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MeSH: methylentetrahydrofolátreduktasa (NADPH2)-metabolismus

12 záznamů v Články Filtry

Článek

Newborn screening for homocystinurias: Recent recommendations versus current practice

Keller, Rebecca
Autor Keller, Rebecca Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. radiz-Rare Disease Initiative Zürich, Clinical Research Priority Program, University of Zürich, Zürich, Switzerland
Chrastina, Petr
Autor Chrastina, Petr Department of Pediatrics and Adolescent Medicine, Charles University-First Faculty of Medicine and General University Hospital, Ke Karlovu 2, 128 08 Praha 2, Czech Republic
Pavlíková, Markéta
Autor Pavlíková, Markéta Department of Pediatrics and Adolescent Medicine, Charles University-First Faculty of Medicine and General University Hospital, Ke Karlovu 2, 128 08 Praha 2, Czech Republic. Department of Probability and Mathematical Statistics, Charles University-Faculty of Mathematics and Physics, Prague, Czech Republic
Gouveia, Sofía
Autor Gouveia, Sofía Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, S. Neonatology, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
Ribes, Antonia
Autor Ribes, Antonia Division of Inborn Errors of Metabolism, Department of Biochemistry and Molecular Genetics, Hospital Clinic de Barcelona, CIBERER, Barcelona, Spain
Kölker, Stefan
Autor Kölker, Stefan Division of Neuropaediatrics and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
Blom, Henk J
Autor Blom, Henk J Department of Internal Medicine, VU Medical Center, Amsterdam, The Netherlands
Baumgartner, Matthias R
Autor Baumgartner, Matthias R Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. radiz-Rare Disease Initiative Zürich, Clinical Research Priority Program, University of Zürich, Zürich, Switzerland
Bártl, Josef
Autor Bártl, Josef Department of Pediatrics and Adolescent Medicine, Charles University-First Faculty of Medicine and General University Hospital, Ke Karlovu 2, 128 08 Praha 2, Czech Republic
Dionisi-Vici, Carlo
Autor Dionisi-Vici, Carlo Division of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy

Journal of inherited metabolic disease. 2019 ; 42 (1) : 128-139. [pub] -

J Inherit Metab Dis
ISSN 1573-2665
Medvik
Zdroj

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

Článek

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry

Journal of inherited metabolic disease. 2019 ; 42 (2) : 333-352. [pub] 20190217

J Inherit Metab Dis
ISSN 1573-2665
Medvik
Zdroj

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

MeSH
dítě MeSH
dospělí MeSH
fenotyp MeSH
homocystinurie metabolismus MeSH
kojenec MeSH
kyselina methylmalonová moč MeSH
lidé MeSH
methylentetrahydrofolátreduktasa (NADPH2) nedostatek metabolismus MeSH
metylace MeSH
mladiství MeSH
mladý dospělý MeSH
novorozenec MeSH
předškolní dítě MeSH
progrese nemoci MeSH
průřezové studie MeSH
psychotické poruchy metabolismus MeSH
registrace MeSH
retrospektivní studie MeSH
svalová spasticita metabolismus MeSH
těhotenství MeSH
věk při počátku nemoci MeSH
vitamin B 12 metabolismus MeSH
vrozené poruchy metabolismu aminokyselin diagnóza terapie MeSH
Check Tag
dítě MeSH
dospělí MeSH
kojenec MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
mužské pohlaví MeSH
novorozenec MeSH
předškolní dítě MeSH
těhotenství MeSH
ženské pohlaví MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH
Geografické názvy
Evropa MeSH

Článek

Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency

Human mutation. 2016 ; 37 (5) : 427-38. [pub] 20160318

Hum Mutat
ISSN 1098-1004
Medvik
Zdroj

Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations.

