A EUROPEAN MULTICENTER STUDY OF PHENYLALANINE-HYDROXYLASE DEFICIENCY - CLASSIFICATION OF 105 MUTATIONS AND A GENERAL SYSTEM FOR GENOTYPE-BASED PREDICTION OF METABOLIC PHENOTYPE

Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydr oxylase (PAH). Previous studies have suggested that the highly variabl e metabolic phenotypes of PAH deficiency correlate with PAH genotypes, We identified both causative mutations in 686 patients from seven Eur opean centers. On the basis of the phenotypic characteristics of 297 f unctionally hemizygous patients, 105 of the mutations were assigned to one of four arbitrary phenotype categories. We proposed and tested a simple model for correlation between genotype and phenotypic outcome. The observed phenotype matched the predicted phenotype in 79% of the c ases, and in only 5 of 184 patients was the observed phenotype more th an one category away from that expected. Among the seven contributing centers, the proportion of patients for whom the observed phenotype di d not match the predicted phenotype was 4%-23% (P <.0001), suggesting that differences in methods used for mutation detection or phenotype c lassification may account for a considerable proportion of genotype-ph enotype inconsistencies. Our data indicate that the PAH-mutation genot ype is the main determinant of metabolic phenotype in most patients wi th PAH deficiency. In the present study, the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in >1 0,000 genotypes, which may be useful for the management of hyperphenyl alaninemia in newborns.