Disorders of Tetrahydrobiopterin Metabolism: Experience from South India

Ray, Somdattaa; Padmanabha, Hansashree; Gowda, Vykuntaraju K; Mahale, Rohan; Christopher, Rita; Sreedharan, Shruthy; Dhar, Debjyoti; Kamate, Mahesh; Nagappa, Madhu; Bhat, Maya; Anjanappa, Rammurthy; Arunachal, Gautham; Mailankody, Pooja; Mathuranath, P. S.; Chandra, Sadandavalli Retnaswami

doi:10.1007/s11011-021-00889-z

Cited by 6 publications

(5 citation statements)

References 32 publications

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“…The frequency of PCD deficiency in the present study was 7.1%, exceeding the 2.6% reported in BIODEFdb (BIODEFdb), which could suggest that the frequency of the different BH4 disorders varies among populations ( Souza et al, 2018 ; Carducci et al, 2020 ; Bozaci et al, 2021 ; Gundorova et al, 2021 ; Ray et al, 2022 ). We only found one homozygous c.289G > A or p.(Glu97Lys) male patient.…”

Section: Discussioncontrasting

confidence: 86%

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

et al. 2022

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Background: Pterin profiles or molecular analyses of hyperphenylalaninemia (HPA) caused by phenylalanine hydroxylase (PAH) deficiency or tetrahydrobiopterin deficiency (BH4D) are not always available in low- or middle-income countries, including Mexico, limiting information regarding the phenotypic and genotypic characteristics of patients exhibiting BH4D.Objective: To report the genotypes underlying BH4D and the clinical presentation in unrelated Mexican HPA pediatric patients with normal PAH genotypes who attended a single metabolic reference center in Mexico.Methods: Automated Sanger sequencing of the PTS, QDPR, and PCBD1 genes of 14 HPA patients was performed. Predicted effects on protein structure caused by missense variants were assessed by in silico protein modeling.Results and discussion: A high prevalence of BH4D was noted in our HPA cohort (9.8%, N = 14/142). Clinically relevant biallelic genotypes were identified in the PTS (N = 7/14 patients), QDPR (N = 6/14 patients), and PCBD1 (N = 1/14 patients) genes. Four novel QDPR variants [c.714dup or p.(Leu239Thrfs*44), c.106-1G>T or p.(?), c.214G>T or p.(Gly72*), and c.187_189dup or p.(Gln63dup)] were identified. In silico protein modeling of six missense variants of PTS [p.(Thr67Met), p.(Glu81Ala), and p.(Tyr113Cys)], QDPR [p.(Cys161Phe) and p.(Pro172Leu)], and PCBD1 [p.(Glu97Lys)] supports their pathogenicity. Progressive neurological symptoms (mainly intellectual and motor impairment and even death in three patients) were noted in all patients with biallelic QDPR genotypes and in 5/7 patients bearing biallelic PTS genotypes. The single homozygous PCBD1 p.(Glu97Lys) patient remains asymptomatic.Conclusion: A higher proportion of BH4D (9.8 vs. 1%–2% worldwide), attributable to a heterogeneous mutational spectrum and wide clinical presentation, was noted in our Mexican HPA cohort, with the PTS-related HPA disorder being the most frequent. Sequencing-based assays could be a reliable approach for diagnosing BH4D in our population.

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Section: Discussioncontrasting

confidence: 86%

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

et al. 2022

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“…His clinical exome analysis revealed a homozygous likely pathogenic variant in exon 4, c.200C>T (pThr67Met) in the PTS gene, causing hyperphenylalaninemia, BH4-deficient, A. There is a case series from India on BH4-deficient hyperphenylalaninemia, and it reported one patient with a PTS gene mutation and a similar phenotype as seen in our patient [19].…”

Section: Discussionsupporting

confidence: 70%

Spectrum of Common and Rare Small Molecule Inborn Errors of Metabolism Diagnosed in a Tertiary Care Center of Maharashtra, India

