Developmental and Phenotypic Outcomes in Mild Phenylalanine Hydroxylase Deficiency

Benign hyperphenylalaninemia (bHPA) is defined as elevated phenylalanine (Phe) levels remaining ≤ 360 μmol/L (6 mg/dL) and not requiring medical intervention. Individuals with bHPA may demonstrate a rise in their Phe levels > 360 μmol/L, effectively developing a mild PKU phenotype requiring therapy to prevent neurocognitive complications. This study aimed to identify risk factors for elevation of Phe > 360 μmol/L and the long-term outcome of bHPA. Retrospective chart review at a single center identified thirty-four individuals with bHPA. Among this group, twelve individuals ultimately demonstrated Phe levels > 360 μmol/L, thus defined as "Risers", as opposed to the "Non-Risers" that remained within bHPA range. Mean Phe level at first newborn screen (NBS) was higher in the Risers group. Clinical assessment pointed to developmental or behavioral issues in two-thirds of the Risers, whereas all Non-Risers had typical development. Our data suggest that bHPA may be associated with increased risk for neurodevelopmental complications among individuals who eventually developed Phe levels > 360 μmol/L. This study emphasizes that individuals with bHPA should be closely followed to track Phe levels and development.