Identification of Mutations in the Pah Gene in Pku Patients in the State of Mato Grosso

Costa, Roseli Divino; Galera, Bianca Borsatto; Rezende, Bianca Costa; Venâncio, Amanda Cristina; Galera, Marcial Francis

doi:10.1590/1984-0462/2020/38/2018351

Cited by 3 publications

(3 citation statements)

References 18 publications

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“…The incidence of PKU in a study carried out previously in the state of Mato Grosso (1:33,068) was similar to the data obtained in this research, 14 as well as in Santa Catarina and Tocantins (1:28,000). 15 The most prevalent disease in newborn screening programs is CH.…”

Section: Discussionsupporting

confidence: 89%

Evaluation of newborn screening in the state of Mato Grosso from 2005 to 2019

Costa,

Ferreira,

Rocha

et al. 2024

Rev. paul. pediatr.

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Objective: To evaluate quality indicators of the Neonatal Screening Referral Service of the state of Mato Grosso (NSRS-MT) from 2005 to 2019. Methods: Cross-sectional, retrospective, exploratory, descriptive, and observational study from 2005 to 2019. The following parameters were analyzed: age of newborns at the first collection, time between sample collection and arrival at the laboratory, time between the arrival and release of results and time between requesting the second sample and arrival at the NSRS. The population coverage of the program and the incidence of each clinical situation screened were also analyzed. Results: NSRS-MT coverage was analyzed and recorded as 76%. The incidence was analyzed for congenital hypothyroidism (CH) 1:1867, phenylketonuria (PKU) 1:33,311, sickle cell disease (SCD) 1:2004, cystic fibrosis (CF) 1:12,663, congenital adrenal hyperplasia (CAH) 1:15,843, and biotinidase deficiency (DB) 1:25,349. The median age (days) at the first consultation was: 44 for HC, 22 for PKU, 60 for DF, 52 for FC, 79 for HAC and 79 for DB. The mean time between exam collection and delivery to the NSRS was 8.4 days; between the arrival and release of results, 9 days; and for the return of recalls, 59 days. Conclusions: Regarding the coverage of the target population and collection at the ideal age, the NSRS-MT presents values below the national average. However, regarding the mean age at the time of the first consultation, the state's performance is better than the national.

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Section: Discussionsupporting

confidence: 89%

Evaluation of newborn screening in the state of Mato Grosso from 2005 to 2019

Costa,

Ferreira,

Rocha

et al. 2024

Rev. paul. pediatr.

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“…Of these variants, only p.Arg270Lys was not found in the present study. The variants p.Arg261Gln, p.Val388Met, and c.1066-11G>A are also frequent in the States of Mato Grosso do Sul and Minas Gerais [ 59 , 60 , 61 ]. The most common pathogenic variants in Argentina and Chile were p.Arg261Gln (10.6%) and p.Val388Met (17.2%), respectively [ 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

Phenylketonuria Diagnosis by Massive Parallel Sequencing and Genotype-Phenotype Association in Brazilian Patients

Tresbach

Sperb‐Ludwig

Ligabue-Braun

et al. 2020

Genes

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Phenylketonuria (PKU) is a common inborn error of amino acid metabolism in which the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine, is functionally impaired due to pathogenic variants in the PAH gene. Thirty-four Brazilian patients with a biochemical diagnosis of PKU, from 33 unrelated families, were analyzed through next-generation sequencing in the Ion Torrent PGM™ platform. Phenotype–genotype correlations were made based on the BioPKU database. Three patients required additional Sanger sequencing analyses. Twenty-six different pathogenic variants were identified. The most frequent variants were c.1315+1G>A (n = 8/66), c.473G>A (n = 6/66), and c.1162G>A (n = 6/66). One novel variant, c.524C>G (p.Pro175Arg), was found in one allele and was predicted as likely pathogenic by the American College of Medical Genetics and Genomics (ACMG) criteria. The molecular modeling of p.Pro175Arg indicated that this substitution can affect monomers binding in the PAH tetramer, which could lead to a change in the stability and activity of this enzyme. Next-generation sequencing was a fast and effective method for diagnosing PKU and is useful for patient phenotype prediction and genetic counseling.

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“…The PAH gene, mapped to chromosome 12q23.2, spans 90 kb and consists of 13 exons that are not equally distributed, as the exons are more condensed in the second moiety of the gene. The PAH gene's coding sequence is 1359 base pairs, which encode 452 amino acid polypeptides with a molecular weight of ~ 52 kDa [ 63 ]. The absence of TATA boxes characterizes the promoter region of the PAH gene.…”

Section: Genetic Etiologymentioning

confidence: 99%

Genetic etiology and clinical challenges of phenylketonuria

et al. 2022

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This review discusses the epidemiology, pathophysiology, genetic etiology, and management of phenylketonuria (PKU). PKU, an autosomal recessive disease, is an inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. The prevalence of PKU varies widely among ethnicities and geographic regions, affecting approximately 1 in 24,000 individuals worldwide. Deficiency in the PAH enzyme or, in rare cases, the cofactor tetrahydrobiopterin results in high blood Phe concentrations, causing brain dysfunction. Untreated PKU, also known as PAH deficiency, results in severe and irreversible intellectual disability, epilepsy, behavioral disorders, and clinical features such as acquired microcephaly, seizures, psychological signs, and generalized hypopigmentation of skin (including hair and eyes). Severe phenotypes are classic PKU, and less severe forms of PAH deficiency are moderate PKU, mild PKU, mild hyperphenylalaninaemia (HPA), or benign HPA. Early diagnosis and intervention must start shortly after birth to prevent major cognitive and neurological effects. Dietary treatment, including natural protein restriction and Phe-free supplements, must be used to maintain blood Phe concentrations of 120–360 μmol/L throughout the life span. Additional treatments include the casein glycomacropeptide (GMP), which contains very limited aromatic amino acids and may improve immunological function, and large neutral amino acid (LNAA) supplementation to prevent plasma Phe transport into the brain. The synthetic BH4 analog, sapropterin hydrochloride (i.e., Kuvan®, BioMarin), is another potential treatment that activates residual PAH, thus decreasing Phe concentrations in the blood of PKU patients. Moreover, daily subcutaneous injection of pegylated Phe ammonia-lyase (i.e., pegvaliase; PALYNZIQ®, BioMarin) has promised gene therapy in recent clinical trials, and mRNA approaches are also being studied.

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Identification of Mutations in the Pah Gene in Pku Patients in the State of Mato Grosso

Cited by 3 publications

References 18 publications

Evaluation of newborn screening in the state of Mato Grosso from 2005 to 2019

Evaluation of newborn screening in the state of Mato Grosso from 2005 to 2019

Phenylketonuria Diagnosis by Massive Parallel Sequencing and Genotype-Phenotype Association in Brazilian Patients

Genetic etiology and clinical challenges of phenylketonuria

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