PKU genotype in Argentinian patients

R ENACAN,; L FERNANDEZ; C FRAGA; N SPECOLA ; L PRIETO ; MG VALLE ; F SANTOS SIMARRO; A CHIESA; M NUÑEZ MIÑANA; M SALERNO; P. LAPUNZINA

Rio de Janeiro

Congreso; 13th International Congress of Inborn Errors of Metabolism .; 2017

SOCIEDAD LATINOAMERICANA DE ERRORES CONGENITOS Y PESQUISA NEONATAL (SLEIMPN)

Background: In Phenylketonuria (PKU), the most frequent protein congenital metabolic disorder, over 900 mutations in the PAH gene (NM_000277.1) have been described (www.pahdb.mcgill.ca). The available data on PAH mutations are useful for the understanding of the clinical features although genotype/phenotype correlations are not always conclusive.In Argentina 1:13000 newborn are affected with either any clinical forms of the disease.Objective: To describe the genotype of a large group of Argentinean PKU patients. Patients and methods: 82 PKU patients of 72 families with hyperphenylalaninemia were genotyped. 10 pair of siblings were included (1 with discordant phenotype). According to their phenylalanine tolerance at age 4-7, patients were classified as classic (n:30) with Phe intake 1200 mg/day). DNA from peripheral blood lymphocytes was extracted. Codifying and adjacent intronic regions of the 13 exons of the PAH gene were amplified by PCR and sequenced by Sanger. Allelic frequency was calculated for the whole cohort and for each phenotypic group.Results: 49 different mutations of the PAH gene were identified. 90% of patients were compound heterozygotes. The 9 pair of siblings with similar phenotype had an identical genotype while the discordant one had also a discordant genotype, presenting only one common allele. So, 145 PKU alleles from 73 patients were analyzed.Nine mutations accounted for 53.6% of mutated alleles p.R408W (9.6%), p.R261Q (8.3%), p.A403V (6.2%), p.V308M (5.5%), p.Y414C ( 5.5%), p.I65T (4.8%), p.L68S (4,8%), p.R158Q (4,8%) and c.1066-11G>A (4.1%).With great heterogeneity the most prevalent mutations in the classical group were p.R408W, p.R158Q, c782G>A and c.1066-11G>A that were found in 30% of alleles in this group. p.R261Q, p.V388M, p.E390G, p.I65T, p.Y414C, p.L48S affected 50% of alleles of the moderate group. Mild forms harbored p.L48S, p.A403V, p.IVS1216A, p.R408W and p.I306V representing 61% of alleles while in PHPA predominant mutations (73%) were p.A403V and p.R408W. Conclusion: We describe the distribution and frequency of PKU mutations in the Argentinean population confirming a high heterogeneity. This findings will surely be useful for the understanding of PKU in our country and will help in the individual follow up of affected patients.