Abstract
The contents of homocysteine (HCy), cyanocobalamin (vitamin B12), folic acid (vitamin B9), and pyridoxine (vitamin B6) were analyzed and the genotypes of the main gene polymorphisms associated with folate metabolism (C677T and A1298C of the MTHFR gene, A2756G of the MTR gene and A66G of the MTRR gene) were determined in children at the onset of multiple sclerosis (MS) (with disease duration of no more than six months), healthy children under 18 years (control group), healthy adults without neurological pathology, adult patients with MS at the onset of disease, and adult patients with long-term MS. A significant increase in the HCy levels was found in children at the MS onset compared to healthy children of the corresponding age. It was established that the content of HCy in children has a high predictive value. At the same time, an increase in the HCy levels was not accompanied by the deficiency of vitamins B6, B9, and B12 in the blood. The lack of correlation between the laboratory signs of vitamin deficiency and HCy levels may be due to the polymorphic variants of folate cycle genes. An increased HCy level should be considered as a marker of functional disorders of folate metabolism accompanying the development of pathological process in pediatric MS. Our finding can be used to develop new approaches to the prevention of demyelination in children and treatment of pediatric MS.
Abbreviations
- CNS:
-
central nervous system
- Hcy:
-
homocysteine
- MS:
-
multiple sclerosis
- MTHF:
-
methylenetetrahydrofolate reductase
- MTR:
-
methionine synthase
- MTRR:
-
methionine synthase reductase
References
Compston, A., and Coles, A. (2008) Multiple sclerosis, Lancet, 372, 1502-1517, https://doi.org/10.1016/S0140-6736(08)61620-7.
Charabati, M., Wheeler, M. A., Weiner, H. L., and Quintana, F. J. (2023) Multiple sclerosis: Neuroimmune crosstalk and therapeutic targeting, Cell, 186, 1309-1327, https://doi.org/10.1016/j.cell.2023.03.008.
Brenton, J. N., Kammeyer, R., Gluck, L., Schreiner, T., and Makhani, N. (2020) Multiple sclerosis in children: current and emerging concepts, Semin Neuro., 40, 192-200, https://doi.org/10.1055/s-0040-1703000.
Simone, I. L., Carrara, D., Tortorella, C., Liguori, M., Lepore, V., Pellegrini, F., Bellacosa, A., Ceccarelli, A., Pavone, I., and Livrea, P. (2002) Course and prognosis in early-onset MS: comparison with adult-onset forms, Neurology, 59, 1922-1928, https://doi.org/10.1212/01.wnl.0000036907.37650.8e.
Renoux, C., Vukusic, S., Mikaeloff, Y., Edan, G., Clanet, M., et al. (2007) Natural history of multiple sclerosis with childhood onset, N. Engl. J. Med., 356, 2603-2613, https://doi.org/10.1056/NEJMoa067597.
Krysko, K. M., Graves, J. S., Rensel, M., Weinstock-Guttman, B., Rutatangwa, A., et al. (2020) US network of Pediatric MS centers. Real-world effectiveness of initial disease-modifying therapies in pediatric multiple sclerosis, Ann. Neurol., 88, 42-55, https://doi.org/10.1002/ana.25737.
Weng, Q., Wang, J., Wang, J., Tan, B., Wang, J., et al. (2017) Folate metabolism regulates oligodendrocyte survival and differentiation by modulating AMPKα activity, Sci. Rep., 7, 1705, https://doi.org/10.1038/s41598-017-01732-1.
McGarel, C., Pentieva, K., Strain, J. J., and McNulty, H. (2015) Emerging roles for folate and related B-vitamins in brain health across the lifecycle, Proc. Nutr. Soc., 74, 46-55, https://doi.org/10.1017/S0029665114001554.
Naninck, E. F. G., Stijger, P. C., and Brouwer-Brolsma, E. M. (2019) The importance of maternal folate status for brain development and function of offspring, Adv. Nutr., 10, 502-519, https://doi.org/10.1093/advances/nmy120.
