Hyperphenylalaninemia Disorders Consortium of the Rare Disease Clinical Research Network

1.项目总结--总体 我们建议建立一个多中心合作联盟，作为罕见疾病临床研究的一部分 研究网络(RDCRN)，将致力于新陈代谢引起的先天错误的临床研究 高苯丙氨酸血症(血液苯丙氨酸升高)，最常见的异常之一 通过新生儿筛查。高苯丙氨酸血症可能是由苯丙氨酸羟基酶(PAH)引起的 缺乏(俗称苯丙酮尿症(PKU))，由于生物蝶呤合成和循环障碍， 或者是最近被描述的一种名为DNAJC12的PAH辅助伴侣蛋白的缺陷。新生儿筛查 从20世纪60年代开始，美国开始限制苯丙氨酸的饮食，以治疗PAH缺乏症。 令人信服的是，通过合作研究来预防婴儿和儿童的严重认知障碍， 但目前还没有针对青少年或成人PAH缺乏症的大型纵向研究，也不再 对患有生物蝶呤合成或循环缺陷的儿童或成人以及DNAJC12的长期随访数据 缺乏症。临床经验和许多已发表的小案例系列表明，不遵守 青春期和成年期的饮食治疗很常见。慢性升高的血液苯丙氨酸是 与执行功能障碍、焦虑、抑郁的高发生率相关，并与教育受损有关 和职业潜力。一些成年人因以下原因而遭受不可逆转的白质损伤和运动障碍 慢性血苯丙氨酸升高。怀孕期间血液苯丙氨酸升高是严重的 致畸导致了所谓的母体PKU综合征。不严格依赖的新疗法 对饮食苯丙氨酸的限制是非常理想的，但适当的治疗目标仍然很差。 明白了。血液中苯丙氨酸的浓度需要多少才能保证最佳结果的持续 有待讨论，并继续寻找与结果相关的其他生物标记物。这样做的目的是 项目是全面和纵向评估健康，神经学，认知，神经精神病学， 患者报告的，以及在所有年龄段的PAH缺乏的大量个体中的生活质量结果， 与生物蝶呤合成或循环障碍或DNAJC12缺乏症的相关性探讨 结果与血液苯丙氨酸或其他生物标志物之间的关系。该财团还将形成一个网络， 准备好随时参与评估设计用于治疗的新型治疗剂的临床试验地点 高苯丙氨酸血症。这项研究的结果将有助于完善和改进目前的 以及未来治疗最常见的先天性新陈代谢错误和更罕见的与 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.