[Cognitive function, brain MRI characteristics and their association with blood phenylalanine levels in patients with phenylketonuria].

Objective

To investigate cognitive function and brain MRI characteristics in children aged 7~18 years with phenylketonuria (PKU) and their association with blood phenylalanine (Phe) control levels.

Methods

This was a cross-sectional study. Clinical data including general characteristics, random blood Phe levels, Wechsler intelligence scale for children scores, and MRI scores were collected from 29 PKU patients aged 7-18 years treated at Guangzhou Women and Children's Medical Center, Guangzhou Medical University from July 2024 to July 2025. Patients were divided into two groups by random blood Phe>600 μmol/L and ≤600 μmol/L and by historical Phe target attainment rate into relatively well-controlled (≥50%) and poorly-controlled (<50%). Independent-samples t-test, Mann-Whitney U test and multiple linear regression were used to examine the effects of blood Phe control, clinical phenotype and other factors on full scale intelligence quotient (FSIQ) and MRI scores.

Results

Among the 29 patients, 17 were males and 12 females, including 17 with classic PKU and 12 with mild PKU. Twenty-seven (93%) were diagnosed early via newborn screening. Physical development was generally normal in 27 patients except for 1 with short stature and 1 with obesity. The random blood Phe level was (634±262) μmol/L. The random blood Phe level in the relatively well-controlled group (19 cases) was significantly lower than that in the poorly-controlled group (10 cases) ((550±266) vs. (794±171) μmol/L, t=2.17, P=0.039). The FSIQ was 90±14. The overall abnormality rate on brain MRI was 86% (25/29), with predominant white matter lesions in the parieto-occipital lobe. The MRI score was 4 (2, 16) points and 10 cases (34%) had a score ≥10 points. Diffusion restriction was observed in 16 cases (55%), of whom 13 cases had random blood Phe>600 μmol/L. The >600 μmol/L group (18 cases) had lower FSIQ, verbal comprehension and working memory scores (all P<0.05), and higher MRI scores (6 (3, 20) vs. 2 (0, 4), Z=2.26, P=0.024) than the ≤600 μmol/L group (11 cases). FSIQ and the scores for verbal comprehension, perceptual reasoning, working memory, and processing speed were all significantly lower in the poorly-controlled group than in the relatively well-controlled group (all P<0.05). Multiple linear regression indicated that long-term Phe metabolic control status (β=0.63, P=0.003) was an independent predictor of FSIQ (F=3.18, P=0.022, adjusted R²=0.33), whereas age (β=0.44, P=0.015) and random blood Phe level (β=0.42, P=0.044) were independent predictors of MRI score (F=4.34, P=0.006, adjusted R²=0.37).

Conclusions

In early-diagnosed PKU patients aged 7~18 years, FSIQ is within the average range, often accompanied by varying degrees of white matter abnormalities. Poor long-term metabolic control of blood Phe is closely associated with cognitive decline. Recent blood Phe level >600 μmol/L correlates with more extensive white matter lesions, frequently accompanied by acute brain injury with restricted diffusion.