Targeting MTHFR for the treatment of migraines

References

• Headache classification committee of the International Headache Society (ihs). the international classification of headache disorders, 3rd edition. Cephalalgia. 2018;38:1–211.
   PubMed Web of Science ®Google Scholar
• Ligthart L, Boomsma DI, Martin NG, et al. Migraine with aura and migraine without aura are not distinct entities: further evidence from a large dutch population study. Twin Res Hum Genet. 2006;9:54–63.
   PubMed Web of Science ®Google Scholar
• Russell MB, Ulrich V, Gervil M, et al. Migraine without aura and migraine with aura are distinct disorders. A population-based twin survey. Headache. 2002;42:332–336.
   PubMed Web of Science ®Google Scholar
• Gasparini CF, Sutherland HG, Griffiths LR. Studies on the pathophysiology and genetic basis of migraine. Curr Genomics. 2013;14:300–315.
   PubMed Web of Science ®Google Scholar
• Goadsby PJ, Holland PR, Martins-Oliveira M, et al. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97:553–622.
   PubMed Web of Science ®Google Scholar
• Noseda R, Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain. 2013;154(Suppl 1):S44–53.
   PubMed Web of Science ®Google Scholar
• Dodick DW. A phase-by-phase review of migraine pathophysiology. Headache. 2018;58(Suppl 1):4–16.
   PubMed Web of Science ®Google Scholar
• De Felice M, Ossipov MH. Cortical and subcortical modulation of pain. Pain Manag. 2016;6:111–120.
   PubMed Web of Science ®Google Scholar
• Scher AI, Bigal ME, Lipton RB. Comorbidity of migraine. Curr Opin Neurol. 2005;18:305–310.
   PubMed Web of Science ®Google Scholar
• Kurth T, Chabriat H, Bousser MG. Migraine and stroke: a complex association with clinical implications. Lancet Neurol. 2012;11:92–100.
   PubMed Web of Science ®Google Scholar
• Schwedt TJ. The migraine association with cardiac anomalies, cardiovascular disease, and stroke. Neurol Clin. 2009;27:513–523.
   PubMed Web of Science ®Google Scholar
• Minen MT, Begasse De Dhaem O, Kroon Van Diest A, et al. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 2016;87:741–749.
   PubMed Web of Science ®Google Scholar
• Rainero I, Govone F, Gai A, et al. Is migraine primarily a metaboloendocrine disorder? Curr Pain Headache Rep. 2018;22:36.
   PubMed Web of Science ®Google Scholar
• Buse DC, Silberstein SD, Manack AN, et al. Psychiatric comorbidities of episodic and chronic migraine. J Neurol. 2013;260:1960–1969.
   PubMed Web of Science ®Google Scholar
• Lipton RB, Fanning KM, Buse DC, et al. Identifying natural subgroups of migraine based on comorbidity and concomitant condition profiles: results of the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. Headache. 2018;58:933–947.
   PubMed Web of Science ®Google Scholar
• Hamed SA. The vascular risk associations with migraine: relation to migraine susceptibility and progression. Atherosclerosis. 2009;205:15–22.
   PubMed Web of Science ®Google Scholar
• Wu J, Davis-Ajami ML, Kevin LZ. Impact of depression on health and medical care utilization and expenses in US adults with migraine: a retrospective cross sectional study. Headache. 2016;56:1147–1160.
   PubMed Web of Science ®Google Scholar
• Amoozegar F. Depression comorbidity in migraine. Int Rev Psychiatry. 2017;29:504–515.
   PubMed Web of Science ®Google Scholar
• Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight project. J Headache Pain. 2010;11:289–299.
   PubMed Web of Science ®Google Scholar
• Vetvik KG, MacGregor EA. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol. 2017;16:76–87.
   PubMed Web of Science ®Google Scholar
• GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet. 2016;390:1211–1259.
   Web of Science ®Google Scholar
• Steiner TJ, Stovner LJ, Vos T. GBD 2015: migraine is the third cause of disability in under 50s. J Headache Pain. 2016;17:104.
