PHENYLKETONURIA GENOTYPES CORRELATED TO METABOLIC PHENOTYPE GROUPS INNORWAY

In order to establish a genotype-phenotype relationship, we have ident ified both mutant phenylalanine hydroxylase (PAH) genes in 108 phenylk etonuria (PKU) patients (27 different alleles, 54 different genotypes) . One major group of patients with very high pretreatment phenylalanin e values (''classical'' PKU) exclusively comprised homozygotes of the PKU mutations I65T, G272X, F299C, Y356X, R408W, IVS 12ntl, and compoun d heterozygotes of various combinations of these alleles with G46S, R2 61Q, R252W, A259T, R158Q, D143G, R243X, E280 K, or Y204C. A second maj or group of patients with lower phenylalanine values (''mild'' PKU) co mprised mutations A300S, R408Q, Y414C in various compound heterozygous states, and R261Q, R408Q, Y414C in homozygotes. The phenylalanine val ues in these groups were non-overlapping. In addition, a smaller group of patients formed the transition between the two main groups. In sib pairs 4 of 15 had discordant pretreatment phenylalanine values. Concl usion Our results are consistent with the view that allelic heterogene ity at the PAH locus dominates the biochemical phenotype in PKU and th at genotype information is able to predict the metabolic phenotype in PKU patients.