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

基本信息

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
项目类别：
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

项目摘要

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发现高苯丙氨酸血症可能是由苯丙氨酸羟化酶（PAH）引起的。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 共伴侣蛋白缺陷。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，通过合作研究清楚地表明，可以预防婴儿和儿童令人信服的严重认知障碍，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临床经验和许多已发表的小型病例系列表明，不遵守。饮食治疗在青春期和成年期是常见的。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脑白质损伤和运动障碍。血液苯丙氨酸长期升高怀孕期间血液苯丙氨酸升高严重。致畸导致所谓的母体 PKU 综合征不严格依赖的新疗法。非常希望限制饮食中的苯丙氨酸，但适当的治疗目标尚不清楚了解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。项目旨在全面、纵向地评估健康、神经学、认知、神经精神、大量各年龄段 PAH 缺乏症患者的患者报告和生活质量结果，生物蝶呤合成或循环障碍，或 DNAJC12 缺陷，并探索该联盟还将形成一个网络，以评估结果与血液苯丙氨酸或其他生物标志物之间的关系。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这项研究的结果将有助于完善和改善目前的治疗方法。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。