Prevalence of tetrahydrobiopterine (BH4)‐responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients

Abstract

Phenylketonuria (PKU, MIM 261600) is an autosomal recessive disorder caused by mutations of the phenylalanine hydroxylase gene (PAH, GenBank U49897.1, RefSeq NM_000277). To date more than 560 variants of the PAH gene have been identified. In Europe there is regional distribution of specific mutations. Due to recent progress in chaperone therapy, the prevalence of BH4-responsive alleles gained therapeutic importance. Here we report the mutational spectrum of PAH deficiency in 147 unrelated Austrian families. Overall mutation detection rate was 98.6 %. There was a total of 62 disease-causing mutations, including five novel mutations IVS4 + 6T>A, p.H290Y, IVS8-2A>G, p.A322V and p.I421S. The five most prevalent mutations found in patients were p.R408W, IVS12 + 1G>A, p.R261Q, p.R158Q and IVS2 + 5G>C. Neonatal phenylalanine levels before treatment were available in 114/147 patients. Prediction of BH4-responsiveness in patients with full genotypes was exclusively made according to published data. Among the 133 patients needing dietary treatment, 28.4 % are expected to be BH4 "non-responsive", 4.5 % are highly likely BH4-responsive, 35.8 % are probably BH4-responsive while no interpretation was possible for 31.3 %. The mutation data reflect the population history of Austria and provide information on the likely proportion of Austrian PKU patients that may benefit from BH4-therapy.

Molecular Genetics and Genotype-Based Estimation of BH4-Responsiveness in Serbian PKU Patients: Spotlight on Phenotypic Implications of p.L48S

“…Unlike recent studies conducted in European PKU patients, all mutations identified in this cohort of patients have already been reported in the literature (Sterl et al 2012;Groselj et al 2012). However, the mutational spectrum was enlarged with seven mutations that were not reported in the previous study on Serbian population.…”

“…According to the classification given in Sterl et al (2012), we classified all 39 Serbian PAH genotypes into BH4 responsive (26.2%), probably BH4 responsive (51%), and non-BH4 responsive (22.8%) (Table 3). Furthermore, we made distinction between genotypes with one and two BH4-responsive alleles.…”

“…In order to make the most accurate estimation of the potential of BH4-supplementation therapy, we classified Serbian PAH genotypes into BH4 responsive, probably BH4 responsive, and non-BH4 responsive (Table 3) (Sterl et al 2012). Furthermore, we made distinction between genotypes with one and two BH4-responsive alleles.…”

“…Also, it was shown that PAH function and response to BH4 administration result from interplay between genotype, metabolic state, and cofactor concentration (Staudigl et al 2011). Several studies analyzed the correlation of genotype and patient's responsiveness to BH4 and made an attempt to predict the BH4-responsiveness on the basis of genotype (Zurfl€ uh et al 2008;Karacic et al 2009;Rivera et al 2011;Sterl et al 2012). In the Kuvan era, genotypization of patients became important, not only because of the definitive diagnosis and prediction of the optimal diet, but also to point out those patients that could benefit from new therapeutic approach.…”

Molecular Characteristics, Phenotypic Diversity and Genotype-Estimated Therapeutic Responsiveness of Serbian Patients with Phenylketonuria / MOLEKULARNE KARAKTERISTIKE, FENOTIPSKA RAZNOLIKOST I PROCENA ODGOVORA NA TERAPIJU ZASNOVANA NA GENOTIPU KOD SRPSKIH PACIJENATA SA FENILKETONURIJOM

“…The following studies attempted to predict BH4-responsiveness on the basis of single allele information or a patient's genotype (48,49,(67)(68)(69)(70)(71)(72)(73). For a number of patients' genotypes, the genotype-based prediction was found to be a useful complementary tool to the obligatory BH4 loading test.…”