌呤（Gprt）转化为嘌呤池。虽然酶缺陷可能导致定义临床表型的神经生理学和神经解剖学异常，但尚不清楚这是否是次黄嘌呤、鸟嘌呤或两者再循环失败的结果。然而，通过最近资助的R21研究，我们发现一些突变对Hprt和Gprt再循环产生很大的差异影响。因此，阐明LND的病理生理学的关键下一步是确定HGprt的两个已知功能中哪一个与疾病表型的特定方面最直接相关。尸检神经化学和正电子发射断层扫描研究指出，在LND的基底神经节多巴胺显着耗尽。神经影像学和死后神经病理学研究表明，LND脑体积的整体（颅内）和局部（尾状核）减少。在这项应用中，我们在神经学，生物化学，神经心理学，神经影像学和病理学方面的优势与广泛的临床经验相结合，以阐明整个HGPRT缺乏症的表型与生物化学和解剖学生物标志物之间的关系。这项修订后的提案现在包括完全整合的分子，生物化学，行为，神经学，神经影像学和尸检研究的疾病，已作为一个原型的单基因疾病与破坏性的神经行为后果。除了这些横断面研究，我们还建议进行最大、最长和第一次定量纵向随访研究，以开始确定LND是否是一种进行性神经退行性疾病。该项目包括完全整合的分子，生物化学，行为，神经学，神经影像学和尸检研究，这将大大促进我们对Lesch-Nyhan病（LND）和相关疾病的理解。公共卫生相关性：LND是一种遗传性代谢紊乱，其特征在于精神发育迟滞、强迫性自伤和严重的神经缺陷。这些研究将为未来的临床试验提供重要信息。

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.