Zou, R., El Marroun, H., Cecil, C., Jaddoe, V. W. V., Hillegers, M., et al. (2021) Maternal folate levels during pregnancy and offspring brain development in late childhood, Clin. Nutr., 40, 3391-3400, https://doi.org/10.1016/j.clnu.2020.11.025.
Polman, C. H., Reingold, S. C., Edan, G., Filippi, M., Hartung, H. P., et al. (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”, Ann. Neurol., 58, 840-846, https://doi.org/10.1002/ana.20703.
Thompson, A. J., Banwell, B. L., Barkhof, F., Carroll, W. M., Coetzee, T., et al. (2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria, Lancet Neurol., 17, 162-173, https://doi.org/10.1016/S1474-4422(17)30470-2.
Ganguly, P., and Alam, S. F. (2015) Role of homocysteine in the development of cardiovascular disease, Nutr. J., 14, 6, https://doi.org/10.1186/1475-2891-14-6.
Ansari, R., Mahta, A., Mallack, E., and Luo, J. J. (2014) Hyperhomocysteinemia and neurologic disorders: a review, J. Clin. Neurol., 10, 281-288, https://doi.org/10.3988/jcn.2014.10.4.281.
Farina, N., Jernerén, F., Turner, C., Hart, K., and Tabet, N. (2017) Homocysteine concentrations in the cognitive progression of Alzheimer’s disease, Exp. Gerontol., 99, 146-150, https://doi.org/10.1016/j.exger.2017.10.008.
Kocer, B., Guven, H., Conkbayir, I., Comoglu, S. S., and Delibas, S. (2016) The effect of hyperhomocysteinemia on motor symptoms, cognitive status, and vascular risk in patients with Parkinson’s disease, Parkinsons Dis., 2016, 1589747, https://doi.org/10.1155/2016/1589747.
Al-Kuraishy, H. M., Al-Gareeb, A. I., Elewa, Y. H. A., Zahran, M. H., Alexiou, A., et al. (2023) Parkinson’s disease risk and hyperhomocysteinemia: the possible link, Cell Mol. Neurobiol., 43, 2743-2759, https://doi.org/10.1007/s10571-023-01350-8.
Ramsaransing, G. S., Fokkema, M. R., Teelken, A., Arutjunyan, A. V., Koch, M., and De Keyser, J. (2006) Plasma homocysteine levels in multiple sclerosis, J. Neurol. Neurosurg. Psychiatry, 77, 189-192, https://doi.org/10.1136/jnnp.2005.072199.
Li, X., Yuan, J., Han, J., and Hu, W. (2020) Serum levels of homocysteine, Vitamin B12 and folate in patients with multiple sclerosis: an updated meta-analysis, Int. J. Med. Sci., 17, 751-761, https://doi.org/10.7150/ijms.42058.
Kararizou, E., Paraskevas, G., Triantafyllou, N., Koutsis, G., Evangelopoulos, M. E., et al. (2013) Plasma homocysteine levels in patients with multiple sclerosis in the Greek population, J. Chin. Med. Assoc., 76, 611-614, https://doi.org/10.1016/j.jcma.2013.07.002.
Bystrická, Z., Laubertová, L., Ďurfinová, M., and Paduchová, Z. (2017) Methionine metabolism and multiple sclerosis, Biomarkers, 22, 747-754, https://doi.org/10.1080/1354750X.2017.1334153.
Oliveira, S. R., Flauzino, T., Sabino, B. S., Kallaur, A. P., Alfieri, D. F., et al. (2018) Elevated plasma homocysteine levels are associated with disability progression in patients with multiple sclerosis, Metab. Brain Dis., 33, 1393-1399, https://doi.org/10.1007/s11011-018-0224-4.
Teunissen, C. E., Killestein, J., Kragt, J. J., Polman, C. H., Dijkstra, C. D., and Blom, H. J. (2008) Serum homocysteine levels in relation to clinical progression in multiple sclerosis, J. Neurol. Neurosurg. Psychiatry, 79, 1349-1353, https://doi.org/10.1136/jnnp.2008.151555.
