[A case of acute lymphoblastic leukemia of MTHFR C677T gene positive with methotrexate hypersensitivity was successfully rescued by hemodialysis].
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SUBMITTER: Ren LW
PROVIDER: S-EPMC8295620 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC10981894 | biostudies-literature
Project description:MTHFR is a crucial enzyme in folate metabolism. This study aimed to determine the relationship between MTHFR genetic polymorphism and elimination and toxicities of methotrexate (MTX). To do that, the study enrolled 145 patients diagnosed with acute lymphoblastic leukemia, who received chemotherapy following the Chinese Children's Cancer Group Acute Lymphoblastic Leukemia (CCCG-ALL)-2015 protocol (clinical trial number: ChiCTR-IPR-14005706). We analyzed the effects of MTHFR C677T and A1298C polymorphisms on MTX elimination and toxicities. Patients with the MTHFR C677T TT genotype could tolerate a significantly higher MTX dose than those with the CC/CT genotype. However, patients with C677T TT genotypes had an increased risk of hypokalemia (1.369 to CC and 1.409 to CT types). The MTX infusion rate in patients with the MTHFR A1298C AC genotype was slightly lower than that in those with CC or AA genotypes. Patients with the A1298C AA genotype had a 1.405-fold higher risk of hepatotoxicity than those with the AC genotype (P > 0.05). There was no significant difference between the prevalence of other toxicities among MTHFR C677T or A1298C genotypes (P > 0.05). Neither MTHFR C677T nor A1298C polymorphisms were significantly associated with delayed MTX clearance. To conclude, MTHFR polymorphisms were not good predictors of MTX-related toxicities.
| S-EPMC8572804 | biostudies-literature
Project description:PurposeMethotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity.Patients and methodsProspective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities.ResultsFourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity.ConclusionMTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.
| S-EPMC3948096 | biostudies-literature
Project description:Drug resistance is a fundamental clinical concern in pediatric acute lymphoblastic leukemia (pALL), and methotrexate (MTX) is an essential chemotherapy drug administered for the treatment. In the current study, the effect of iron in response to methotrexate and its underlying mechanisms were investigated in pALL cells. CCRF-CEM and Nalm6 cell lines were selected as T and B-ALL subtypes. Cells were pretreated with ferric ammonium citrate, exposed to the IC50 concentration of MTX and cell viability was assessed using MTT, colony formation, and flow cytometry assays. Iron-loaded cells were strongly resistant to MTX cytotoxicity. The inhibitory effect of N-acetyl cysteine to reverse the acquired MTX resistance was greater than that of the iron chelator, deferasirox, highlighting the importance of iron-mediated ROS in MTX resistance. Subsequently, the upregulation of BCL2, SOD2, NRF2, and MRP1 was confirmed using quantitative RT-PCR. Moreover, a positive correlation was demonstrated between the MRP1 expression levels and bone marrow iron storage in pALL patients. Further supporting our findings were the hematoxylin and eosin-stained histological sections showing that iron-treated nude mice xenografts demonstrated significantly more liver damage than those unexposed to iron. Overall, iron is introduced as a player with a novel role contributing to methotrexate resistance in pALL. Our findings suggest that the patients' bone marrow iron stores are necessary to be assessed during the chemotherapy, and transfusions should be carefully administrated.
| S-EPMC7221302 | biostudies-literature
Project description:AimTo investigate the relationships of polymorphisms in genes whose protein products are related in the metabolic pathway of folic acid, particularly MTRR A66G, RFC1 G80A, and MTHFR C677T and A1298C, and disease activity in Mexican patients with rheumatoid arthritis (RA) treated with methotrexate (MTX).Materials and methodsSixty-eight patients with RA were included in the study who were being treated with MTX, either with or without other drugs. In addition to general data, disease activity was measured by the disease activity score 28 (DAS28). Single nucleotide polymorphisms (SNPs) genotyping was performed by allelic discrimination using real-time polymerase chain reaction.ResultsDifferences in genotype (homozygotic or heterozygotic for each allele), allele distributions, and phenotype were not statistically different between the RA group and control populations. We did not find any association between the studied polymorphisms and disease activity nor with the intragroup variables (e.g., clinical activity, body mass index, and single- or combined-drug treatment) or between genetic markers; we also did not find any association within the RA group or between the RA group and control populations.ConclusionAdditional studies of more polymorphisms related to this or other metabolic pathways are required to determine the influence of genetics on disease activity in RA.
| S-EPMC5695735 | biostudies-literature
Project description:Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism.
| S-EPMC4241316 | biostudies-literature
Project description:Sixty-three children (1-14 years of age) newly diagnosed with T-cell acute lymphoblastic leukemia were treated from January 2001 to December 2014. Patient outcomes were evaluated based on the regimen received; Capizzi methotrexate (C-MTX) vs. high-dose methotrexate (HDMTX). Complete remission (CR) was achieved in 54 of 60 (90.0%) patients and 3 patients died during induction. The 5-year overall survival (OS) and disease-free survival (DFS) were 88.3?±?6.5% and 85?±?7.5%, respectively. Post-induction, 35 patients were treated with HDMTX and 25 with C-MTX. There was no difference in OS or DFS for patients treated with HDMTX vs. C-MTX (P?>?0.05 for both). Central nervous system involvement (CNS3) was associated with inferior survival outcomes compared to Non-CNS3 patients (OS, CNS3 73.3?±?9.1% vs.non-CNS3 93.2?±?2.6%, (P?=?0.045) and DFS, CNS3 66.7?±?10.4% vs. non-CNS3 90.9?±?3.1% (P?=?0.0163)). Delayed radiation in CNS3 was associated with relapse (P?=?0.0037) regardless of regimen. Thus optimization of CNS-directed therapy for patients with CNS3 is needed.
