# Hyperphenylalaninemia Disorders Consortium of the Rare Disease Clinical Research Network

> **NIH NIH U54** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $1,567,686

## Abstract

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.

## Key facts

- **NIH application ID:** 10019398
- **Project number:** 5U54HD100982-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Cary O. Harding
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,567,686
- **Award type:** 5
- **Project period:** 2019-09-16 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019398

## Citation

> US National Institutes of Health, RePORTER application 10019398, Hyperphenylalaninemia Disorders Consortium of the Rare Disease Clinical Research Network (5U54HD100982-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10019398. Licensed CC0.

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