The study of the full spectrum of variants leading to hyperphenylalaninemia have revealed 10 new variants in the PAH gene

Kuznetcova, I.; Гундорова, П.; Рыжкова, О. П.; Polyakov, A. V.

doi:10.1007/s11011-019-00461-w

Cited by 6 publications

(6 citation statements)

References 18 publications

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“…Thus, the prevalence of HPABH 4 (0.87%) is probably overvalued. Really it accounts for around 0.5%, as shown before by Kuznetcova et al [ 22 ].…”

Section: Discussionsupporting

confidence: 62%

“…Probands № 18–22 were previously described by our group, Kuznetcova et al [ 22 ]. This study presents updated information on these families, with family examination and biochemical analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Pterin profile analysis became available in 2018 in Moscow and is carried out for the patients’ urine samples on individual request. Among patients with a PKU or HPA diagnosis, rare HPA types are detected by DNA diagnostics, including the Next generation sequencing (NGS) panel method [ 22 ]. In this study we present comprehensive data on Russian patients with rare HPA forms.…”

Section: Introductionmentioning

confidence: 99%

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BH4-deficient hyperphenylalaninemia in Russia

et al. 2021

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A timely detection of patients with tetrahydrobiopterin (BH4) -deficient types of hyperphenylalaninemia (HPABH4) is important for assignment of correct therapy, allowing to avoid complications. Often HPABH4 patients receive the same therapy as phenylalanine hydroxylase (PAH) -deficiency (phenylketonuria) patients—dietary treatment—and do not receive substitutive BH4 therapy until the diagnosis is confirmed by molecular genetic means. In this study, we present a cohort of 30 Russian patients with HPABH4 with detected variants in genes causing different types of HPA. Family diagnostics and biochemical urinary pterin spectrum analyses were carried out. HPABH4A is shown to be the prevalent type, 83.3% of all HPABH4 cases. The mutation spectrum for the PTS gene was defined, the most common variants in Russia were p.Thr106Met—32%, p.Asn72Lys—20%, p.Arg9His—8%, p.Ser32Gly—6%. We also detected 7 novel PTS variants and 3 novel QDPR variants. HPABH4 prevalence was estimated to be 0.5–0.9% of all HPA cases in Russia, which is significantly lower than in European countries on average, China, and Saudi Arabia. The results of this research show the necessity of introducing differential diagnostics for HPABH4 into neonatal screening practice.

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“…Thus, the prevalence of HPABH 4 (0.87%) is probably overvalued. Really it accounts for around 0.5%, as shown before by Kuznetcova et al [ 22 ].…”

Section: Discussionsupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BH4-deficient hyperphenylalaninemia in Russia

et al. 2021

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“…To date, there are no available data to estimate the proportion of large rearrangements unnoticed for Sanger sequencing methodology, which are expected in less than 1% of PAH-related HPA patients worldwide [3]. At least in Russian patients, gross exonic deletions (mainly involving exon 3 and 5) identified by Multiplex Ligationdependent Probe Amplification (MLPA) analysis account for 0.39% of pathogenic PAH alleles [29]. Thus, in these four patients with monoallelic genotypes-who presented persistent HPA, three of which required nutritional treatment-further studies, such as MLPA analysis, could be an option in order to discard gross PAH rearrangements.…”

Section: Discussionmentioning

confidence: 99%

An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations

Vela-Amieva

Alcántara-Ortigoza

Ibarra-González

et al. 2021

Genes

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Establishing the genotypes of patients with hyperphenylalaninemia (HPA)/phenylketonuria (PKU, MIM#261600) has been considered a cornerstone for rational medical management. However, knowledge of the phenylalanine hydroxylase gene (PAH) mutational spectrum in Latin American populations is still limited. Herein, we aim to update the mutational PAH spectrum in the largest cohort of HPA/PKU Mexican patients (N = 124) reported to date. The biallelic PAH genotype was investigated by Sanger automated sequencing, and genotypes were correlated with documented biochemical phenotypes and theoretical tetrahydrobiopterin (BH4) responsiveness. Patients were biochemically classified as having classic PKU (50%, 62/124), mild PKU (20.2%, 25/124) and mild HPA (29.8%, 37/124). Furthermore, 78.2% of the included patients (97/124) were identified by newborn screening. A total of 60 different pathogenic variants were identified, including three novel ones (c. 23del, c. 625_626insC and c. 1315 + 5_1315 + 6insGTGTAACAG), the main categories being missense changes (58%, 35/60) and those affecting the catalytic domain (56.6%, 34/60), and c. 60 + 5G > T was the most frequent variant (14.5%, 36/248) mainly restricted (69.2%) to patients from the central and western parts of Mexico. These 60 types of variants constituted 100 different biallelic PAH genotypes, with the predominance of compound-heterozygous ones (96/124, 77%). The expected BH4 responsiveness based on the PAH genotype was estimated in 52% of patients (65/124), mainly due to the p. (Val388Met) (rs62516101) allele. Instead, our study identified 27 null variants with an allelic phenotype value of zero, with a predominance of c. 60 + 5G > T, which predicts the absence of BH4 responsiveness. An identical genotype reported in BIOPKUdb was found in 92/124 (74%) of our patients, leading to a genotype–phenotype concordance in 80/92 (86.9%) of them. The high number of variants found confirms the heterogeneous and complex mutational landscape of HPA/PKU in Mexico.

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“…To date, more than 1000 mutations have been described and reported in the locus-specific PAH database (http://www.biopku. org, accessed on 23 December 2021), including single-nucleotide variants (SNVs), short insertions and deletions (InDels) and large structural variants (SVs) [29][30][31].…”

Section: Genetics Of Hyperphenylalaninemiamentioning

confidence: 99%

The Utility of Genomic Testing for Hyperphenylalaninemia

Tendi

Guarnaccia

Morello

et al. 2022

JCM

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Hyperphenylalaninemia (HPA), the most common amino acid metabolism disorder, is caused by defects in enzymes involved in phenylalanine metabolism, with the consequent accumulation of phenylalanine and its secondary metabolites in body fluids and tissues. Clinical manifestations of HPA include mental retardation, and its early diagnosis with timely treatment can improve the prognosis of affected patients. Due to the genetic complexity and heterogeneity of HPA, high-throughput molecular technologies, such as next-generation sequencing (NGS), are becoming indispensable tools to fully characterize the etiology, helping clinicians to promptly identify the exact patients’ genotype and determine the appropriate treatment. In this review, after a brief overview of the key enzymes involved in phenylalanine metabolism, we represent the wide spectrum of genes and their variants associated with HPA and discuss the utility of genomic testing for improved diagnosis and clinical management of HPA.

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The study of the full spectrum of variants leading to hyperphenylalaninemia have revealed 10 new variants in the PAH gene

Cited by 6 publications

References 18 publications

BH4-deficient hyperphenylalaninemia in Russia

BH4-deficient hyperphenylalaninemia in Russia

An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations

The Utility of Genomic Testing for Hyperphenylalaninemia

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