Phenylalanine hydroxylase deficiency in Mexico: genotype–phenotype correlations, BH₄ responsiveness and evidence of a founder effect

Abstract

The mutational spectrum of the phenylalanine hydroxylase gene (PAH) in Mexico is unknown, although it has been suggested that PKU variants could have a differential geographical distribution. Genotype-phenotype correlations and genotype-based predictions of responsiveness to tetrahydrobiopterin (BH4 ) have never been performed. We sequenced the PAH gene and determined the geographic origin of each allele, mini-haplotype associated, genotype-phenotype correlations and genotype-based prediction of BH4 responsiveness in 48 Mexican patients. The mutational spectrum included 34 variants with c.60+5G>T being the most frequent (20.8%) and linked to haplotype 4.3 possibly because of a founder effect and/or genetic drift. Two new variants were found c.1A>T and c.969+6T>C. The genotype-phenotype correlation was concordant in 70.8%. The genotype-based prediction to BH4 -responsiveness was 41.7%, this information could be useful for the rational selection of candidates for BH4 testing and therapy.

Mutational spectrum of phenylketonuria in Jiangsu province

“…Several studies have investigated the correlation between patients' genotypes and their response to drug treatment; they suggest that genotype plays an important role in BH4 responsiveness [8,14,21]. The current study predicted BH4 responsiveness among individuals with at least one mutation expressing substantial residual activity in vitro (>10 %).…”

“…Therefore, the complete PAH genotype, rather than just a single responsive mutation, is needed to predict BH4 responsiveness. In addition, the only precise method for determining patient responsiveness to the drug is the BH4 loading test, which is particularly important for patients with only one responder allele and those with new allele variants [14]. In PKU patients, the dosage used for BH4 treatment is 10-20 mg/kg body weight [2], and the price for BH4 is 36.5 USD/100 mg tablet (http://www.drugbank.ca/ drugs/DB00360); therefore, the cost for BH4 treatment is very high.…”

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

“…The most frequent pathogenic PAH variant of non‐Iberian origin, IVS2+5G>C (6.4%), associated with haplotype 5.9, has been previously reported as a common variant in Southeast and South Brazil (Figure a). It has not been reported in Portugal, Spain, and Hispanic America (Desviat et al., ; Hamilton et al., ; Perez et al., ; Vela‐Amieva et al., ) (Figure b,c). It is found in Middle Eastern and Central and Eastern European PKU patients (Biglari et al., ; Danecka et al., ; Kasnauskiene, Giannattasio, Lattanzio, Cimbalistiene, & Kucinskas, ; Zschocke & Hoffmann, ; Zschocke 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. …”

“…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.…”