Vitamin B12 and folate deficiencies, elevated homocysteine and their roles in the biochemical basis of neuropsychiatric diseases in children and adolescents: Case series, review and recommendations

Year 2024, Volume: 10 Issue: 2, 206 - 228, 30.06.2024

Erman Esnafoglu

https://doi.org/10.19127/mbsjohs.1417861

Abstract

Vitamin B12 and folate deficiencies can be frequently seen in children and adolescents and may manifest with neuropsychiatric symptoms. Vitamin B12 and folate deficiencies and the associated increase in homocysteine are related to one-carbon metabolism (OCM) and may play a role in the pathogenesis of childhood and adolescent psychiatric disorders.
Therefore, a case series and review on OCM will be presented here. Twelve cases with vitamin B12 and folate deficiency and increased homocysteine among those admitted to the child and adolescent psychiatry clinic were retrospectively examined. It was found that vitamin B12 and folate deficiency and increased homocysteine may cause depressive symptoms, anxiety disorders, obsessive compulsive disorder, anger control problems, self-harming behaviors, suicidal thoughts and attempts in children and adolescents.
According to these data, vitamin B12 and folate deficiency and the resulting increase in homocysteine may cause psychiatric symptoms in some children and adolescents. In addition, literature on OCM has been reviewed.
The diagnosis and treatment methods for vitamin B12 and folate deficiencies are summarized for clinicians.

Keywords

vitamin B12, folate, homocysteine, one-carbon metabolism, child and adolescent psychiatry, anxiety, depression

Ethical Statement

The study was approved by the Ethics Committee of Ordu University Faculty of Medicine (ethics committee approval no: 2023-75).

Supporting Institution

non

Thanks

I would like to thank my patients and their families and Sezanur Arslanturk clinical psychologist for performing psychometric tests.

