Abstract
IMPORTANCE
Long-term metabolic control remains difficult in phenylketonuria despite newborn screening and early treatment, and longitudinal evidence is limited, particularly in China.
OBJECTIVE
To describe age-associated metabolic patterns and factors associated with phenylalanine control in children with early-treated phenylketonuria.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included children with early-treated phenylketonuria identified through newborn screening and followed up through up to age 18 years in Beijing, China, from January 1998 to February 2024. Blood phenylalanine measurements from February 1998 to March 2025 were analyzed from the first normal posttreatment test until before age 18 years. Data were analyzed from October 2025 to March 2026.
EXPOSURES
Diagnosis type, family socioeconomic status (SES), and birth year.
MAIN OUTCOMES AND MEASURES
Outcomes of interest were longitudinal blood phenylalanine concentrations and first deterioration in annual control state. Linear mixed-effects and multistate Cox models were used.
RESULTS
Among 325 children (179 [55.1%] male; median [IQR] follow-up, 8.32 [5.41 to 12.26] years) included, 227 (69.8%) had classic phenylketonuria, and 98 (30.2%) had mild phenylketonuria. Metabolic control worsened with age: the mean (SD) phenylalanine concentration was 197 (76.7) µmol/L during the first year of life and exceeded 360 µmol/L from age 6 years onward. By age 12 years, only 17 of 78 children (21.8%) with available data remained in a good annual control state. In adjusted linear mixed-effects models, classic phenylketonuria was associated with higher square root–transformed phenylalanine concentrations than mild phenylketonuria (β = 0.82; 95% CI, 0.16 to 1.47;
P
= .02), whereas high SES was associated with lower concentrations (β = −2.00; 95% CI, −2.82 to −1.19;
P
< .001). In multistate Cox models, classic phenylketonuria was associated with a higher hazard of metabolic control worsening from good to fair control (hazard ratio [HR], 1.50; 95% CI, 1.08 to 2.09;
P
= .02), whereas high SES (HR, 0.54; 95% CI, 0.35 to 0.83;
P
= .005) and more recent birth year (HR per 5-year increase, 0.68; 95% CI, 0.61 to 0.76;
P
< .001) were associated with lower hazard.
CONCLUSIONS AND RELEVANCE
In this retrospective cohort study of children with early-treated phenylketonuria in Beijing, metabolic control worsened with age and was poorer in classic phenylketonuria than mild phenylketonuria. Higher SES and more recent birth year were associated with better control. These findings support sustained, age-specific management throughout childhood and adolescence.