Dataset Information

Genotype-phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil.

ABSTRACT: BACKGROUND:Genetic heterogeneity and compound heterozygosis give rise to a continuous spectrum of phenylalanine hydroxylase deficiency and metabolic phenotypes in phenylketonuria (PKU). The most used parameters for evaluating phenotype in PKU are pretreatment phenylalanine (Phe) levels, tolerance for dietary Phe, and Phe overloading test. Phenotype can vary from a "classic" (severe) form to mild hyperphenylalaninemia, which does not require dietary treatment. A subset of patients is responsive to treatment by the cofactor tetrahydrobiopterin (BH4 ). Genotypes of PKU patients from Rio de Janeiro, Brazil, were compared to predicted and observed phenotypes. Genotype-based estimations of responsiveness to BH4 were also conducted. METHODS:Phenotype was defined by pretreatment Phe levels. A standard prediction system based on arbitrary assigned values was employed to measure genotype-phenotype concordance. Patients were also estimated as BH4 -responders according to the responsiveness previously reported for their mutations and genotypes. RESULTS:A 48.3% concordance rate between genotype-predicted and observed phenotypes was found. When the predicted phenotypes included those reported at the BIOPKU database, the concordance rate reached 77%. A total of 18 genotypes from 30 patients (29.4%) were estimated as of potential or probable BH4 responsiveness. Inconsistencies were observed in genotypic combinations including the common "moderate" mutations p.R261Q, p.V388M, and p.I65T and the mild mutations p.L48S, p.R68S, and p.L249F. CONCLUSION:The high discordance rate between genotype-predicted and observed metabolic phenotypes in this study seems to be due partially to the high frequency of the so-called "moderate" common mutations, p.R261Q, p.V388M, and p.I65T, which are reported to be associated to erratic or more severe than expected metabolic phenotypes. Although our results of BH4 estimated responsiveness must be regarded as tentative, it should be emphasized that genotyping and genotype-phenotype association studies are important in selecting patients to be offered a BH4 overload test, especially in low-resource settings like Brazil.

SUBMITTER: Vieira Neto E

PROVIDER: S-EPMC6503030 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Genotype-phenotype correlations and BH<sub>4</sub> estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil.

Vieira Neto Eduardo E Laranjeira Francisco F Quelhas Dulce D Ribeiro Isaura I Seabra Alexandre A Mineiro Nicole N Carvalho Lilian M LM Lacerda Lúcia L Ribeiro Márcia G MG

Molecular genetics & genomic medicine 20190303 5

<h4>Background</h4>Genetic heterogeneity and compound heterozygosis give rise to a continuous spectrum of phenylalanine hydroxylase deficiency and metabolic phenotypes in phenylketonuria (PKU). The most used parameters for evaluating phenotype in PKU are pretreatment phenylalanine (Phe) levels, tolerance for dietary Phe, and Phe overloading test. Phenotype can vary from a "classic" (severe) form to mild hyperphenylalaninemia, which does not require dietary treatment. A subset of patients is resp ...[more]

PMID: 30829006

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Project description:Phenylketonuria (PKU) is an autosomal recessive disease resulting from mutations in the PAH gene. Most of the patients are compound heterozygotes, and genotype is a major factor in determining the phenotypic variability of PKU. More than 1,000 variants have been described in the PAH gene. Rio de Janeiro's population has a predominance of Iberian, followed by African and Amerindian ancestries. It is expected that most PKU variants in this Brazilian state have originated in the Iberian Peninsula. However, rare European, African or pathogenic variants that are characteristic of the admixed population of the state might also be found. A total of 102 patients were included in this study. Genomic DNA was isolated from dried blood spots. Sanger sequencing was used for PAH gene variant identification. Deletions and duplications were also screened using MLPA analysis. Haplotypes were also determined. Nine (8.8%) homozygous and 93 (91.2%) compound heterozygous patients were found. The spectrum included 37 causative mutations. Missense, nonsense, and splicing pathogenic variants corresponded to 63.7%, 2.9%, and 22.6% of the mutant alleles, respectively. Large (1.5%), and small deletions, inframe (5.4%) and with frameshift (3.9%), comprised the remainder. The most frequent pathogenic variants were: p.V388M (12.7%), p.R261Q (11.8%), IVS10-11G>A (10.3%), IVS2+5G>C (6.4%), p.S349P (6.4%), p.R252W (5.4%), p.I65T (4.4%), p.T323del (4.4%), and p.P281L (3.4%). One novel variant was detected: c.934G>T (p.G312C) [rs763115697]. The three most frequent pathogenic variants in our study (34.8% of the alleles) were also the most common in other Brazilian states, Portugal, and Spain (p.V388M, p.R261Q, IVS10-11G>A), corroborating that the Iberian Peninsula is the major source of PAH mutations in Rio de Janeiro. Pathogenic variants that have other geographical origins, such IVS2+5G>C, p.G352Vfs*48, and IVS12+1G>A were also detected. Genetic drift and founder effect may have also played a role in the mutation spectrum we observed.

Project description:Trichophyton, Microsporum, Nannizzia and Epidermophyton genera cause dermatophytosis, the most common and highly contagious infectious skin disease. Rio de Janeiro is one of the most visited cities in the Southern Hemisphere, located in the most visited state of Brazil. This retrospective study investigated epidemiological and laboratorial aspects of dermatophytosis in Rio de Janeiro state, Brazil, by using spatiotemporal analysis. More than half of all individuals were infected by one or more dermatophytes. A variation between 18 and 106 years-old of the studied population was verified, and women more frequently affected. Patients were more frequently infected by Trichophyton spp., most of them T. rubrum, followed by T. mentagrophytes. M. canis and N. gypsea were more frequently isolated in the age group between 40 and 60 years old, while T. rubrum predominates among younger patients. All species presented homogeneous distribution while T. tonsurans appears to be restricted to the Rio de Janeiro capital and E. floccosum to the municipality of Macaé (190 Km apart from RJ). Rio de Janeiro state presented spatial clusters of dermatophytosis with high density in Guanabara Bay (E. floccosum, M. canis, N. gypsea, T. tonsurans) and Niterói (T. rubrum, T. mentagrophytes) but low density in Macaé (E. floccosum). Significant spatiotemporal clusters on dermatophytosis cases were detected in distinct municipalities (p-value ≤ 0.05). The Vulnerability Index (r = 0.293) and Demographic Density (r = 0.652) distributed according to neighborhoods in Niterói were direct related with dermatophytosis cases whereas Income (r = -0.306) was inversely correlated (p-value ≤ 0.05). The dermatophytosis spatiotemporal distinct distribution after two major international events in Rio de Janeiro, Brazil, highlight the pressing need for specific measures of its prevention and controlling. This is particularly relevant in touristic tropical localities which must consider both socio-economical and traveler's medicine variables.

Dataset Information

Genotype-phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil.

Publications

Genotype-phenotype correlations and BH<sub>4</sub> estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil.

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