Molecular epidemiology, genotype–phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria

Abstract

Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.

Mutation analysis of the PAH gene in phenylketonuria patients from Rio de Janeiro, Southeast Brazil

“…The three most frequent mutations in our study, representing 34.8% of the alleles, were also the most common in Southeast Brazil (Acosta et al., ; Santos et al., ), Portugal (Rivera et al., ), and Spain (Aldamiz‐Echevarria et al., ): p.V388M, p.R261Q, IVS10‐11G>A. Nevertheless, in Spain they represented only 22.7% of the PKU alleles ( p = .0004), and in Minas Gerais they responded for 52.5% of the alleles ( p = .0008).…”

“…Homozygosity rate in Rio de Janeiro PKU population revealed a high genetic heterogeneity ( j = 0.063), similar to that found in South Portugal (0.059) (Rivera et al., ), Galicia (0.054) (Couce et al., ), USA (nationwide index of 0.06) (Guldberg et al., ), and in California for the European descent subgroup (0.06) (Enns et al., ). Nevertheless, considering that the higher the value of j , the more homogeneous the population with respect to the PAH locus, our population was more homogeneous than the PKU population of Spain (0.029) (Aldamiz‐Echevarria et al., ), and the Hispanic population of California (0.04) (Enns et al., ).…”

“… Mutation previously described in Chile (Hamilton et al., ), Mexico (Vela‐Amieva et al., ), Spain (Aldamiz‐Echevarria et al., ; Trujillano et al., ) and/or Galicia (Couce et al., ) but haplotype not informed. …”

“…Homozygosity index ( j ) at the PAH locus in a given population is determined by , where is the frequency of the allele (Aldamiz‐Echevarria et al., ; Rivera et al., ).…”

“…Approximately 6‐9 different alleles account for the majority of mutant chromosomes described in previous PKU population genetics studies done in Latin America – Brazil (Acosta, Silva, Carvalho, Gomes, & Zago, ; Santana da Silva et al., ; Santos et al., ), Chile (Hamilton et al., ), and Mexico (Vela‐Amieva et al., ), and the Iberian Peninsula (Aldamiz‐Echevarria et al., ; Couce et al., ; Rivera et al., ); the remainder are minor, rare, and even private disease‐causing alleles.…”