| S-EPMC6215054 | biostudies-literature
Project description:BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) gene variant C677T has been implicated as a genetic risk factor in migraine susceptibility, particularly in Migraine with Aura. Migraine, with and without aura (MA and MO) have many diagnostic characteristics in common. It is postulated that migraine symptomatic characteristics might themselves be influenced by MTHFR. Here we analysed the clinical profile, migraine symptoms, triggers and treatments of 267 migraineurs previously genotyped for the MTHFR C677T variant. The chi-square test was used to analyse all potential relationships between genotype and migraine clinical variables. Regression analyses were performed to assess the association of C677T with all migraine clinical variables after adjusting for gender. FINDINGS: The homozygous TT genotype was significantly associated with MA (P < 0.0001) and unilateral head pain (P = 0.002). While the CT genotype was significantly associated with physical activity discomfort (P < 0.001) and stress as a migraine trigger (P = 0.002). Females with the TT genotype were significantly associated with unilateral head pain (P < 0.001) and females with the CT genotype were significantly associated with nausea (P < 0.001), osmophobia (P = 0.002), and the use of natural remedy for migraine treatment (P = 0.003). Conversely, male migraineurs with the TT genotype experienced higher incidences of bilateral head pain (63% vs 34%) and were less likely to use a natural remedy as a migraine treatment compared to female migraineurs (5% vs 20%). CONCLUSIONS: MTHFR genotype is associated with specific clinical variables of migraine including unilateral head pain, physical activity discomfort and stress.
| S-EPMC2919563 | biostudies-literature
Project description:OBJECTIVES:To check for the association of genetic polymorphisms related to the methylenetetrahydrofolate reductase (MTHFR) gene namely C677T and A1298C with hypertension in Saudi affected subjects from Qassim region. SUBJECTS AND METHODS:Participants included 123 Saudi hypertensive cases (83 males and 40 females) in addition to 250 (142 males and 108 females) unrelated healthy controls from the same locality. Their age mean ±SD was 50.93 ± 15.43 years. For all subjects, DNA was extracted followed by real-time PCR amplifications for characterization of genotypes and alleles related to MTHFR C677T and A1298C gene polymorphisms RESULTS:Total cases showed significantly higher carriage rate for the mutant allele 677T compared to controls (40.7% vs. 26%, OR=1.9, 95% CI= 1.2-3.1) with a lower frequency of the wild type 677CC genotype (59.3% vs. 74%, p=0.004). The same was observed among cases-subgroups of hypertension associated with obesity with a notably higher odds ratio (OR=2.6, 95% CI=1.3-5.01, p=0.004). Total cases showed also significantly higher frequency of mutant 1298 C allele carriage rate compared to controls (59.3% vs. 42.4%, OR=1.98, 95% CI= 1.3-3.1) with a lower frequency of the normal AA genotype (40.7% vs. 57.6%, p=0.003). The same was observed among cases-subgroups of hypertension associated with both diabetes and obesity and among cases of hypertension with obesity, also with higher odds ratio (OR=2.6 and 2.2 respectively). CONCLUSION:This work showed that genetic polymorphisms related to the MTHFR gene are associated with the risk of hypertension particularly when accompanied with obesity and diabetes among Saudi subjects.
| S-EPMC3523778 | biostudies-literature
Project description:IntroductionAbnormal levels of the enzyme methylenetetrahydrofolate reductase (MTHFR) are associated with an increased risk of both cardiovascular and cerebrovascular disease and higher concentrations of homocysteine. Abnormal levels are also related to birth defects, pregnancy complications, cancer and toxicity to methotrexate (MTX). Polymorphisms of MTHFR affect the activity of the enzyme. Genetic associations have been related to treatment efficacy.ObjectiveTo establish the frequency of the C> T polymorphism at nucleotide 677 of the MTHFR gene in a group of Colombian individuals.MethodsData from pharmacogenetic microarrays that include MTX sensibility-associated polymorphisms were retrospectively collected (Pathway Genomics(®)). The frequency of the C> T MTHFR rs1801133 marker polymorphism was analyzed.ResultsMicroarray data from 68 men and 84 women were analyzed. Comparisons of genotype C/C vs. C/T and T/T were statistically significantly different (p= 0.00, p= 0.026, respectively), as were C/T and T / T (p= 0.0001).ConclusionsResults for the C/C and C/T genotypes in a Colombian population are similar to other previously studied groups of healthy subjects. Subjects from our population might be at risk of developing diseases associated with MTHFR polymorphisms and might present toxicity and adverse effects if treated with MTX, which suggests the need to evaluate therapeutic alternatives based on individual pharmacogenetic studies.
| S-EPMC4536819 | biostudies-literature