Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

Mutations in the phenylalanine hydroxylase (PAH) gene result in phenylketonuria (PKU). Tetrahydrobiopterin (BH4)-responsive hyperphenylalaninemia has been recently described as a variant of PAH deficiency caused by specific mutations in the PAH gene. It has been suggested that BR4-responsiveness may be predicted from the corresponding genotypes. Data from BH4 loading tests indicated an incidence of BH4-responsiveness of > 40% in the general PKU population and > 80% in mild PKU patients. The current project entailed genotype analysis of 315 BH4-responsive patients tabulated in the BIOPKUdb database and comparison with the data from the PAHdb locus-specific knowledgebase, as well as with previously published PAH mutations for several European countries, Northern China, and South Korea. We identified 57 mutations, presenting with a substantial residual PAH activity (average similar to 47%), presumed to be associated with BH4-responsiveness. More than 89% of patients are found to be compound heterozygotes. The three most common mutations found in > 5% of BH4-responsive patients are p.A403V, p.R261Q, and p.Y414C. Using the Hardy-Weinberg formula the predicted average frequency of BH4-responsiveness in European populations was calculated to be 55% (range 17-79%, lowest in Baltic countries and Poland and highest in Spain), 57% in Northern China, and 55% for South Korea. The genotype predicted prevalence of BH4,responsiveness was higher than prevalence data obtained from BH4 loading tests. Inconsistent results were observed for mutations p.L48S, p.I65T, p.R158Q, p.R261Q, and p.Y414C. Our data suggest that BH4-responsiveness may be more common than assumed and to some extent may be predicted or excluded from the patient's genotype.