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: 10481857
• 负责人: Cary O. Harding
• 金额: $ 153.63万
• 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/10481857
• 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; Diet therapy; Dietary Proteins; Disease; Early Diagnosis; Employment; Enzymes; Esthesia; Evaluation; Executive Dysfunction; Exhibits; Family; 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; brain fog; cognitive disability; cohort; design; dietary; 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. 项目概要——总体 我们建议建立一个多中心合作联盟，作为罕见疾病临床的一部分 研究网络（RDCRN）将致力于针对先天性代谢缺陷引起的临床研究 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由苯丙氨酸羟化酶（PAH）引起 生物蝶呤合成和循环障碍导致的缺乏症（俗称苯丙酮尿症 (PKU)）， 或者最近描述的一种名为 DNAJC12 的 PAH 共伴侣蛋白的缺陷。新生儿筛查 美国从 20 世纪 60 年代开始针对 PAH 缺乏症开始实行膳食苯丙氨酸限制， 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，还没有针对患有 PAH 缺乏症的青少年或成人进行大型纵向研究，也没有长期研究 有关生物蝶呤合成或回收缺陷或 DNAJC12 的儿童或成人的长期随访数据 不足。临床经验和许多已发表的小型病例系列表明，不遵守 饮食疗法在青春期和成年期很常见。血苯丙氨酸长期升高是 与执行功能障碍、焦虑、抑郁以及教育受损的高发生率相关 和职业潜力。一些成年人由于以下原因遭受不可逆的白质损伤和运动障碍： 血液苯丙氨酸长期升高。怀孕期间血苯丙氨酸升高严重 致畸，导致所谓的母体 PKU 综合征。不严格依赖的新疗法 非常希望限制膳食苯丙氨酸，但适当的治疗目标尚不清楚 明白了。需要多少浓度的血液苯丙氨酸才能保证持续获得最佳结果 有待争论，并继续寻找与结果相关的其他生物标志物。本次活动的目标 项目旨在全面、纵向地评估健康、神经学、认知、神经精神、 患者报告的以及一大群患有多环芳烃缺乏症的各个年龄段个体的生活质量结果， 与生物蝶呤合成或循环障碍，或与 DNAJC12 缺陷相关，并探索相关性 结果与血液苯丙氨酸或其他生物标志物之间的关系。该联盟还将组建一个网络 准备好参与评估旨在治疗的新型治疗药物的临床试验场所 高苯丙氨酸血症疾病。这项研究的结果将有助于完善和改进当前的 以及针对最常见的先天性代谢错误和与代谢相关的罕见疾病的未来治疗方法 高苯丙氨酸血症。