The correlation of genotype and phenotype in Portuguese hyperphenylalaninemic patients

To understand the basis for the clinical heterogeneity of phenylalanine hydroxylase deficiency among Portuguese hyperphenylalaninemic patients, genotype-phenotype correlations were established. A group of 61 patients was completely genotyped, leading to the identification of 20 different mutant alleles in 36 different genotypic combinations, including a mutant allele not reported previously. The severity of those mutations found within this hyperphenylalaninemic population, which have not been previously expressed in vitro, were assessed. The results obtained by the present study exhibit a strong correlation between the predicted residual enzyme activity, as deduced from the genotype of the patients, and the biochemical phenotype represented by the diagnostic parameters (phenylalanine levels before the beginning of treatment and the dietary phenylalanine tolerance). It was observed that only a judicious follow-up and compliance with the appropriate diet permits the correct assessment of the clinical phenotype of the patients. Additionally, based upon the correlation observed between genotypes and diagnostic parameters, it was possible to predict the potential residual enzyme activity of those mutations (identified in our patients) which have not yet been studied in vitro.