Intellectual, neurologic, and neuropsychologic outcome in untreated subjects with nonphenylketonuria hyperphenylalaninemia. German Collaborative Study on Phenylketonuria

Based on the serum phenylalanine levels under free diet patients with hyperphenylalaninemia are classified as "classical" (>1200 micromol/L), "mild" (600-1200 micromol/L), or "non-phenylketonuria (PKU)-hyperphenylalaninemia" (<600 micromol/L). Recent studies revealed intellectual, neurologic, and neuropsychologic deficits as well as abnormalities of cerebral white matter (magnetic resonance imaging, MRI) in patients with early and adequately treated PKU. In addition deficits in IQ were reported for a group of 4-y-old patients with untreated mild PKU and non-PKU hyperphenylalaninemia (serum phenylalanine levels below 900 micromol/L). As a consequence, a lifelong diet with serum phenylalanine levels below 400 micromol/L was recommended even for those patients with serum phenylalanine levels remaining consistently between 400 and 600 micromol/L. Generally patients with non-PKU hyperphenylalaninemia were not treated, as a normal outcome was suspected, but the clinical development of patients with non-PKU hyperphenylalaninemia was not so far studied systematically. We assessed 28 untreated patients with non-PKU hyperphenylalaninemia (age: mean = 21.8, SD = 4.2 y) for IQ, school and job career, clinical-neurologic development, fine motor performances, selective and sustained attention, as well as for frontal lobe-dependent "executive functions." In addition, cranial MRI was obtained in 10 of these patients. Compared with healthy control subjects, matched for age, sex, and socioeconomic status, the patients reached normal results in all clinical and psychometric tests. Cranial MRI revealed no abnormalities. Additionally, no significant correlations between serum phenylalanine levels and test results were obtained. In the absence of any demonstrative effect, treatment is unlikely to be of significant effect in patients with non-PKU hyperphenylalaninemia.