Phenylalanine hydroxilase (PAH) Genotyping in PKU Argentine

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

CABA

Congreso; XI Congreso Latinoamericano de errores congénitos del metabolismo y pesquisa neonatal; 2019

Sociedad latinoamericana de errores congenitos y pesquisa neonatal (SLEIMPN)

Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism that leads to severe mental retardation and is predominantly caused by mutations in the phenylalanine hydroxylase gene. Objective To characterize genotypically a cohort of Argentinean patientsMethods Genotyping was carried out in 103 Argentine PKU patients from 90 unrelated families. The cohort included 12 pair of siblings that had an identical phenotype and genotype and 1 pair of discordant brothers that shared only one common allele.101patients were completely characterized and in 2 only 1 mutation was found..51 known pathogenic mutations and 3 new variants were found by sanger sequencing . 9,7% individuals were homozygous . Mutations were distributed along the 13 exons and concentrated in exon 7(30%) exon 11(10%), exon2 (8%) exon 12 ( 6%) and exon 10 (6%). 64% were missense, 8% nonsense , 14% frameshift and 12% affected splicing. 65 % were placed in the enzyme catalytic domain, 15% in the regulatory and 8% in the oligomerization zone.Regarding allele frequency (AF) calculated excluding one of the coincident siblings the 9 more frequent mutation that accounted for 57% of 179 alleles were : p.R261Q (AF:10.6%), c.1066-11G>A(AF:9,5%). p.R408W (AF:8,30%), p.Y414C(AF: 5,50%)p.A403V(AF:5%) p.V388M( AF:5%) p.R158Q(AF:5%) p.L48S(AF:4%) and p.I65T(AF:4%). Predicted phenotype was assigned by Guldberg activity value (AV) and compared with the classification of phenotype based in tolerance to Phe intake assessed between 4 and 7 years of age under stable conditions. Based on tolerance 31% were hyperphenilalaninemias 16.5%were mild PKU 29% moderate PKU and 23.5 % severe PKU Overall concordance with predicted phenotype was 63% with coincidence between prediction and clinical assessment of 93% in HPA, 73% in mild PKU and 63% in severe patients. Nevertheless a weak concordance (21%) was found in the moderate PKU group where AV prediction was milder that the one assessed by tolerance.In this group 68% of patients harboured p.R261Q and p.V388M mutations . Conclusion: PAH gene mutation spectrum in our cohort is highly heterogeneous, with predominant Mediterranean influence ( mainly Spanish ) , but with differences with other Latin-American countries .The finding of R261Q and V388M mutations influenced the phenotype prediction