The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study.

Background: Pathogenesis and clinical consequences of white matter abnormalities on magnetic resonance imaging (MRI) in phenylketonuric (PKU) patients are incompletely known.

Objective: To study white matter alterations progression and outcome and its relationships with phenylalanine levels and intelligence quotient (IQ) in early treated PKU subjects who underwent serial MRIs during a prolonged follow-up.

Methods: 47 early treated PKU patients (mean age 25.1 ± 5.6 years; range 12-37 years) have been enrolled when two or more consecutive brain MRIs, a complete biochemical history, and MRI-concurrent blood phenylalanine levels were available. The severity and extension of white matter abnormalities were expressed in a computed score. Consecutive IQ assessments were available in 24 patients. We analyzed intra- and interindividual white matter alterations variations and their relationship with quality of biochemical control and cognitive outcome.

Results: Early treated PKU patients showed a high rate of white matter alterations with a relevant increase in frequency/severity from the second decade of life onwards. Age and quality of dietary control before or between subsequent examinations showed an independent cumulative effect on white matter alterations outcome. No significant association was found between white matter alterations and cognitive outcome. A remarkable interindividual variability was found and several patients disclosed incongruity between the trajectory of white matter alterations and biochemical control. About 30% of white matter alterations variability remains unexplained by the disease-associated determinants.

Conclusions: The evolution of white matter alterations is not significantly affected by intellectual outcome and is affected by aging, chronic exposure to phenylalanine, and unknown individual factors.