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

描述（申请人提供）：Lesch-Nyhan病（LND）是一种嘌呤代谢遗传性疾病，其特征是严重的运动障碍、智力障碍（精神发育迟滞）、强迫性自残和高尿酸血症。还有部分或较温和的表型，称为 Lesch-Nyhan 变体 (LNV)。 LND 和 LNV 的发病机制均始于 Hprt 基因的突变，该基因编码次黄嘌呤-鸟嘌呤磷酸核糖基转移酶 (HGprt)。这种酶有两个不同的功能：它将次黄嘌呤 (Hprt) 和鸟嘌呤 (Gprt) 回收到嘌呤库中。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由于未能回收次黄嘌呤、鸟嘌呤或两者所致。然而，通过最近资助的 R21 研究，我们发现一些突变对 Hprt 和 Gprt 循环产生巨大的差异影响。因此，阐明 LND 病理生理学的关键下一步是确定 HGprt 的两个已知功能中的哪一个与疾病表型的特定方面最直接相关。死后神经化学和正电子发射断层扫描研究表明，LND 中基底神经节的多巴胺明显减少。神经影像学和死后神经病理学研究表明 LND 脑体积整体（颅内）和局部（尾状核）减少。在此应用中，我们将神经学、生物化学、神经心理学、神经影像学和病理学的优势与丰富的临床经验结合起来，以阐明整个 HGprt 缺乏症的表型与生化和解剖生物标志物之间的关系。这项修订后的提案现在包括对一种疾病进行完全整合的分子、生化、行为、神经学、神经影像学和尸检研究，该疾病已成为具有毁灭性神经行为后果的单基因疾病的原型。除了这些横断面研究之外，我们还建议进行最大、最长且首次的定量纵向随访研究，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、生化、行为、神经学、神经影像学和尸检研究，这将极大地增进我们对 Lesch-Nyhan 病 (LND) 和相关病症的理解。公众健康相关性：LND 是一种遗传性代谢性疾病，其特点是智力低下、强迫性自残和严重的神经功能缺陷。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.