engleski

Genotype-based prediction of BH4-responsiveness in PKU patients

One part of phenylalanine hydroxylase (PAH)-deficient patients may benefit from tetrahydrobiopterin (BH4) therapy instead or in addition to the low-protein diet. Diagnosis of BH4-responsiveness is usually done through the newborn screening for PKU, followed by a BH4 loading test. More than 60 specific mutations in the PAH gene, presenting with a substantial residual activity, were identified in BH4-responsive patients. However, there is no accurate correlation between genotype and BH4-responsiveness. The aim of our study was to provide more information on predictive value of BH4-responsive mutations in Croatian PAH-deficient population. We predicted BH4-responsiveness (> 30% blood phenylalanine reduction within 24 hours) in all individuals with at least one mutation expressing in vitro substantial residual activity (>10%). From a group of 127 patients, 62 were selected (based only on the genotype) as potentially BH4- responsive and 39 were loaded with BH4 (20 mg/kg). The overall frequency of BH4-responsiveness was 36% (14 out of 39 patients with 23 different genotypes), significantly less than expected. The most common BH4- responsive genotypes (p.E390G/p.R408W and p.P281L/p.E390G) were corresponding for >30% residual PAH activity. Analysis of predicted relative PAH activities of recombinantly expressed mutant alleles revealed a significant difference (p<0.002) between BH4-responders and non-responders. This study reveals the importance of a full genotype (instead of just a single responsive mutation) for the prediction of BH4-responsiveness. With exception of the p.E390G mutation, single allele mutations are not reliable for the selection of potential BH4-responsive individuals. It seems that a substantial residual PAH activity resulting from a combination of both alleles is needed to predict BH4-responsiveness in PKU patients.

genotype-phenotype correlation; BH4-responsiveness; PKU

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