Hyperhomocysteinemia syndrome in children with various diseases
PEDIATRICS
Abstract
Introduction. The problem of the relationship of homocysteine level with the development of pathological conditions is becoming more and more relevant every year. The article presents a literature review of works devoted to the study of this issue.Aim—to study the role of homocysteine in the development of various diseases in children using literary sources.Materials and methods. Using keywords (homocysteine, hyperhomocysteinemia, adolescents, children) we searched for papers published from 1969 to 2025 in Pub Med, World Wide Science and e LIBRARY databases. 1200 studies were found, and 42 were selected for review, including 5 systematic reviews and meta-analyses.Results. Hyperhomocysteinemia initiates activation of the unified cellular-humoral defense system of the organism, manifested in the development of hypercoagulation, increase in the number of leukocyte-platelet coaggregates, increase in the level of autoantibodies, cytokines, adhesion molecules, change in the phenotype of lymphocytes, which has a damaging effect on organs and systems, causing their damage.Conclusions.Domestic and foreign studies of homocysteine, in healthy and sick children show the association of homocysteine, with various pathologies in children and adolescents. First of all, they confirm the significance of this indicator as a diagnostic biomarker. Further in-depth and large-scale study of this issue is necessary.
References
1. Mc Cully K.S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969;56(1):111–128.
2. Hermann A., Sitdikova G. Homocysteine: biochemistry, molecular biology and role in disease. Biomolecules. 2021;11(5):737. https://doi.org/10.3390/biom11050737.
3. Selhub J., Jacques P.F., Wilson P.W., Rush D., Rosenberg I.H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;270(22):2693–2698. https://doi.org/10.1001/jama.1993.03510220049033.
4. Esnafoglu E., Ozturan D.D. The relationship of severity of depression with homocysteine, folate, vitamin B12, and vitamin D levels in children and adolescents. Child Adolesc Ment Health. 2020;25(4):249–255. https://doi.org/10.1111/camh.12387.
5. Ozkarakaya I.S., Celik B., Karakukcu C., Torun Y.A. Effect of zinc supplementation on hemogram parameters and circulating concentrations of homocysteine, vitamin B12, and folate in zinc-deficient children and adolescents. J Trace Elem Med Biol. 2021;65:126724. https://doi.org/10.1016/j.jtemb.2021.126724.
6. Caleyachetty R., Echouffo-Tcheugui J.B., Tait C.A., Schilsky S., Forrester T., Kengne A.P. Prevalence of behavioural risk factors for cardiovascular disease in adolescents in low-income and middle-income countries: an individual participant data meta-analysis. Lancet Diabetes Endocrinol. 2015;3(7):535–544. https://doi.org/10.1016/S2213-8587(15)00076-5.
7. Morris A.A., Kožich V., Santra S., Andria G., Ben-Omran T.I., Chakrapani A.B., Chapman K.A. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017;40:49–74. https://doi.org/10.1007/s10545-016-9979-0.
8. Лукша А.В., Наумов А.В., Максимович Н.А. Функциональное состояние эндотелия сосудов при гипергомоцистеинемии у детей с артериальной гипертензией. Журнал Гродненского государственного медицинского университета. 2023;21(1):40–45. https://doi.org/10.25298/2221-8785-2023-21-1-40-45.
9. Paganelli F., Mottola G., Fromonot J., Marlinge M., Deharo P., Guieu R., Ruf J. Hyperhomocysteinemia and cardiovascular disease. Int J Mol Sci. 2021;22(4):1690. https://doi.org/10.3390/ijms22041690.
10. Lonn E. Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. Nat Clin Pract Cardiovasc Med. 2006;354(15):414–415. https://doi.org/110.1056/NEJMoa060900.
11. Миняйлова Н.Н., Шишкова Ю.Н., Ровда Ю.И. Гипергомоцистеинемия у детей с избыточным жироотложением как фактор, сопряженный с инсулинорезистентностью и кардиальным риском. Педиатрия. 2017;96(3):39. https://doi.org/10.24110/0031-403X-2017-96-3-39-47.
12. Miao L., Deng G.X., Yin R.X., Nie R.J., Yang S., Wang Y., Li H. No causal effects of plasma homocysteine levels on the risk of coronary heart disease or acute myocardial infarction: A Mendelian randomization study. Eur J Prev Cardiol. 2021;28(2):227–234. https://doi.org/10.1177/2047487319894679.
13. Asmae T., Cito M., Gaouzi A., Chabraoui L. Hyperhomocysteinemia and risk factors of metabolic syndrome in obese children. Open access journal article. 2022;1(1):1–4. https://doi.org/10.35702/cases.10004.
