The Hyperphenylalaninaemias

Abstract

Primary inherited hyperphenylalaninaemia is probably best defined as a ratio of blood phenylalanine to tyrosine persistently greater than 3 (approximate normal ranges for blood concentrations: phenylalanine 35–120 μmol/1; tyrosine 40–130 μmol/1). Hyperphenylalaninaemia arises due to a block in the conversion of phenylalanine into tyrosine due to a defect in either the enzyme phenylalanine hydroxylase (98% of subjects) or in the metabolism of the cofactor tetrahydrobiopterin (BH₄). Increases production of phenylketones [hence phenylketonuria (PKU)] occurs in parallel with the rise in phenylalanine level. BH4 is also the cofactor required for conversion of tyrosine into L-dopa, of tryptophan into 5-hydroxy-tryptophan and of arginine into nitric oxide (NO). In Caucasians, persistent hyperphenylalaninaemia occurs in between t in 4000 and t in 40,000 newborns. Although there is a considerable variation in genotype and phenotype, the gteat majority of affected subjects are at risk of intellectual and neurological impairments and handicaps, which can be prevented by introduction of strictly controlled treatment within a few weeks of birth (a phenylalanine-restricted diet with the addition of drug therapy for subjects with cofactor defects). Neonatal screening detects all but a few affected subjects. Definitive diagnosis relies on the measurement of blood phenylalanine and tyrosine and the exclusion of cofactor defects by measurement of pterins and dihydropteridine reductase (DHPR). The foetus, like the newborn infant, is at risk of damage proportionate to the degree of hyperphenylalaninaemia. The offspring of affected and untreated mothers present with low birth weight, reduced longitudinal pre- and postnatal growth, microcephaly, facial dysmorphism and a range of other congenital anomalies, notably in the heart and large vessels. It is of great importance that potential mothers with hyperphenylalaninaemia receive well-controlled treatment from before conception to the end of pregnancy. Within one generation, failure to achieve proper management for maternal PKU will result in loss of the benefits of neonatal screening.