Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia

There is international consensus that patients with phenylalanine (Phe) levels <360 <mu>M on a free diet do not need Phe-lowering dietary treatment whereas patients with levels >600 muM do. Clinical outcome of patients showing Phe levels between 360 and 600 muM in serum on a free nutrition has so far only been assessed in a small number of cases. Therefore, different recommendations exist for patients with mild hyperphenylalaninemia. We investigated in a nationwide study 31 adolescent and adult patients who persistently displayed serum Phe levels between 360 and 600 muM On a normal nutrition with a corresponding genotype. Because of limited accuracy of measurements, Phe levels should be looked on as an approximation, but not as an absolute limit in every instance. In addition to serum Phe levels, the assessment program consisted of comprehensive psychological testing, magnetic resonance imaging of the head, H-1 magnetic resonance spectroscopy, and genotyping. We found a nor mal intellectual (intelligence quotient, 103 +/- 15; range, 79-138) and educational (school performance and job career) outcome in these subjects as compared with healthy control subjects (intelligence quotient, 104 +/- 11; range, 80-135). Magnetic resonance imaging revealed no changes of cerebral white matter in any patient, and 1H magnetic resonance spectroscopy revealed brain Phe levels below the limit of detection (<200 <mu>M). In the absence of any demonstrable effect, dietary treatment is unlikely to be of value in patients with mild hyperphenylalinemia and serum Phe levels <600 <mu>M on a free nutrition, and should no longer be recommended. Because of a possible late-onset pheylketonuria, Phe levels of untreated patients should be monitored carefully at least during the first year of life. Nevertheless, problems of maternal phenylkeconuria should still he taken into account.