DISCORDANT PHENYLKETONURIA PHENOTYPES IN ONE FAMILY - THE RELATIONSHIP BETWEEN GENOTYPE AND CLINICAL OUTCOME IS A FUNCTION OF MULTIPLE EFFECTS

Four members spanning three generations of one family have phenylketon uria of varying degrees of severity. Two first cousins were screened i n the neonatal period and have had dietary phenylalanine restriction s ince diagnosis, the older patient having been classified as having mor e severe PKU and the younger one as having mild PKU. Their mutual gran dfather and his older brother also have a significant hyperphenylalani naemia and are of normal intelligence despite never having had restric ted phenylalanine intake. Mutation analysis of the phenylalanine hydro xylase (PAH) gene has established that there are four different mutati ons, two in exon 2 (F39L and L48S) and two in exon 3 (R111X and S67P), which give rise to PKU in this family. In order to establish their re lative severity, we screened the PKU populations of western Scotland a nd the south west of England for these mutations. The exon 3 mutations are rare; however, F39L is relatively common in Scotland and L48S in England. A comparison of diagnostic blood phenylalanine concentrations in subjects carrying L48S/null or F39L/null mutations with those carr ying two null mutations suggest that these exon 2 mutations are less d eleterious. Thus, in this family, the different biochemical phenotypes can be explained, in part, by different genotypes at the PAH locus bu t our results show that the relationship between genotype and clinical outcome is more complex and is a function of multiple effects.