Genotype and intellectual phenotype in untreated phenylketonuria patients

Previous studies have shown that genotype correlates with biochemical phenotype in treated phenylketonuria. If there is a strong correlation between genotype and intellectual phenotype of untreated patients, it would be possible to determine which individuals would have normal intelligence without treatment. In this study, 42 families with untreated phenylketonuria were analyzed to examine whether there was an association between genotype and untreated intellectual phenotype. Previously 12 of the 42 families were genotyped; now the genotyping of these patients is almost complete (40/42), a more thorough investigation was possible. Although the predicted phenylalanine hydroxylase (PAH) enzyme activity, based on genotype, showed an association with the patients' intellectual phenotype, the extensive overlap between the groups means the association is of little clinical value. Unrelated individuals with the same genotype and also siblings were found to have very different intellectual phenotypes. These phenotypic differences could not be explained by a difference in diet; therefore, we propose that another gene or genes may be modifying the intellectual phenotype of untreated patients. A preliminary search for possible modifying genes was performed. The possibility that a modifying gene was linked to the PAH gene on chromosome 12 was investigated using markers closely linked to the gene; however, no evidence for a modifying gene close to the PAH gene was found. Tyrosine hydroxylase was chosen as a candidate gene, because it can perform the same reaction as PAH. Using a common polymorphism within the gene, we found that this gene did not cause the discordant results and thus, did not modify the PAH phenotype.