Hyperphenylalaninemia Disorders Consortium of the Rare Disease Clinical Research Network

1.项目概要-总体 我们建议建立一个多中心合作联盟，成为罕见病临床研究的一部分。 研究网络（RDCRN），将致力于对先天性代谢缺陷的临床研究 高苯丙氨酸血症（血苯丙氨酸升高），最常见的异常检测之一 通过新生儿筛查。高苯丙氨酸血症可能由苯丙氨酸羟化酶（PAH）引起 缺乏症（也俗称苯丙酮尿症（PKU）），由生物蝶呤合成和再循环障碍引起， 或最近描述的称为DNAJC 12的PAH共伴侣蛋白的缺乏。新生儿筛查 和饮食苯丙氨酸限制，在美国开始于20世纪60年代的PAH缺乏症， 通过合作研究令人信服地证明，可以预防婴儿和儿童的严重认知障碍， 但目前，还没有对青少年或成人PAH缺乏症的大型纵向研究， 有生物蝶呤合成或再循环缺陷的儿童或成人的长期随访数据，也没有DNAJC 12 缺陷临床经验和许多已发表的小型病例系列表明， 饮食疗法在青少年和成年期是常见的。慢性血苯丙氨酸升高 与执行功能障碍、焦虑、抑郁的高发病率相关， 职业潜力。一些成年人遭受不可逆的白色物质损伤和运动障碍， 血液中苯丙氨酸水平长期升高妊娠期间血苯丙氨酸升高， 致畸性导致所谓的母体PKU综合征。不严格依赖的新疗法 在饮食苯丙氨酸限制是高度期望的，但适当的治疗目标还差 明白什么浓度的血苯丙氨酸是必要的，以保证最佳的结果继续 有待讨论，并继续寻求与结果相关的其他生物标志物。这一目标 项目是全面和纵向评估健康，神经，认知，神经精神， 在一个大型队列中，所有年龄段PAH缺乏症患者的患者报告和生活质量结局， 与生物蝶呤合成或再循环障碍，或与DNAJC 12缺乏，并探讨相关性 结果与血苯丙氨酸或其他生物标志物之间的关系。该联盟还将建立一个网络， 准备好随时参与评估用于治疗的新型治疗药物的临床试验地点 高苯丙氨酸血症病症。这项研究的结果将允许细化和改善目前的 和未来治疗最常见的先天性代谢缺陷和罕见的条件相关的 高苯丙氨酸血症

1. PROJECT SUMMARY – OVERALL We propose to construct a multicenter collaborative consortium to be part of the Rare Diseases Clinical Research Network (RDCRN) that will be dedicated to clinical research on inborn errors of metabolism causing hyperphenylalaninemia (elevated blood phenylalanine), one of the most common abnormalities detected through newborn screening. Hyperphenylalaninemia may be caused by phenylalanine hydroxylase (PAH) deficiency (also colloquially known as phenylketonuria (PKU)), by disorders of biopterin synthesis and recycling, or by a recently described deficiency of a PAH co-chaperone protein named DNAJC12. Newborn screening and dietary phenylalanine restriction, initiated in the US beginning in the 1960s for PAH deficiency, has been convincingly shown through collaborative study to prevent severe cognitive disability in infants and children, but currently, there are no large longitudinal studies of adolescents or adults with PAH deficiency and no long term follow up data at all on children or adults with biopterin synthesis or recycling defects nor of DNAJC12 deficiency. Clinical experience and many small published case series demonstrate that non-adherence to dietary therapy in adolescence and adulthood is commonplace. Chronically elevated blood phenylalanine is associated with a high incidence of executive dysfunction, anxiety, depression, and with impaired educational and vocational potential. Some adults suffer irreversible white matter damage and motor impairment due to chronically elevated blood phenylalanine. Elevated blood phenylalanine during pregnancy is severely teratogenic leading to the so-called maternal PKU syndrome. Novel therapies that are not strictly dependent upon dietary phenylalanine restriction are highly desired, but the appropriate treatment goals are yet poorly understood. What concentration of blood phenylalanine is necessary to guarantee optimal outcome continues to be debated and other biomarkers that correlate with outcome continue to be sought. The objectives of this project are to comprehensively and longitudinally evaluate the health, neurologic, cognitive, neuropsychiatric, patient-reported, and quality-of-life outcomes in a large cohort of individuals of all ages with PAH deficiency, with biopterin synthesis or recycling disorders, or with DNAJC12 deficiency and to explore correlations between outcomes and blood phenylalanine or other biomarkers. The consortium will also form a network of clinical trial sites prepared to readily participate in the evaluation of novel therapeutic agents designed to treat hyperphenylalaninemia disorders. The results of this study will allow refinement and improvement of current and future therapies for the most common inborn error of metabolism and the rarer conditions associated with hyperphenylalaninemia.