14. Ровда Ю.И., Дорохов Н.А., Скударнов Е.В., Строзенко Л.А., Малюга О.М., Зенченко О.А. и др. Изменение уровня гомоцистеина крови на фоне дисплазии соединительной ткани у детей. Бюллетень медицинской науки. 2022;(4):5–12. https://doi.org/10.31684/25418475-2022-4-5.
15. Кабурова Д.Н., Усманова Д.Д. Лабораторная диагностика генетических предикторов гомоцистеина в развитии мигрени. Medical Sciene of Uzbekistan. 2023;(1):19–20. https://doi.org/10.56121/2181-3612-2023-1-19-20.
16. Söbü E., Düzkalır H.G., Özcabı B., Kaya Özçora G.D. The association between vitamin B12, folate, homocysteine levels, and carotid intima-media thickness in children with obesity: a cross-sectional study. J Pediatr Endocrinol Metab. 2022;35(8):1051–1058. https://doi.org/10.1515/jpem-2022-0250.
17. Тадтаева З.Г., Яковлева Е.Е., Амелин А.В. Полиморфизм гена фолатного обмена метилентетранидрофолат-редуктазы (MTHFR) и гипергомоцистеинемия при мигрени. Патологическая физиология и экспериментальная терапия. 2021;65(4):109–115. https://doi.org/10.25557/0031-2991.2021.04.109-115.
18. Березовская Т.С., Мироманова Н.А. Диагностическое значение определения гомоцистеина в сыворотке крови у детей при нейроинфекциях. Журнал инфектологии. 2018;10(1):42–46. https://doi.org/10.22625/2072-6732-2018-10-1-42-46.
19. Нестеренко О.В., Утц С.В., Бородулин В.Б., Горемыкин В.И., Елизарова С.Ю., Бобылева Е.В. и др. Гипергомоцистеинемия у детей с пиелонефритом. Российский вестник перинатологии и педиатрии. 2016;61(4):88–92. https://doi.org/10.21508/1027-4065-2016-61-4-88-92.
20. Cordaro M., Siracusa R., Fusco R., Cuzzocrea S., Di Paola R., Impellizzeri D. Involvements of hyperhomocysteinemia in neurological disorders. Metabolites. 2021;11(1): 37. https://doi.org/10.3390/metabo11010037.
21. Chien S.J., Lin I.C., Hsu C.N., Lo M.H., Tain Y.L. Homocysteine and arginine to asymmetric dimethylarginine ratio associated with blood pressure abnormalities in children with early cronic kidney disease. Circ J. 2015;79(9):2031–2037. https://doi.org/10.1253/circj.CJ-15-0412.
22. Li B., Xu Y., Pang D., Zhao Q., Zhang L., Li M., Zhu C. Interrelation between homocysteine metabolism and the development of autism spectrum disorder in children. Front Mol Neurosci. 2022;15:947513. https://doi.org/10.3389/fnmol.2022.947513.
23. Godfrey K.M., Titcombe P., El-Heis S., Albert B.B., Tham E.H., Barton S.J. Ni PPe R Study Group. Maternal B-vitamin and vitamin D status before, during, and after pregnancy and the influence of supplementation preconception and during pregnancy: Prespecified secondary analysis of the Ni PPe R double-blind randomized controlled trial. PLo S Med. 2023;20(12): e1004260. https://doi.org/10.1371/journal.pmed.1004260.
24. Наумов А.В. Гомоцистеин. Медико-биологические проблемы. Минск: Профессиональные издания; 2013. 311 с.
25. Чиркова Н.Н., Кисляк О.А. Гипергомоцистеинемия как фактор риска сердечно-сосудистых заболеваний. Лечебное дело. 2006;(2):48–52. EDN: MSYPSH.
26. Фефелова Е.В. Патогенетические эффекты гипергомоцистеинемии в эксперименте и клинике. Автореф. … дис. д-ра мед. наук. Чита; 2021.
27. Zhang Z., Wei C., Zhou Y., Yan T., Wang Z., Li W., Zhao L. Homocysteine induces apoptosis of human umbilical vein endothelial cells via mitochondrial dysfunction and endoplasmic reticulum stress. Oxid Med Cell Longev. 2017;2017:5736506. https://doi.org/10.1155/2017/5736506.
