Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) studies the health, neurologic, cognitive, neuropsychiatric, patient-reported, and quality-of-life outcomes in a large cohort of individuals with inherited disorders involving elevated blood phenylalanine including phenylalanine hydroxylase deficiency (also known as phenylketonuria or PKU), defects in biopterin synthesis or recycling, or deficiency of the chaperone protein DNAJC12. The consortium:
- Includes a patient advocacy group, the National PKU Alliance (NPKUA) as a critical partner
- Provides informational and educational resources to patients, their families, their providers, and the public regarding these rare disorders
- Trains the next generation of rare disease researchers and practitioners. The consortium is also forming a clinical trial network to evaluate novel therapies for these rare disorders.
Our multicenter collaborative consortium is dedicated to conducting clinical research on inborn errors of metabolism causing hyperphenylalaninemia (elevated blood phenylalanine), one of the most common abnormalities detected through newborn screening. Newborn screening and dietary phenylalanine restriction, initiated in the United States beginning in the 1960s for PAH deficiency, has been convincingly shown through collaborative study to prevent severe cognitive disability in infants and children. However, there are currently 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.
The PHEFREE Consortium is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, and the National Center for Advancing Translational Sciences.
- Phenylalanine hydroxylase deficiency (also known as phenylketonuria or PKU)
- Defects in biopterin synthesis or recycling
- Deficiency of the chaperone protein DNAJC12
- Cognitive, behavioral, psychiatric, educational, vocational, and health outcomes in individuals with these disorders under available treatments
- Validation of phenylalanine as the most appropriate biomarker for outcomes in these disorders
- Investigation of other biomarkers
- Evaluation of therapies
- Establish a clinical trials network for evaluation of novel therapies
- Longitudinal Natural History of Disorders Associated with Hyperphenylalaninemia
- Quantitative Measurement of Phenylalanine Metabolism in Sapropterin-Responsive Hyperphenylalaninemia
Cary O. Harding, MD
Oregon Health & Science University
National Institutes of Health