Mititelu, R. R., Albu, C. V., Bacanoiu, M. V., Padureanu, V., Padureanu, R., et al. (2021) Homocysteine as a predictor tool in multiple sclerosis, Discoveries (Craiova), 9, e135, https://doi.org/10.15190/d.2021.14.
Pietrzik, K., and Brönstrup, A. (1998) Vitamins B12, B6 and folate as determinants of homocysteine concentration in the healthy population, Eur. J. Pediatr., 157, S135-S138, https://doi.org/10.1007/pl00014298.
Jakubowski, H. (2019) Homocysteine modification in protein structure/function and human disease, Physiol. Rev., 99, 555-604, https://doi.org/10.1152/physrev.00003.2018.
Thybikov, N. N., and Thybikova, N. M. (2007) The role of homocysteine in human pathology [in Russian], Usp. Sovr. Biol., 127, 471-481.
Smith, A. D., and Refsum, H. (2021) Homocysteine – from disease biomarker to disease prevention, J. Intern. Med., 290, 826-854, https://doi.org/10.1111/joim.13279.
Tsai, M. Y., Bignell, M., Yang, F., Welge, B. G., Graham, K. J., and Hanson, N. Q. (2000) Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A(2756)G of methionine synthase, with lowered plasma homocysteine levels, Atherosclerosis, 149, 131-137, https://doi.org/10.1016/s0021-9150(99)00297-x.
Raghubeer, S., and Matsha, T. E. (2021) Methylenetetrahydrofolate (MTHFR), the one-carbon cycle, and cardiovascular risks, Nutrients, 13, 4562, https://doi.org/10.3390/nu13124562.
Li, W. X., Dai, S. X., Zheng, J. J., Liu, J. Q., and Huang, J. F. (2015) Homocysteine metabolism gene polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) jointly elevate the risk of folate deficiency, Nutrients, 7, 6670-6687, https://doi.org/10.3390/nu7085303.
Ruet, A. (2018) Update on pediatric-onset multiple sclerosis, Rev. Neurol. (Paris), 174, 398-407, https://doi.org/10.1016/j.neurol.2018.04.003.
Khabirov, F. A., Khaybullin, T. I., Granatov, E. V., Averyanova, L. A., Babicheva, N. N., Khaibullina, A. R., Shikhova, V. A., and Yakupov, M. A. (2022) Differential diagnosis of multiple sclerosis in children [in Russian], S. S. Korsakov J. Neurol. Psychiatry, 122, 60-67, https://doi.org/10.17116/jnevro202212207260.
Pfeifenbring, S., Bunyan, R. F., Metz, I., Röver, C., Huppke, P., et al. (2015) Extensive acute axonal damage in pediatric multiple sclerosis lesions, Ann. Neurol., 77, 655-667, https://doi.org/10.1002/ana.24364.
Alroughani, R., and Boyko, A. (2018) Pediatric multiple sclerosis: a review, BMC Neurol., 18, 27, https://doi.org/10.1186/s12883-018-1026-3.
Ghezzi, A., Goretti, B., Portaccio, E., Roscio, M., and Amato, M. P. (2010) Cognitive impairment in pediatric multiple sclerosis, Neurol. Sci., 31 (Suppl 2), S215-S218, https://doi.org/10.1007/s10072-010-0437-8.
Weisbrot, D., Charvet, L., Serafin, D., Milazzo, M., Preston, T., et al. (2014) Psychiatric diagnoses and cognitive impairment in pediatric multiple sclerosis, Mult. Scler., 20, 588-593, https://doi.org/10.1177/1352458513504249.
Portaccio, E., De Meo, E., Bellinvia, A., and Amato, M. P. (2021) Cognitive issues in pediatric multiple sclerosis, Brain Sci., 11, 442, https://doi.org/10.3390/brainsci11040442.
Zhloba, A. A., and Subbotina, T. F. (2019) The evaluation of folate status using total homocysteine in hypertensive patients [in Russian], Med. J. Russ. Federat., 25, 158-165, https://doi.org/10.18821/0869-2106-2019-25-3-158-165.