Tamrakar¹,

Kale²,

Magar³

et al. 2022

Cureus

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Inborn errors of metabolism (IEM) form a large group of genetic diseases involving defects in genes coding for enzymes, receptors, and cofactors in the metabolic pathways of small and large molecules. The present study is the comprehensive data analysis of the tandem mass spectrometry (TMS) and urine metabolic pattern for the diagnosis of IEMs by gas chromatography and mass spectrometry (GC/MS) in samples received for high-risk IEM screening. MethodsWe conducted a retrospective analysis of children diagnosed with IEMs presenting at the genetic clinic of Mahatma Gandhi Missions (MGM) Medical College, Aurangabad. This article summarizes retrospective data of 40 pediatric cases over a three-year period, diagnosed with small molecule IEM based on the standard testing criteria. ResultsOut of 40, 17 patients (42.5%) were found to have organic acidemias, four (10%) had fatty acid oxidation defects, six (15%) had disorders of aminoacidopathies, seven (17.5%) had mitochondrial diseases, and three (7.5%) had urea cycle defects. One patient in each group (2.5% each) had carbohydrate metabolism defects, purine metabolic defects, and neurotransmitter metabolic defects. ConclusionsThis clinico-etiological profile study has thrown light on the clinical features and natural course of many common and rare IEMs, and it may provide clinicians with a deeper understanding of these conditions, allowing for improved early diagnosis and treatment of these diseases. Because of the high degree of consanguinity and marriages in the same community, common as well as many rare inherited metabolic diseases were diagnosed and novel genetic variants were identified.

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“…As an effective and cost-beneficial strategy for BH4D, many countries have conducted NBS in such cases. ( Li et al, 2018 ; Souza et al, 2018 ; Ray et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Mutation spectrum of PTS gene in patients with tetrahydrobiopterin deficiency from jiangxi province

et al. 2022

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Background: Hyperphenylalaninemia (HPA) is the most common inborn error in amino acid metabolism. It can be primarily classified into phenylalanine hydroxylase (PAH) deficiency and tetrahydrobiopterin (BH4) deficiency. BH4 deficiency (BH4D) is caused by genetic defects in enzymes involved in the biosynthesis and regeneration of BH4. 6-pyruvoyl-tetrahydropterin synthase (PTPS/PTS), which is encoded by the PTS gene, participates in the biosynthesis of BH4. PTPS deficiency (PTPSD) is the major cause of BH4D. In this study, we investigated that the prevalence of BH4D in Jiangxi province was approximately 12.5 per 1,000,000 live births (69/5,541,627). Furthermore, the frequency of BH4D was estimated to be 28.8% (69/240) in the HPA population of Jiangxi. In this study, we aimed to characterize the mutational spectrum of the PTS gene in patients with PTPSD from Jiangxi province.Method: Newborn screening data of Jiangxi province from 1997 to 2021 were analyzed and 53 families with PTPSD were enrolled for the analysis of the PTS gene variants by Sanger sequencing.Results: 106 variants were identified in 106 alleles of 53 patients with PTPSD, including 13 types of variants reported previously, and two novel variants (c.164-36A>G and c.146_147insTG). The predominant variant was c.259C>T (47.2%), followed by c.84-291A>G (19.8%), c.155A>G (8.5%), c.286G>A (6.6%) and c.379C>T (4.7%).Conclusion: The results of this study can not only provide guidance for the molecular diagnosis and genetic counseling in cases of PTPS deficiency but also enrich the PTS mutation database.

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Disorders of Tetrahydrobiopterin Metabolism: Experience from South India

Cited by 6 publications

References 32 publications

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

Spectrum of Common and Rare Small Molecule Inborn Errors of Metabolism Diagnosed in a Tertiary Care Center of Maharashtra, India

Mutation spectrum of PTS gene in patients with tetrahydrobiopterin deficiency from jiangxi province

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