Phenylalanine hydroxylase (PAH) deficiency is inherited as an autosomal recessive trait and the associated hyperphenylalaninaemia phenotype is highly variable, primarily due to a great allelic heterogeneity at the PAH locus (approximately 400 disease-associated mutations are known). The arbitrary classification of PAH deficiency on the basis of clinical parameters has been complicated by the lack of international guidelines, leading to a wide confusion in both methodology and terminology. Recently, significant improvements in methods for detection of mutations have paved the way for an alternative system for classification of PAH deficiency, which is based solely on PAH genotypes. This paper gives a summary of the recent progress made in establishing a direct correlation between individual PAH mutations and biochemical and metabolic phenotypes, including the use of "functionally hemizygous" patients to classify both common and rare mutant alleles, and a simple and general model to predict the combined phenotypic effect of two mutant PAH alleles.
Conclusion: Genotype-based prediction of the biochemical phenotype is now feasible in the majority of newborns with hyperphenylalaninemia, which may be useful for refining diagnosis and anticipating dietary requirements. A recent observation suggests that the genotype also determines cognitive development if dietary therapy is discontinued at 6 years of age.