Neuropsychiatric Function Improvement in Pediatric Patients with Phenylketonuria.

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.

Neuropsychiatric comorbidities in adults with phenylketonuria: A retrospective cohort study.

Adults with phenylketonuria (PKU) may experience neurologic and psychiatric disorders, including intellectual disability, anxiety, depression, and neurocognitive dysfunction. Identifying the prevalence and prevalence ratios of these conditions will inform clinical treatment. This nested, case-controlled study used International Classification of Diseases, Ninth Revision (ICD-9) codes from the MarketScan® insurance claims databases from 2006 to 2012 and healthcare claims data for US-based employer and government-sponsored health plans. Prevalence and prevalence ratio calculations of neuropsychiatric comorbidities for adults (≥20years old) with PKU were compared with two groups [diabetes mellitus (DM) and general population (GP)] matched by age, gender, geographic location, and insurance type. Age cohorts (i.e., 20-29, 30-39, 40-49, 50-59, 60-69, and 70+years, and a combined subset of 20-39) were used to stratify data. The PKU cohort experienced significantly higher rates of several comorbid neurologic, psychiatric and developmental conditions. Compared to GP, PKU was associated with significantly higher prevalence for numerous neuropsychiatric conditions, most notably for intellectual disability (PR=7.9, 95% CI: 6.4-9.9), autism spectrum disorder (PR=6.1, 95% CI: 3.6-10.4), Tourette/tic disorders (PR=5.4, 95% CI: 2.1-14.1), and eating disorders (4.0, 95% CI: 3.2-5.0). Rates of fatigue/malaise, epilepsy/convulsions, sleep disturbance, personality disorders, phobias, psychosis, and migraines among those with PKU exceeded rates for the GP but were comparable to those with DM, with significantly lower rates of concomitant disorders occurring in younger, compared to older, adults with PKU. Lifelong monitoring and treatment of co-occurring neuropsychiatric conditions are important for effective PKU management.

Sapropterin Dihydrochloride Mixed With Common Foods and Beverages.

Sapropterin dihydrochloride is used to lower blood phenylalanine levels in tetrahydrobiopterin-responsive phenylketonuria in conjunction with a phenylalanine-restricted diet. This study investigated the solubility and stability of sapropterin tablets and a sapropterin powder formulation when mixed in selected beverages and foods. Solubility was partial for the tablets and complete for the powder. The stability testing showed that 93% or more of active sapropterin dihydrochloride is present at 1 hour after either tablets or powders are mixed with certain foods and beverages. Mixing sapropterin powder with foods and beverages might facilitate its administration in patients who have difficulty swallowing the drug according to prescribing information.