BACKGROUND: The prevalence of phenylalanine hydroxylase (PAH)-deficient phenylketonuria (PKU) in Turkey is high (1 in 6500 births), but data concerning the genotype distribution and impact of the genotype on tetrahydrobiopterin (BH(4)) therapy are scarce.
OBJECTIVE: To characterize the phenotypic and genotypic variability in the Turkish PKU population and to correlate it with physiological response to BH(4) challenge.
METHODS: We genotyped 588 hyperphenylalaninemic patients and performed a BH(4) loading test (20mg/kg bw) in 462 patients. Residual PAH activity of mutant proteins was calculated from available in vitro expression data. Data were tabulated in the BIOPKU database (www.biopku.org).
RESULTS: Eighty-eight mutations were observed, the most common missense mutations being the splice variant c.1066-11G>A (24.6%). Twenty novel mutations were detected (11 missense, 4 splice-site, and 5 deletion/insertions). Two mutations were observed in 540/588 patients (91.8%) but in 9 patients atypical genotypes with >2 mutations were found (8 with p.R155H in cis with another variant) and in 19 patients mutations were found in BH(4)-metabolizing genes. The most common genotype was c.1066-11G>A/c.1066-11G>A (15.5%). Approximately 22% of patients responded to BH(4) challenge. A substantial in vitro residual activity (average >25% of the wild-type enzyme) was associated with response to BH(4). In homozygous genotypes (n=206), both severity of the phenotype (r=0.83) and residual PAH activity (r=0.85) correlate with BH(4) responsiveness.
CONCLUSION: Together with the BH(4) challenge, these data enable the genotype-based classification of BH(4) responsiveness and document importance of residual PAH activity. This first report of a large-scale genotype assessment in a population of Turkish PKU patients also documents a high prevalence (47%) of the severe classic phenotype.