   PubMed Web of Science ®Google Scholar
• Bonafede M, Sapra S, Shah N, et al. Direct and indirect healthcare resource utilization and costs among migraine patients in the United States. Headache. 2018;58:700–714.
   PubMed Web of Science ®Google Scholar
• Baigi K, Stewart WF. Headache and migraine: a leading cause of absenteeism. Handb Clin Neurol. 2015;131:447–463.
   PubMedGoogle Scholar
• Linde M, Gustavsson A, Stovner LJ, et al. The cost of headache disorders in Europe: the Eurolight project. Eur J Neurol. 2012;19:703–711.
   PubMed Web of Science ®Google Scholar
• Mulder EJ, Van Baal C, Gaist D, et al. Genetic and environmental influences on migraine: a twin study across six countries. Twin Res. 2003;6:422–431.
   PubMedGoogle Scholar
• Svensson DA, Larsson B, Waldenlind E, et al. Shared rearing environment in migraine: results from twins reared apart and twins reared together. Headache. 2003;43:235–244.
   PubMed Web of Science ®Google Scholar
• Pietrobon D. Familial hemiplegic migraine. Neurotherapeutics. 2007;4:274–284.
   PubMed Web of Science ®Google Scholar
• Anttila V, Wessman M, Kallela M, et al. Genetics of migraine. Handb Clin Neurol. 2018;148:493–503.
   PubMedGoogle Scholar
• Montagna P. Migraine genetics. Expert Rev Neurother. 2008;8:1321–1330.
   PubMedGoogle Scholar
• Hiekkala ME, Vuola P, Artto V, et al. The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: a clinical and genetic study in Finnish migraine families. Cephalalgia. 2018. 333102418761041. DOI:10.1177/0333102418761041
   PubMed Web of Science ®Google Scholar
• Lebas A, Guyant-Marechal L, Hannequin D, et al. Severe attacks of familial hemiplegic migraine, childhood epilepsy and ATP1A2 mutation. Cephalalgia. 2008;28:774–777.
   PubMed Web of Science ®Google Scholar
• Dichgans M, Freilinger T, Eckstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet. 2005;366:371–377.
   PubMed Web of Science ®Google Scholar
• Lafreniere RG, Cader MZ, Poulin JF, et al. A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med. 2010;16:1157–1160.
   PubMed Web of Science ®Google Scholar
• Menon S, Cox HC, Kuwahata M, et al. Association of a Notch 3 gene polymorphism with migraine susceptibility. Cephalalgia. 2011;31:264–270.
   PubMed Web of Science ®Google Scholar
• Gormley P, Anttila V, Winsvold BS, et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet. 2016;48:856–866.
   PubMed Web of Science ®Google Scholar
• Stuart S, Cox HC, Lea RA, et al. The role of the MTHFR gene in migraine. Headache. 2012;52:515–520.
   PubMed Web of Science ®Google Scholar
• Malik R, Freilinger T, Winsvold BS, et al. Shared genetic basis for migraine and ischemic stroke: a genome-wide analysis of common variants. Neurology. 2015;84:2132–2145.
   PubMed Web of Science ®Google Scholar
• Agostoni EC, Longoni M. Migraine and cerebrovascular disease: still a dangerous connection? Neurol Sci. 2018;39(Suppl 1):33–37.
   PubMedGoogle Scholar
• Eising E,A, Dutston N, van den Maagdenberg AM, et al. Epigenetic mechanisms in migraine: a promising avenue? BMC Med. 2013;11:26.
   PubMed Web of Science ®Google Scholar
• Weiner AS, Boyarskikh UA, Voronina EN, et al. Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G polymorphisms influence on leukocyte genomic DNA methylation level. Gene. 2014;533:168–172.
   PubMed Web of Science ®Google Scholar
• Milutinovic S, D’Alessio AC, Detich N, et al. Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis. 2007;28:560–571.
   PubMed Web of Science ®Google Scholar
• Gerring ZF, McRae AF, Montgomery GW, et al. Genome-wide DNA methylation profiling in whole blood reveals epigenetic signatures associated with migraine. BMC Genomics. 2018;19:69.
   PubMed Web of Science ®Google Scholar
• Labruijere S, Stolk L, Verbiest M, et al. Methylation of migraine-related genes in different tissues of the rat. PLoS One. 2014;9:e87616.
