Phoenix from the ashes: dramatic improvement in severe late-onset methylenetetrahydrofolate reductase (MTHFR) deficiency with a complete loss of vision

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

Download Full-text

Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency

Journal of Inherited Metabolic Disease ◽

10.1007/s10545-015-9860-6 ◽

2015 ◽

Vol 39 (1) ◽

pp. 115-124 ◽

Cited By ~ 22

Author(s):

Martina Huemer ◽

Regina Mulder-Bleile ◽

Patricie Burda ◽

D. Sean Froese ◽

Terttu Suormala ◽

...

Keyword(s):

Methylenetetrahydrofolate Reductase ◽

Residual Activity ◽

Clinical Pattern ◽

Mthfr Deficiency

Download Full-text

Superior Ophthalmic Vein Thrombosis with Complete Loss of Vision as a Complication of Autoimmune and Infective Conditions

Ocular Immunology and Inflammation ◽

10.1080/09273948.2017.1313433 ◽

2017 ◽

Vol 26 (7) ◽

pp. 1066-1068 ◽

Cited By ~ 4

Author(s):

Jelena Juri Mandić ◽

Krešimir Mandić ◽

Danijela Mrazovac

Keyword(s):

Complete Loss ◽

Superior Ophthalmic Vein ◽

Loss Of Vision ◽

Vein Thrombosis

Download Full-text

Peripheral Nervous System Involvement in Late-Onset Cobalamin C Disease?

Frontiers in Neurology ◽

10.3389/fneur.2020.594905 ◽

2020 ◽

Vol 11 ◽

Author(s):

Xujun Chu ◽

Lingchao Meng ◽

Wei Zhang ◽

Jinjun Luo ◽

Zhaoxia Wang ◽

...

Keyword(s):

Nervous System ◽

Peripheral Nervous System ◽

Methylenetetrahydrofolate Reductase ◽

Late Onset ◽

Hot Spot ◽

Axonal Neuropathy ◽

Methylmalonic Aciduria ◽

Lower Limbs ◽

Compound Heterozygous ◽

Limb Weakness

Background: Cobalamin C (cblC) has a fundamental role in both central and peripheral nervous system function at any age. Neurologic manifestations may be the earliest and often the only manifestation of hereditary or acquired cblC defect. Peripheral neuropathy remains a classical but underdiagnosed complication of cblC defect, especially in late-onset cblC disease caused by mutations in the methylmalonic aciduria type C and homocysteinemia (MMACHC) gene. So the clinical, electrophysiological, and pathological characteristics of late-onset cblC disease are not well-known.Methods: A retrospective study of patients with late-onset cblC disease was conducted at our hospital on a 3-year period. The neuropathy was confirmed by the nerve conduction study. Sural biopsies were performed in 2 patients.Results: Eight patients were identified, with a mean onset age of 16.25 ± 6.07 years. All patients had methylmalonic aciduria, homocysteinemia, compound heterozygous MMACHC gene mutations were detected in all patients, and 7/8 patients with c.482G>A mutation. One patient concomitant with homozygote c.665C>T mutation in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. All patients showed limb weakness and cognitive impairment. Five patients had possible sensorimotor axonal polyneuropathy predominantly in the distal lower limbs. Sural biopsies showed loss of myelinated and unmyelinated fibers. Electro microscopy revealed crystalline-like inclusions bodies in Schwann cells and axonal degeneration.Conclusion: Late-onset cblC disease had possible heterogeneous group of distal axonal neuropathy. c.482G>A mutation is a hot spot mutation in late-onset cblC disease.

Download Full-text

Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate

Journal of Clinical Medicine ◽

10.3390/jcm9092836 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2836

Author(s):

Maša Vidmar Golja ◽

Alenka Šmid ◽

Nataša Karas Kuželički ◽

Jurij Trontelj ◽

Ksenija Geršak ◽

...

Keyword(s):

Methylenetetrahydrofolate Reductase ◽

Fold Increase ◽

Mthfr Gene ◽

Folate Supplementation ◽

Disease States ◽

Metabolic Defects ◽

Key Enzyme ◽

Cell Processes ◽

Activity Groups ◽

Mthfr Deficiency

Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (n = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells’ metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices.

Download Full-text