Molecular correlations in phenylketonuria: Mutation patterns and corresponding biochemical and clinical phenotypes in a heterogeneous California population

We studied 133 California phenylketonuria (PKU) patients and one obligate h eterozygote to delineate the molecular basis of PKU in a population with gr eater ethnic diversity than in previous studies, and to determine whether a correlation exists between genotype and clinical phenotype, with the latte r defined by both the diagnostic pretreatment blood phenylalanine (PHE) lev el and cognitive (IQ) test scores. To determine PAH genotypes, we used PCR- mediated amplification, denaturing gradient gel electrophoresis, and direct sequencing on dried whole blood samples. Where possible, mutation severity was defined according to predicted in vitro PAH enzyme activity estimated by using Cos cell expression analysis for a given mutation. We then asked w hether mutation severity, as defined by such expression analysis, correlate d with pretreatment PHE levels or with IQ test results. A mutation was iden tified in 236 (88%) of 267 mutant alleles. Seventeen new mutant alleles wer e found; A47E, T81P, I102T,E182G,T328D,Y343P,K371R,Y387H,A389E, E422K, IVS9 nt5, IVS11nt20, delS70, del364-368/del198-220, delF299, delT323, and -1C/T. In striking contrast to a number of studies in other populations, in this study, based on predicted PAH activity, we observed no correlation between mutation severity and pretreatment PHE levels. There was also no correlatio n between genotype and IQ, We conclude that in samples collected from an et hnically heterogeneous population, there is no correlation of mutation seve rity with either pretreatment PHE levels or IQ measurement in treated patie nts. We caution that genetic counseling in PKU should incorporate the notio n that prognosis may not be predicted with precision based on mutation anal ysis in a given patient.