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Brain Age in Adult Patients With Early-Treated Phenylketonuria
Laura Winiger1,2, Raphaela Muri1,3, Tobias Kaufmann4,5,6
1Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
Journal of Inherited Metabolic Disease
|February 17, 2026
Summary
Phenylketonuria (PKU) may affect brain aging, with adults with PKU showing an elevated brain age gap in the insula. This finding suggests atypical brain development linked to metabolic disturbances.
Area of Science:
- Neuroscience
- Radiology
- Metabolic Disorders
Background:
- Phenylketonuria (PKU) is a metabolic disorder associated with structural brain alterations.
- The impact of PKU on brain aging has not been previously investigated.
Purpose of the Study:
- To investigate brain age in adults with early-treated classical PKU compared to healthy controls.
- To explore the relationship between brain age gap, metabolic control, and cognitive function in PKU.
Main Methods:
- Structural MRI was used to estimate brain age using machine learning models.
- Brain age gap (BAG) was calculated as the difference between estimated brain age and chronological age.
- Cognitive assessments, mood evaluations, and blood sampling for phenylalanine (Phe) levels were performed.
Main Results:
- Adults with PKU exhibited a significantly higher brain age gap in the insula compared to controls.
- The cingulate brain age gap correlated positively with phenylalanine levels and white matter lesion load.
- Subcortical and cingulate brain age gaps showed associations with cognitive performance, though these did not survive FDR correction.
Conclusions:
- Elevated insular brain age gap in early-treated PKU suggests atypical brain development due to metabolic disturbances.
- Longitudinal studies are needed to understand brain aging trajectories and cognitive implications in PKU.
- Findings highlight the potential long-term neurological consequences of managing metabolic disorders like PKU.
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