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. 项目总结-整体