Phenylalanine Hydroxylase (PAH) Genotyping in PKU Argentine Patients

Rosa E Enacán,Mariana Nuñez Miñana,Ana Elena Chiesa,Claudia I Fraga,Maria Gabriela Valle,Norma Specola,Fernando Santos-Simarro,Mercedes Salerno,Laura Prieto,Pablo Lapunzina,Luis Fernandez

doi:10.1590/2326-4594-jiems-2019-0012

Abstract

Abstract Phenylketonuria (PKU, OMIM 261600) is predominantly caused by mutations in the PAH gene. One hundred and three Argentine PKU patients were studied by Sanger sequencing; 101 were completely characterized (90.3% were compound heterozygotes). Fifty-four different pathogenic variants were identified. Mutations were distributed all along the PAH gene but concentrated in exon 7 (26%), 12 (12%), 11 (10%), and 6 (10%). 77% were missense, and 77% affected the enzyme catalytic domain, nine mutations accounted for 57% of 179 studied alleles: p.Arg261Gln (Allele frequency(AF):10.6%), c.1066-11G>A (AF:9,5%), p.Arg408Trp (AF:8,3%), p.Tyr414Cys (AF:5,5%), p.Ala403Val, p.Val388Met, and p.Arg158Gln (AF: 5% each), p.Leu48Ser, and p.Ile65Thr (AF:4% each). The predicted phenotype was assigned by Guldberg´s arbitrary value (AV) and compared with the clinical phenotype based in tolerance to Phe intake. 29.1% (n:30) were hyperphenylalaninemias, 18.5% (n:19) mild-PKU, 27.2% (n:28) moderate-PKU and 25.2 % (n:26) classical-PKU. Genotype/phenotype correlation was statistically significant (p<0.001) Overall concordance was 62,5%: 93.3% in hyperphenylalaninemia, 64.7% in mild-PKU and 65.4% in classical patients. The moderate-PKU showed a weak concordance (17%) with milder AV prediction than clinical assessment. 74% of discordant moderate patients harbored p.Arg261Gln, and p.Val388Met. Our cohort is highly heterogeneous, with predominant Mediterranean influence (mainly Spanish), but with differences with other Latin-American countries.

Highlights

IntroductionMore than 1100 variants have been reported in phenylalanine hydroxylase (PAH), and new data are continuously added to databases (http:// www.biopku.org/home/pah.asp) PAH pathogenic variants lead to impaired function of the hepatic enzyme which catalyzes the conversion of the essential amino acid L-phenylalanine (Phe) to L-tyrosine (Tyr) , a precursor of the neurotransmitters dopamine, noradrenaline, and adrenaline
Phenylketonuria (PKU, OMIM 261600) is an inborn error of metabolism of phenylalanine (Phe), predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene located on chromosome 12 (12q22-q24.2) [1]To date, more than 1100 variants have been reported in PAH, and new data are continuously added to databases PAH pathogenic variants lead to impaired function of the hepatic enzyme which catalyzes the conversion of the essential amino acid L-phenylalanine (Phe) to L-tyrosine (Tyr), a precursor of the neurotransmitters dopamine, noradrenaline, and adrenaline. the exact pathogenesis of the disease remains unclear, the defect causes Phenylalanine (Phe) accumulation and neurotransmitter depletion and, unless treated opportunely, patients suffer from intellectual impairment of different magnitude
More than 1100 variants have been reported in PAH, and new data are continuously added to databases PAH pathogenic variants lead to impaired function of the hepatic enzyme which catalyzes the conversion of the essential amino acid L-phenylalanine (Phe) to L-tyrosine (Tyr), a precursor of the neurotransmitters dopamine, noradrenaline, and adrenaline

Summary

Introduction

More than 1100 variants have been reported in PAH, and new data are continuously added to databases (http:// www.biopku.org/home/pah.asp) PAH pathogenic variants lead to impaired function of the hepatic enzyme which catalyzes the conversion of the essential amino acid L-phenylalanine (Phe) to L-tyrosine (Tyr) , a precursor of the neurotransmitters dopamine, noradrenaline, and adrenaline. The exact pathogenesis of the disease remains unclear, the defect causes Phenylalanine (Phe) accumulation (hyperphenylalaninemia) and neurotransmitter depletion and, unless treated opportunely, patients suffer from intellectual impairment of different magnitude. The disease is inherited as an autosomal recessive disorder, and its severity is a spectrum that reflects in the phenylalanine blood levels the residual activity of the affected enzyme. Buenos Aires, Argentina 2 Unidad de Metabolismo. Hospital de Niños “Sor Ludovica” de La Plata, Buenos Aires, Argentina 3 Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario

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