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

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.