Bates, C. J., Mansoor, M. A., Gregory, J., Pentiev, K., and Prentice, A. (2002) Correlates of plasma homocysteine, cysteine and cysteinyl-glycine in respondents in the British National Diet and Nutrition Survey of young people aged 4-18 years, and a comparison with the survey of people aged 65 years and over, Br. J. Nutr., 87, 71-79, https://doi.org/10.1079/BJN2001479.
Polushin, A. Yu., Odinak, M. M., Yanishevsky, S. N., Golokhvastov, S. Yu., and Tsygan, N. V. (2013) Hyperhomocysteinemia as predictor of stroke severity on background of extensive brain substance damage [in Russian], Vestn. Russ. Milit. Med. Acad., 4, 89-94.
Ho, P. I., Ortiz, D., Rogers, E., and Shea, T. B. (2002) Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage, J. Neurosci. Res., 70, 694-702, https://doi.org/10.1002/jnr.10416.
Beard, R. S., Jr., Reynolds, J. J., and Bearden, S. E. (2011) Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions, Blood, 118, 2007-2014, https://doi.org/10.1182/blood-2011-02-338269.
Tawfik, A., Elsherbiny, N. M., Zaidi, Y., and Rajpurohit, P. (2021) Homocysteine and age-related central nervous system diseases: role of inflammation, Int. J. Mol. Sci., 22, 6259, https://doi.org/10.3390/ijms22126259.
Dubchenko, E., Ivanov, A., Spirina, N., Smirnova, N., Melnikov, M., et al. (2020) Hyperhomocysteinemia and endothelial dysfunction in multiple sclerosis, Brain Sci., 10, 637, https://doi.org/10.3390/brainsci10090637.
Spirina, N. N., Spirin, N. N., Kiseleva, E. V., Dubchenko, E. A., and Boyko, A. N. (2021) Homocysteine and markers of endothelial dysfunction in multiple sclerosis [in Russian], S. S. Korsakov J. Neurol. Psychiatry, 121, 90-93, https://doi.org/10.17116/jnevro202112107290.
Perła-Kaján, J., and Jakubowski, H. (2019) Dysregulation of epigenetic mechanisms of gene expression in the pathologies of hyperhomocysteinemia, Int. J. Mol. Sci., 20, 3140, https://doi.org/10.3390/ijms20133140.
Coppedè, F., Stoccoro, A., Tannorella, P., and Migliore, L. (2019) Plasma homocysteine and polymorphisms of genes involved in folate metabolism correlate with DNMT1 gene methylation levels, Metabolites, 9, 298, https://doi.org/10.3390/metabo9120298.
Funding
The work was carried out with financial support from the Russian Science Foundation and the St. Petersburg Science Foundation (project no. 22-25-20191).
Author information
Authors and Affiliations
Contributions
V.I.L. wrote the text of the article; E.A.Ts. and E.A.Ch. conducted the experiments; V.I.L., G.N.B., E.Yu.S., A.V.D., and I.N.A. discussed the results; E.Yu.S. edited the manuscript; A.V.D. developed the concept; A.V.D. and I.N.A. supervised the study.
Corresponding author
Ethics declarations
All procedures performed during the study were in accordance with the ethical standards of the national research ethics committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed voluntary consent was obtained from all patients and control subjects included in the study. The study was approved by the Local Ethics Committee of the Federal State Budgetary Institution “IEM” protocol no. 2/22 dated 04/06/2022. The authors of this work declare that they have no conflicts of interest.
Additional information
Publisher’s Note. Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Lioudyno, V.I., Tsymbalova, E.A., Chernyavskaya, E.A. et al. Association of Increased Homocysteine Levels with Impaired Folate Metabolism and Vitamin B Deficiency in Early-Onset Multiple Sclerosis. Biochemistry Moscow 89, 562–573 (2024). https://doi.org/10.1134/S0006297924030143
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0006297924030143