MeSH
databáze genetické MeSH
homocystinurie genetika MeSH
katalytická doména MeSH
lidé MeSH
methylentetrahydrofolátreduktasa (NADPH2) chemie nedostatek genetika metabolismus MeSH
modely nemocí na zvířatech MeSH
mutace * MeSH
novorozenec MeSH
novorozenecký screening MeSH
psychotické poruchy genetika MeSH
svalová spasticita genetika MeSH
věk při počátku nemoci MeSH
zvířata MeSH
Check Tag
lidé MeSH
novorozenec MeSH
zvířata MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations

Cancer chemotherapy and pharmacology. 2015 ; 76 (5) : 1081-91. [pub] 20150805

Cancer Chemother Pharmacol
ISSN 1432-0843
Medvik
Zdroj

PURPOSE: To describe concentration versus time profiles of capecitabine and its metabolites 5'-DFUR, 5'-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR). METHODS: In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA. RESULTS: Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0-t(last) and C max were 96.7 % (98 % CI 90.7-103.2 %) and 87.2 % (98 % CI 74.9-101.5 %), respectively. Within-subject variability for AUC0-t(last) and C max (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043). CONCLUSIONS: The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.

Článek

Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients

Human mutation. 2015 ; 36 (6) : 611-21. [pub] 20150427

Hum Mutat
ISSN 1098-1004
Medvik
Zdroj

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%-42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide-responsiveness, and 24 abnormal kinetics of S-adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N-terminal catalytic domain, whereas missense mutations in the C-terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S-adenosylmethionine. Characterization of patients in this way provides a basis for improved diagnosis using expanded enzymatic criteria, increases understanding of the molecular basis of MTHFR dysfunction, and points to the possible role of cofactor or substrate in the treatment of patients with specific mutations.

MeSH
aktivace enzymů MeSH
alely MeSH
alternativní sestřih MeSH
exony MeSH
fibroblasty metabolismus MeSH
genetické asociační studie * MeSH
homocystinurie diagnóza genetika metabolismus MeSH
introny MeSH
jednonukleotidový polymorfismus MeSH
kinetika MeSH
lidé MeSH
methylentetrahydrofolátreduktasa (NADPH2) nedostatek genetika metabolismus MeSH
mutace MeSH
psychotické poruchy diagnóza genetika metabolismus MeSH
stabilita proteinů MeSH
svalová spasticita diagnóza genetika metabolismus MeSH
Check Tag
lidé MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

The impact of C677T and A1298C MTHFR polymorphisms on methotrexate therapeutic response in East Bohemian region rheumatoid arthritis patients

Rheumatology international. 2015 ; 35 (7) : 1149-61. [pub] 20150125

Rheumatol Int
ISSN 1437-160X
Medvik
Zdroj

Some single-nucleotide polymorphisms (SNPs) might be predictive of methotrexate (MTX) therapeutic outcome in rheumatoid arthritis (RA). The aim of this study was to determine whether SNPs in the methylenetetrahydrofolate reductase (MTHFR) gene are predictive of MTX response. Comparison was made using EULAR response criteria and according to the change of DAS28 (∆DAS28) after a 6-month MTX treatment in RA patient cohort. The two SNPs C677T (rs1801133) and A1298C (rs1801131) have been genotyped. A total of 120 patients were enrolled in the study, and all of them fulfilled the American College of Rheumatology 1987 RA criteria and are currently or previously taking MTX oral treatment, either as a monotherapy (n = 65) or in a combination with other disease-modifying antirheumatic drugs (n = 55). Genotyping was performed using qPCR allelic discrimination. We did not found any association of C677T and A1298C genotypes with MTX treatment inefficacy in dominant model (OR 1.23, 95 % CI 0.57-2.65, P = 0.697; and OR 0.98, 95 % CI 0.47-2.14, P = 1.0, respectively), or in recessive and codominant models. However, when ∆DAS28 after a 6-month therapy was used as a measure of treatment efficacy, the 677CT and 1298AC genotypes were found to be significantly associated with less favorable response to MTX (P = 0.025 and P = 0.043, respectively). In addition, even lower ∆DAS28 was determined for double-mutated 677CT-1298AC heterozygotes. It means that a synergistic effect of 677CT and 1298AC genotypes was observed. Nevertheless, the DAS28 baseline was lower here comparing to other genotypes. Unexpectedly, quite the opposite trend-i.e., better response to MTX-was found in genotypes 677CC-1298CC and 677TT-1298AA. It is an intriguing finding, because these double-mutated homozygotes are known for their low MTHFR-specific activity. Global significance was P = 0.013, η (2) = 0.160-i.e., large-size effect. Thus, our data show greater ability of 677CC-1298CC and 677TT-1298AA genotypes to respond to MTX treatment.