   PubMed Web of Science ®Google Scholar
• Igari S, Ohtaki A, Yamanaka Y, et al. Properties and crystal structure of methylenetetrahydrofolate reductase from Thermus thermophilus HB8. PLoS One. 2011;6:e23716.
   PubMed Web of Science ®Google Scholar
• Froese DS, Kopec J, Rembeza E, et al. Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. Nat Commun. 2018;9:2261.
   PubMed Web of Science ®Google Scholar
• Fang K, Chen Z, Liu M, et al. Apoptosis and calcification of vascular endothelial cell under hyperhomocysteinemia. Med Oncol. 2015;32:403.
   PubMed Web of Science ®Google Scholar
• Dionisio N, Jardín I, Salido GM, et al. Homocysteine, intracellular signaling and thrombotic disorders. Curr Med Chem. 2010;17:3109–3119.
   PubMed Web of Science ®Google Scholar
• Görtz P, Hoinkes A, Fleischer W, et al. Implications for hyperhomocysteinemia: not homocysteine but its oxidized forms strongly inhibit neuronal network activity. J Neurol Sci. 2004;218:109–114.
   PubMed Web of Science ®Google Scholar
• Boldyrev AA. Molecular mechanisms of homocysteine toxicity. Biochemistry (Mosc). 2009;74:589–598.
   PubMed Web of Science ®Google Scholar
• Sharma M, Tiwari M, Tiwari RK. Hyperhomocysteinemia: impact on neurodegenerative diseases. Basic Clin Pharmacol Toxicol. 2015;117:287–296.
   PubMed Web of Science ®Google Scholar
• Welch G, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042–1050.
   PubMed Web of Science ®Google Scholar
• Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet. 1999;354:407–413.
   PubMed Web of Science ®Google Scholar
• Ma J, Stampfer MJ, Giovannucci E, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions and risk of colorectal cancer. Cancer Res. 1997;57:1098–1102.
   PubMed Web of Science ®Google Scholar
• Weisberg I, Tran P, Christensen B, et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64:169–172.
   PubMed Web of Science ®Google Scholar
• Rosenblatt DS, Lue-Shing H, Arzoumanian A, et al. Methylenetetrahydrofolate reductase (MR) deficiency: thermolability of residual MR activity, methionine synthase activity, and methylcobalamin levels in cultured fibroblasts. Biochem Med Metab Biol. 1992;47:221–225.
   PubMedGoogle Scholar
• den Heijer M, Rosendaal FR, Blom HJ, et al. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost. 1998;80:874–877.
   PubMed Web of Science ®Google Scholar
• Clarke R, Bennett DA, Parish S, et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med. 2012;9:e1001177.
   PubMed Web of Science ®Google Scholar
• Kelly PJ, Rosand J, Kistler JP, et al. Homocysteine, MTHFR 677C–>T polymorphism, and risk of ischemic stroke: results of a meta-analysis. Neurology. 2002;59:529–536.
   PubMed Web of Science ®Google Scholar
• Rai V. Association of C677T polymorphism (rs1801133) in MTHFR gene with depression. Cell Mol Biol. 2017;63:60–67.
   PubMed Web of Science ®Google Scholar
• Hua Y, Zhao H, Kong Y, et al. Association between the MTHFR gene and Alzheimer’s disease: a meta-analysis. Int J Neurosci. 2011;121:462–471.
   PubMed Web of Science ®Google Scholar
• Wu YL, Ding XX, Sun YH, et al. Methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson’s disease: a meta-analysis. J Neurol Sci. 2013;335:14–21.
   PubMed Web of Science ®Google Scholar
• Pu D, Jiang SW, Wu J. Association between MTHFR gene polymorphism and the risk of ovarian cancer: a meta-analysis of the literature. Curr Pharm Des. 2014;20:1632–1638.
   PubMed Web of Science ®Google Scholar
• Kowa H, Yasui K, Takeshima T, et al. The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine. Am J Med Genet. 2000;96:762–764.
