Neuropsychiatric Function Improvement in Pediatric Patients with Phenylketonuria

Mitzie L Grant; Elaina R Jurecki; Shawn E McCandless; Stephen M Stahl; Deborah A Bilder; Amarilis Sanchez-Valle; David Dimmock

doi:10.1016/j.jpeds.2023.113526

Neuropsychiatric Function Improvement in Pediatric Patients with Phenylketonuria

J Pediatr. 2023 Sep:260:113526. doi: 10.1016/j.jpeds.2023.113526. Epub 2023 May 30.

Authors

Mitzie L Grant¹, Elaina R Jurecki², Shawn E McCandless³, Stephen M Stahl⁴, Deborah A Bilder⁵, Amarilis Sanchez-Valle⁶, David Dimmock⁷

Affiliations

¹ Drexel University College of Medicine, Philadelphia, PA.
² BioMarin Pharmaceutical Inc, Novato, CA. Electronic address: erjurecki@outlook.com.
³ University of Colorado, Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO.
⁴ Department of Psychiatry, University of California San Diego, San Diego, CA.
⁵ Department of Psychiatry, Division of Child & Adolescent Psychiatry, University of Utah, Salt Lake City, UT.
⁶ Department of Pediatrics, Division of Genetics and Metabolism, University of South Florida, Tampa, FL.
⁷ Creyon Bio Inc, San Diego, CA.

PMID: 37263523
DOI: 10.1016/j.jpeds.2023.113526

Abstract

Objective: To evaluate effects of sapropterin dihydrochloride on blood phenylalanine (Phe) and symptoms of neuropsychiatric impairment in children and adolescents with phenylketonuria (PKU).

Study design: PKU subjects 8-17 years of age (n = 86) were randomized to double-blind treatment with sapropterin (n = 43) or placebo (n = 43) for 13 weeks, then all received open-label sapropterin therapy for an additional 13 weeks. Blood Phe and symptoms of inattention, hyperactivity/impulsivity (Attention-Deficit/Hyperactivity Disorder Rating Scale IV [ADHD RS-IV]), executive functioning (Behavior Rating Inventory of Executive Function), depression (Hamilton Rating Scale for Depression), and anxiety (Hamilton Rating Scale for Anxiety) were assessed.

Results: Following the 13-week randomization phase, the sapropterin and placebo groups had mean changes in blood Phe of -20.9% and +2.9%, respectively. Corresponding least square mean differences in ADHD RS-IV scores were significantly greater for the sapropterin vs the placebo group: Total (-3.2 points, P = .02), Inattention subscale (-1.8 points, P = .04), and Hyperactivity/Impulsivity subscale (-1.6 points, P = .02). Forest plots favored sapropterin treatment over placebo for all ADHD RS-IV and Behavior Rating Inventory of Executive Function indices. There were no significant differences in reported problems with attention or executive function between the 2 groups at baseline or at week 26 following the 13-week open-label treatment period. Anxiety and depression scores did not differ significantly between cohorts at any time. Sapropterin was well tolerated, with a favorable safety profile.

Conclusions: Sapropterin reduced blood Phe and was associated with significant improvement in parent-reported symptoms of inattention, hyperactivity/impulsivity, and executive functioning in children and adolescents with PKU.

Trial registration: ClinicalTrials.gov, NCT01114737. Registered 27 April 2010, https://clinicaltrials.gov/ct2/show/NCT01114737.

Keywords: ADHD; PKU; neuropsychiatric; phenylalanine; phenylketonuria; sapropterin.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Attention Deficit Disorder with Hyperactivity* / drug therapy
Child
Cognition
Double-Blind Method
Executive Function
Humans
Infant
Phenylalanine
Phenylketonurias* / drug therapy
Treatment Outcome

Substances

Phenylalanine

Associated data

ClinicalTrials.gov/NCT01114737