MeSH
antirevmatika škodlivé účinky metabolismus terapeutické užití MeSH
dospělí MeSH
farmakogenetika MeSH
fenotyp MeSH
heterozygot MeSH
homozygot MeSH
jednonukleotidový polymorfismus * MeSH
lidé středního věku MeSH
lidé MeSH
lineární modely MeSH
logistické modely MeSH
methotrexát škodlivé účinky metabolismus terapeutické užití MeSH
methylentetrahydrofolátreduktasa (NADPH2) genetika metabolismus MeSH
odds ratio MeSH
polymerázová řetězová reakce MeSH
prospektivní studie MeSH
průřezové studie MeSH
retrospektivní studie MeSH
revmatoidní artritida diagnóza farmakoterapie enzymologie genetika MeSH
rizikové faktory MeSH
senioři nad 80 let MeSH
senioři MeSH
výsledek terapie MeSH
Check Tag
dospělí MeSH
lidé středního věku MeSH
lidé MeSH
mužské pohlaví MeSH
senioři nad 80 let MeSH
senioři MeSH
ženské pohlaví MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH
Geografické názvy
Česká republika MeSH

Článek

Patologie kyseliny listové a těhotenství
[Pathology of folic acid and pregnancy]

Koucký, Michal
Autor Autorita ORCID Gynekologicko-porodnická klinika 1. LF UK a VFN, Praha

Via practica. 2012 ; 9 (2) : 75-78.

ISSN 1336-4790
Medvik
Zdroj

Článek

Rare allelic variants determine folate status in an unsupplemented European population

The Journal of nutrition. 2012 ; 142 (8) : 1403-9.

J Nutr
ISSN 1541-6100
Medvik
Zdroj

The role of folates as coenzymes in 1-carbon metabolism and the clinical consequences of disturbed folate metabolism are widely known. Folate status is a complex trait determined by both exogenous and endogenous factors. This study analyzed the association between 12 genetic variants and folate status in a Czech population with no folate fortification program. These 12 genetic variants were selected from 56 variant alleles found by resequencing the coding sequences and adjacent intronic regions of 6 candidate genes involved in folate metabolism or transport (FOLR1, FOLR2, FOLR3, MTHFR, PCFT, and RFC) from 29 individuals with low plasma and erythrocyte folate concentrations. Regression analyses of a cohort of 511 Czech controls not taking folate supplements revealed that only 2 variants in the MTHFR gene were associated with altered folate concentrations in plasma and/or erythrocytes. In our previous study, we observed that the common variant MTHFR c.665C > T (known as c.677C > T; p.A222V) was associated with decreased plasma folate concentrations. In the present study, we show in addition that the rare variant MTHFR c.1958C > T (p.T653M) is associated with significantly increased erythrocyte folate concentrations (P = 0.02). Multivariate regression analysis revealed that this uncommon variant, which is present in 2% of Czech control chromosomes, explains 0.9% of the total variability of erythrocyte folate concentrations; the magnitude of this effect size was comparable with that of the common MTHFR c.665C > T variant. This result indicates that the rare genetic variants may determine folate status to a similar extent as the common allelic variant.