Keywords

Phenylketonuria; Cognitive Function; Neuropsychiatric Symptoms; Sapropterin Dihydrochloride; BH4; ADHD

Abstract

Phenylketonuria (PKU) is a rare metabolic disorder that occurs in approximately 1 in 10,000 births worldwide. Individuals with PKU cannot properly metabolize phenylalanine (Phe) due to a deficiency in phenylalanine hydroxylase (PAH), leading to elevated Phe levels and associated cognitive and neuropsychiatric impairments. Although early dietary management has reduced the risk of severe intellectual disability, many individuals with PKU continue to experience deficits in attention, executive functions, and mood regulation. Sapropterin dihydrochloride, a synthetic form of the PAH cofactor tetrahydrobiopterin (BH4), offers a pharmacological alternative that enhances residual enzyme activity in responsive individuals. While its efficacy in lowering blood Phe levels is well established, research on neuropsychiatric outcomes remains limited. Medline, Web of Science, Cochrane, PubMed, and ClinicalTrials.gov were searched to identify studies evaluating sapropterin’s neuropsychiatric effects. A total of 208 publications were uploaded to Covidence and screened by two independent blinded reviewers. After removing 40 duplicates, 168 studies remained for title and abstract screening. Fourteen proceeded to full-text review, and 8 met inclusion criteria—6 from the screened pool and 2 through hand-search. Quality assessment was completed using the NIH Study Quality Assessment Tool, and relevant outcome data were extracted. Across included studies, sapropterin demonstrated varying but promising effects in select neuropsychiatric domains. Several randomized trials reported improvements in ADHD symptoms, particularly inattention, whereas findings for hyperactivity and impulsivity were less consistent. One study reported improvements in executive functioning, while others did not find significant differences between treatment and control groups after adjustments from Phe levels were accounted for. Evidence regarding anxiety and depression showed minimal change. IQ outcomes were more consistently positive, with pediatric studies indicating stable or improved trajectories during treatment. These findings suggest that sapropterin may support attention, executive functioning, and IQ stability in individuals with PKU. Further research is needed to clarify its long-term neuropsychiatric effects.

Thesis Completion Year

2025

Thesis Completion Semester

Fall

Thesis Chair

Lee, Eunkyung

College

College of Health Professions and Sciences

Department

Health Sciences

Thesis Discipline

Health Sciences

Language

English

Access Status

Open Access

Length of Campus Access

1 year

Campus Location

Orlando (Main) Campus

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Rights Statement

In Copyright