   PubMed Web of Science ®Google Scholar
• Rubino E, Ferrero M, Rainero I, et al. Association of the C677T polymorphism in the MTHFR gene with migraine: a meta-analysis. Cephalalgia. 2009;29:818–825.
   PubMed Web of Science ®Google Scholar
• Samaan Z, Gaysina D, Cohen-Woods S, et al. Methylenetetrahydrofolate reductase gene variant (MTHFR C677T) and migraine: a case control study and meta-analysis. BMC Neurol. 2011;11:66.
   PubMed Web of Science ®Google Scholar
• Liu R, Geng P, Ma M, et al. MTHFR C677T polymorphism and migraine risk: a meta-analysis. J Neurol Sci. 2014;336:68–73.
   PubMed Web of Science ®Google Scholar
• Schürks M, Rist PM, Kurth T. MTHFR 677C>T and ACE D/I polymorphisms in migraine: a systematic review and meta-analysis. Headache. 2010;50:588–599.
   PubMed Web of Science ®Google Scholar
• Scher AI, Eiriksdottir G, Garcia M, et al. Lack of association between the MTHFR C677T variant and migraine with aura in an older population: could selective survival play a role? Cephalalgia. 2013;33:308–315.
   PubMed Web of Science ®Google Scholar
• Kara I, Sazci A, Ergul E, et al. Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk. Brain Res Mol Brain Res. 2003;111:84–90.
   PubMedGoogle Scholar
• Stuart S, Cox HC, Lea RA, et al. The role of the MTHFR gene in migraine. Headache. 2012;52:512–520.
   Web of Science ®Google Scholar
• Salehi M, Amin-Beidokhti M, Safarpour Lima B, et al. The rs4846049 polymorphism in the 3ʹUTR region of the MTHFR gene increases the migraine susceptibility in an Iranian population. J Pain Res. 2018;11:145–149.
   PubMed Web of Science ®Google Scholar
• Liu A, Menon S, Colson NJ, et al. Analysis of the MTHFR C677T variant with migraine phenotypes. BMC Res Notes. 2010;3:213.
   PubMedGoogle Scholar
• Magis D, Allena M, Coppola G, et al. Search for correlations between genotypes and electrophysiological patterns in migraine: the MTHFR C677T polymorphism and visual evoked potentials. Cephalalgia. 2007;27:1142–1149.
   PubMed Web of Science ®Google Scholar
• De Tommaso M, Difruscolo O, Sardaro M, et al. Influence of MTHFR genotype on contingent negative variation and MRI abnormalities in migraine. Headache. 2007;47:253–265.
   PubMed Web of Science ®Google Scholar
• Oterino A, Valle N, Bravo Y, et al. MTHFR T677 homozygosis influences the presence of aura in migraineurs. Cephalalgia. 2004;24:491–494.
   PubMed Web of Science ®Google Scholar
• Isobe C, Terayama Y. A remarkable increase in total homocysteine concentrations in the CSF of migraine patients with aura. Headache. 2010;50:1561–1569.
   PubMed Web of Science ®Google Scholar
• Sadeghi O, Maghsoudi Z, Askari G, et al. Association between serum levels of homocysteine with characteristics of migraine attacks in migraine with aura. J Res Med Sci. 2014;19:1041–1045.
   PubMed Web of Science ®Google Scholar
• Todt U, Freudenberg J, Goebel I, et al. MTHFR C677T polymorphism and migraine with aura. Ann Neurol. 2006;60:621–622.
   PubMed Web of Science ®Google Scholar
• Kaunisto MA, Kallela M, Hamalainen E, et al. Testing of variants of the MTHFR and ESRI genes in 1798 Finnish individuals fails to confirm the association with migraine with aura. Cephalalgia. 2006;26:1462–1472.
   PubMed Web of Science ®Google Scholar
• Wang D, Chen YM, Ruan MH, et al. Homocysteine inhibits neural stem cells survival by inducing DNA interstrand cross-links via oxidative stress. Neurosci Lett. 2016;635:24–32.
   PubMed Web of Science ®Google Scholar
• Ho PI, Ortiz D, Rogers E, et al. Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. J Neurosci Res. 2002;70:694–702.
   PubMed Web of Science ®Google Scholar
• Kruman II, Culmsee C, Chan SL, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 2000;20:6920–6926.