28. Марцева Е.М., Евдокимова Н.В., Прокопьева Н.Э. Роль гомоцистеина в патогенезе артериальной гипертензии при ожирении и коморбидных заболеваниях. Children’s Medicine of the North-West. 2023;11(4):39–46. https://doi.org/10.56871/Cm N-W.2023.18.64.004.
29. Бутенко А.В. Гомоцистеин: влияние на биохимические процессы в организме человека. Молодой ученый. 2016;105(1):78–82. EDN: VIIUKR.
30. Yoganathan S., Bhasin H., Garg D., Malik P., Saini A.G., Chandran M. Childhood neurological disorders with hyperhomocystinemia: a case-based review. Pediatr Neurol. 2023;146:26–30. https://doi.org/10.1016/j.pediatrneurol.2023.06.003.
31. Liampas I.N., Siokas V., Aloizou A.M., Tsouris Z., Dastamani M., Aslanidou P., Brotis A., Dardiotis E. Pyridoxine, folate and cobalamin for migraine: A systematic review. Acta Neurol Scand. 2020;42(2):108–120. https://doi.org/10.1111/ane.13251.
32. Habib S.S., Al-Khlaiwi T., Almushawah A., Alsomali A., Habib S.A. Homocysteine as a predictor and prognostic marker of atherosclerotic cardiovascular disease: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2023;27(18):8598–8608. https://doi.org/ 10.26355/eurrev_202309_33784.
33. Ding N., Ma S., Chang Q., Xie L., Li G., Hao Y. et al. Novel long noncoding lnc ARF mediated hyperhomocysteinemia-induced atherosclerosis via autophagy inhibition in foam cells. J Adv Res. 2025;73:311–328. https://doi.org/10.1016/j.jare.2024.08.030.
34. Qu R., Han A., Zhao Y., Qu X., Zhu Y. Characteristics of clinical manifestations and molecular genetics of inherited hyperhomocysteinemia in children and adolescents: a single center experience from China. Front Neurol. 2025;9(16):1588273. https://doi.org/10.3389/fneur.2025.1588273.
35. Chen W., Liang X., Liang G., Zhao X., Wang J., Jiang Q. Hyperhomocysteinemia and its association with decreased glomerular filtration rate in patients with chronic kidney disease: a comprehensive meta-analysis. Peer J. 2025;15:13:e20064. https://doi.org/10.7717/peerj.20064.
36. Bai B., Liu L., Liu Y., Yang S., Wu H., Zhang K., Shi L., Zhang Q. High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension. J Transl Med. 2025;23(1):525. https://doi.org/10.1186/s12967-025-06483-6.
37. Orimadegun B.E., Ademola A.A., Asinobi A.O. Vitamin B supplementation and homocysteine reduction in nigerian children with nephrotic syndrome: a randomized controlled trial. World J Nutr Health. 2025;12(1):8–15. https://doi.org/10.12691/jnh-12-1-2.
38. Zhang Q., Ma S., Kang X., Liu Y., Ma F., Yu F. et al. A dual-targeting bio-liposomes nanodrug repair endothelial cell dysfunction and restore macrophage cholesterol flow homeostasis to treat early atherosclerosis. J Nanobiotechnology. 2025;23(1):365. https://doi.org/10.1186/s12951-025-03436-5.
39. Rouphael M., Bitar T., Alarcan H., Gerges P., Sacre Y., Andres C.R., Hleihel W. Exploration of homocysteine metabolism and genetics in autism spectrum disorder. Nutrients. 2025;17(23):3761. https://doi.org/10.3390/nu17233761.
40. Al-Tai M.R., Kareem A.A., Saadi N.W., Omran T.B., Abdul Majeed B.A., Ibrahim I.F., Alattar L.A. A study of Iraqi patients with homocysteine remethylation disorders in a tertiary pediatric centre. Mol Genet Metab Rep. 2025;11(43):101217. https://doi.org/10.1016/j.ymgmr.2025.101217.
41. Rumińska M., Witkowska-Sędek E., Krajewska M., Stelmaszczyk-Emmel A., Sobol M., Pyrżak B. Evaluation of total homocysteine levels in relation to abdominal fat mass and traditional cardiovascular risk factors in overweight and obese adolescents. Life (Basel). 2025;15(8):1329. https://doi.org/10.3390/life15081329.
42. Zhao W., Zhang Y., Pi Y., Li Y., Zhang H. Clinical and molecular spectrum of patients with methylmalonic acidemia and homocysteinemia complicated by cardiovascular manifestations. Orphanet J Rare Dis. 2025;20(1):443. https://doi.org/10.1186/s13023-025-03907-w.
