Molecular basis for the phenotypical diversity of phenylketonuria and related hyperphenylalaninaemias

Abstract

Conclusion Phenylalanine hydroxylase deficiency results in a fairly continuous spectrum of metabolic phenotypes, which can now be predicted by means of molecular analysis. Methods for direct detection of previously identified mutations and mutation scanning techniques (SSCP and DGGE) have facilitated genotyping of the hyperphenylalaninaemic neonate. Genotyping will confirm that the hyperphenylalaninaemic neonate has PAH deficiency and not a BH 4 ‐deficient form of hyperphenylalaninaemia or acquired hyperphenylalaninaemia. Genotyping will also distinguish between non‐PKU HPA neonates and PKU patients. Finally, genotyping predicts the metabolic phenotype, facilitating optimal dietary therapy from the neonatal period. A possible relationship between mutation genotype and the ultimate prognosis of PKU (MRI changes, cognitive development), and the question of whether the maternal genotype and the mutant allele of her offspring may influence pregnancy outcome are challenges for future studies.