   PubMed Web of Science ®Google Scholar
• Abushik PA, Niittykoski M, Giniatullina R, et al. The role of NMDA and mGluR5 receptors in calcium mobilization and neurotoxicity of homocysteine in trigeminal and cortical neurons and glial cells. J Neurochem. 2014;129:264–274.
   PubMed Web of Science ®Google Scholar
• Kopjas TL. The use of folic acid in vascular headache of the migraine type. Headache. 1969;8:167–170.
   PubMedGoogle Scholar
• Di Rosa G, Attinà S, Spanò M, et al. Efficacy of folic acid in children with migraine, hyperhomocysteinemia and MTHFR polymorphisms. Headache. 2007;47:1342–1344.
   PubMed Web of Science ®Google Scholar
• Lea R, Colson N, Quinlan S, et al. The effects of vitamin supplementation and MTHFR (C677T) genotype on homocysteine-lowering and migraine disability. Pharmacogenet Genomics. 2009;19:422–428.
   PubMed Web of Science ®Google Scholar
• Menon S, Lea RA, Roy B, et al. Genotypes of the MTHFR C677T and MTRR A66G genes act independently to reduce migraine disability in response to vitamin supplementation. Pharmacogenet Genomics. 2012;22:741–749.
   PubMed Web of Science ®Google Scholar
• Menon S, Nasir B, Avgan N, et al. The effect of 1 mg folic acid supplementation on clinical outcomes in female migraine with aura patients. J Headache Pain. 2016;17:60.
   PubMed Web of Science ®Google Scholar
• Askari G, Nasiri M, Mozaffari-Khosravi H, et al. The effects of folic acid and pyridoxine supplementation on characteristics of migraine attacks in migraine patients with aura: A double-blind, randomized placebo-controlled, clinical trial. Nutrition. 2017;38:74–79.
   PubMed Web of Science ®Google Scholar
• Shaik MM, Tan HL, Kamal MA, et al. Do folate, vitamins B₆ and B₁₂ play a role in the pathogenesis of migraine? The role of pharmacoepigenomics. CNS Neurol Disord Drug Targets. 2014;13:828–835.
   PubMed Web of Science ®Google Scholar
• Bigal ME, Serrano D, Reed M, et al. Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology. 2008;71:559–566.
   PubMed Web of Science ®Google Scholar
• Malone D, Bhowmick A, Wachholtz A. Migraine: treatments, comorbidities, and quality of life, in the USA. J Pain Res. 2015;8:537–547.
   PubMed Web of Science ®Google Scholar
• Semmler A, Moskau-Hartmann S, Stoffel-Wagner B, et al. Homocysteine plasma levels in patients treated with antiepileptic drugs depend on folate and vitamin B12 serum levels, but not on genetic variants of homocysteine metabolism. Clin Chem Lab Med. 2013;51:665–669.
   PubMed Web of Science ®Google Scholar
• Desouza C, Keebler M, McNamara DB, et al. Drugs affecting homocysteine metabolism: impact on cardiovascular risk. Drugs. 2002;62:605–616.
   PubMed Web of Science ®Google Scholar
• Jadavji NM, Wieske F, Dirnagl U, et al. Methylenetetrahydrofolate reductase deficiency alters levels of glutamate and γ-aminobutyric acid in brain tissue. Mol Genet Metab Rep. 2015;3:1–4.
   PubMed Web of Science ®Google Scholar
• Rainero I, Grimaldi LM, Salani G, et al. Association between the tumor necrosis factor-alpha −308 G/A gene polymorphism and migraine. Neurology. 2004;62(1):141–143.
   PubMed Web of Science ®Google Scholar
• Chen S, Dong Z, Zhao Y, et al. Homocysteine induces mitochondrial dysfunction involving the crosstalk between oxidative stress and mitochondrial pSTAT3 in rat ischemic brain. Sci Rep. 2017;7(1):6932.
   PubMedGoogle Scholar
• Zhang LM, Dong Z, Yu SY. Migraine in the era of precision medicine. Ann Transl Med. 2016;4:105.
   PubMed Web of Science ®Google Scholar