Genetic and phenotypic aspects of phenylalanine hydroxylase deficiency in Spain: molecular survey by regions

We present an extensive study of the genetic diversity of phenylalanine hyd roxylase deficiency in the Spanish phenylketonuria population, We have anal ysed 195 PKU patients by DGGE analysis identifying 67 different mutations w hich represent 89% of the total mutant chromosomes. Seventeen mutations fir st described in Spain have not yet been detected elsewhere; ten of these ar e reported here for the first time, The clinical significance of this high genetic heterogeneity was examined by analysing the genotype-phenotype corr elations, mainly focusing on the mild hyperphenylalaninaemia (MHP) phenotyp e, The genotypes found in a group of 93 MHP patients, the largest analysed so far, are described in detail, as well. as the relative frequencies of th e MHP mutations identified. From the total pool of mutations, 27 can be con sidered severe, 18 can be defined as mild and 13 as associated with MHP,The prevalent mutations correspond to one severe mutation (IVS10nt-11), one MH P mutation (A403V) and two mild mutations (I65T and V388M), The high freque ncy of mutations with a low degree of severity can explain the relatively h igher prevalence of MHP and mild PKU phenotypes in Spain compared with Nort hern European populations. We have looked at the geographical distribution in Spain of the more common mutations, finding evidence of local mutation c lustering, which could be the result of differences in the ethnic backgroun d and/or of genetic drift within each region.