Hyperphenylalaninemia Disorders Consortium of the Rare Disease Clinical Research Network

罕见疾病临床研究网络高苯丙氨酸血症疾病联盟

• 批准号: 10019398
• 负责人: Cary O. Harding
• 金额: $ 156.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019398
• 关键词: Access to Information; Adolescence; Adolescent; Adult; Affect; Age; Anxiety; Attentional deficit; Basic Science; Behavioral; Biological Markers; Biopterin; Blood; Brain; Case Series; Child; Chronic; Clinical; Clinical Research; Clinical Trials Network; Cognitive; Consumption; Data; Defect; Diagnosis; Diet; Dietary Proteins; Disease; Early Diagnosis; Employment; Enzymes; Esthesia; Evaluation; Executive Dysfunction; Exhibits; Family; Fogs; Fostering; Functional disorder; Funding; Future; Goals; Health; Hereditary Disease; Hyperphenylalaninaemias; Impairment; Inborn Errors of Metabolism; Incidence; Individual; Infant; Inherited; International; Interpersonal Relations; Learning Disabilities; Life; Link; Longevity; Longitudinal Studies; Longitudinal observational study; Longterm Follow-up; Maternal Phenylketonuria; Measures; Medical; Mental Depression; Molecular Chaperones; Names; Neonatal Screening; Neurologic; Neuropsychology; Normal Range; Outcome; Patient Outcomes Assessments; Patients; Persons; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Pregnancy; Proteins; Provider; Publications; Publishing; Quality of life; Rare Diseases; Recycling; Reporting; Research; Research Personnel; Research Proposals; Resources; Scientist; Screening Result; Siblings; Site; Supplementation; Syndrome; Teratogens; Therapeutic Agents; Therapeutic Effect; Time; Training; Treatment Protocols; United States National Institutes of Health; Validation; Vision; cognitive disability; cohort; design; education resources; executive function; experience; fetal; functional outcomes; improved; inattention; motor impairment; neuropsychiatry; next generation; novel; novel therapeutics; patient advocacy group; prevent; psychiatric symptom; rare condition; severe intellectual disability; standard of care; symposium; tetrahydrobiopterin; treatment research; web site; white matter; white matter damage

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.

1。项目摘要 - 总体 我们建议构建一个多中心协作财团，成为罕见疾病临床的一部分 研究网络（RDCRN）将致力于临床研究的临床研究，导致新陈代谢错误 苯基丙氨酸血症（升高血苯丙氨酸），这是检测到的最常见异常之一 通过新生儿筛查。苯基丙氨酸血症可能是由苯丙氨酸羟化酶（PAH）引起的 缺乏症（也被称为苯酮尿症（PKU）），通过生物蛋白质合成和回收的疾病， 或最近描述的PAH共伴酮蛋白的缺陷，称为DNAJC12。新生儿筛查 从1960年代开始，饮食中的苯丙氨酸限制一直是PAH缺乏的， 通过协作研究令人信服地表明，以防止婴儿和儿童的严重认知障碍， 但是目前，没有大量的对青少年或PAH缺乏症的成年人的纵向研究 术语后续数据有关生物蛋白质合成或回收缺陷或DNAJC12的儿童或成年人 不足。临床经验和许多小型案例系列表明，不遵守 青少年和成年的饮食疗法很普遍。长期升高的血液苯丙氨酸是 与高管功能障碍，动画，抑郁症以及教育受损的高度事件有关 和投票潜力。有些成年人由于 长期升高的血液苯丙氨酸。怀孕期间血液苯丙氨酸升高严重 致造性导致所谓的遗产PKU综合征。不严格依赖的新型疗法 饮食中苯丙氨酸的限制是高度期望的，但适当的治疗目标却很差 理解齿。需要哪种浓度的血苯丙氨酸来保证最佳结果继续 辩论和其他与结果相关的生物标志物仍在继续。目标的目标 项目将全面和纵向评估健康，神经，认知，神经精神病学， 患者报告和生活质量成果在各个年龄段的人群中都有PAH缺乏， 生物蛋白合成或回收疾病，或DNAJC12缺乏症并探索相关性 在结果与血液苯丙氨酸或其他生物标志物之间。该财团还将形成一个网络 准备容易参与旨在治疗的新型治疗剂评估的临床试验地点 过苯基血症疾病。这项研究的结果将允许改进和改进电流 以及对新陈代谢错误以及与稀有疾病有关的最常见毒品疗法 苯基丙氨酸血症。