References

• Garcia-Casal MN, Osorio C, Landaeta M, Leets I, Matus P, Fazzino F, Marcos E. High prevalence of folic acid and vitamin B12 deficiencies in infants, children, adolescents and pregnant women in Venezuela. Eur J Clin Nutr. 2005;59(9):1064-1070.
• Pawlak R, Lester SE, Babatunde T. The prevalence of cobalamin deficiency among vegetarians assessed by serum vitamin B12: a review of literature. Eur J Clin Nutr. 2014;68(5):541-548.
• Pawlak R, Parrott SJ, Raj S, Cullum-Dugan D, Lucus D. How prevalent is vitamin B12 deficiency among vegetarians? Nutr Rev. 2013;71(2):110-117.
• Chakraborty S, Chopra M, Mani K, Giri AK, Banerjee P, Sahni NS, et al. Prevalence of vitamin B12 deficiency in healthy Indian school‐going adolescents from rural and urban localities and its relationship with various anthropometric indices: a cross‐sectional study. J Hum Nutr Diet. 2018;31(4):513-522.
• González-Gross M, Benser J, Breidenassel C, Albers U, Huybrechts I, Valtueña J, et al. Helena Study group. Gender and age influence blood folate, vitamin B12, vitamin B6, and homocysteine levels in European adolescents: the Helena Study. Nutr Res. 2012;32(11):817-826.
• Lavriša Ž, Hristov H, Hribar M, Žmitek K, Kušar A, Koroušić Seljak B, et al. Dietary Intake and Status of Vitamin B12 in Slovenian Population. Nutrients. 2022;14(2):334.
• Sodawat R, Kumar N, Singh C. A prospective cross-sectional study of prevalence of neuropsychiatric manifestations in adole-scents with vitamin B 12 deficiency anemia. Int J Med Sci Educ. 2019;6(3):51-56.
• Esnafoğlu E, Yaman E. Vitamin B12, folic acid, homocysteine and vitamin D levels in children and adolescents with obsessive compulsive disorder. Psych Res. 2017;254:232-237.
• Esnafoglu E, Ozturan DD. 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.
• Tan Y, Zhou L, Huang J, Chen X, Wu Y, Song X, et al. Vitamin B12, Folate, Homocysteine, Inflammatory Mediators (Interleukin-6, Tumor Necrosis Factor-α and C-Reactive Protein) Levels in Adolescents with Anxiety or Depressive Symptoms. Neuropsychiatr Dis Treat. 2023;785-800.
• Murakami K, Miyake Y, Sasaki S, Tanaka K, Arakawa M. Dietary folate, riboflavin, vitamin B-6, and vitamin B-12 and depressive symptoms in early adolescence: the Ryukyus Child Health Study. Psychosom Med. 2010;72(8):763-768.
• Paşca SP, Nemeş B, Vlase L, Gagyi CE, Dronca E, Miu AC, Dronca M. High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism. Life sciences. 2006;78(19):2244-2248.
• Zhang Y, Hodgson NW, Trivedi MS, Abdolmaleky HM, Fournier M, Cuenod M, Deth RC. Decreased brain levels of vitamin B12 in aging, autism and schizophrenia. PloS one. 2016;11(1):e0146797.
• Altun H, Kurutaş EB, Şahin N, Güngör O, Fındıklı E. The levels of vitamin D, vitamin D receptor, homocysteine and complex B vitamin in children with autism spectrum disorders. Clin Psychopharmacol Neurosci. 2018;16(4):383.
• Esnafoğlu E. Serum Folate, Vitamin B12, Homocysteine and Vitamin D Levels in Children with Specific Learning Disorder. Bozok Tıp Dergisi. 2018;8(3):59-64.
• Kevere L, Purvina S, Bauze D, Zeibarts M, Andrezina R, Rizevs A, Purvins I. Elevated serum levels of homocysteine as an early prognostic factor of psychiatric disorders in children and adolescents. Schizophr Res Treatment.2012:1-7
• Kevere L, Purvina S, Bauze D, Zeibarts M, Andrezina R, Piekuse L, Purvins I. Homocysteine and MTHFR C677T polymorphism in children and adolescents with psychotic and mood disorders. Nord J Psychiatry. 2014;68(2):129-136.
• Serin HM, Arslan EA. Neurological symptoms of vitamin B12 deficiency: analysis of pediatric patients. Acta Clin Croat. 2019;58(2):295.
• Baig S. Diet Restrictions, Epigenetics and Depression. J Coll Physicians Surg Pak. 2023;33(2):127-128.
• Santhosh-Kumar CR, Hassell KL, Deutsch JC, Kolhouse JF. Are neuropsychiatric manifestations of folate, cobalamin and pyridoxine deficiency mediated through imbalances in excitatory sulfur amino acids?. Med Hypotheses. 1994;43(4):239-244.
• Tawfik A, Elsherbiny NM, Zaidi Y, Rajpurohit P. Homocysteine and age-related central nervous system diseases: role of inflammation. Int J Mol Sci. 2021;22(12):6259.
• Partearroyo T, Úbeda N, Montero A, Achón M, Varela-Moreiras G. Vitamin B12 and folic acid imbalance modifies NK cytotoxicity, lymphocytes B and lymphoprolipheration in aged rats. Nutrients. 2013;5(12):4836-4848.
• Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM. Folate, vitamin B12, homocysteine, and the MTHFR 677C→ T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003;60(6):618-626.
• Chung KH, Chiou HY, Chen YH. Associations between serum homocysteine levels and anxiety and depression among children and adolescents in Taiwan. Sci Rep. 2017;7(1):1-7.
• Sangle P, Sandhu O, Aftab Z, Anthony AT, Khan S. Vitamin B12 supplementation: preventing onset and improving prognosis of depression. Cureus.2020;12(10).
• Stover PJ. Physiology of folate and vitamin B 12 in health and disease. Nutr Rev. 2004;62(1):3-12.
• Kishi T, Fujita N, Eguchi TA, Ueda K. Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci. 1997;145(1):109-112.
• Khaneghah AM, Hashemi SMB, Es I, Gholamhosseinpour A, Loizzo MR, Giardinieri A, et al. (2019) Water-soluble vitamins. In Barba FJ, Saraiva JMA, Cravotto G, Lorenzo JM (ed) Innovative Thermal and Non-Thermal Processing, Bioaccessibility and Bioavailability of Nutrients and Bioactive Compounds. Woodhead Publishing, Duxford, United Kingdom; 2019. P.241-266.
• Al Mutairi F. Hyperhomocysteinemia: clinical insights. J Cent Nerv Syst Dis. 2020;12:1179573520962230.
• Cicero AF, Minervino A. Combined action of SAMe, Folate, and Vitamin B12 in the treatment of mood disorders: a review. Eur Rev Med Pharmacol Sci. 2022;26(7):2443-2459.
• Troen AM. Folate and vitamin B12: function and importance in cognitive development. In Bhutta ZA, Hurrell RF, Rosenfeld IF (eds): Meeting Micronutrient Requirements for Health and Development. Nestlé Nutr Inst Workshop Ser, Karger Publishers 2012;70:161–171.
• Hannibal L, Lysne V, Bjørke-Monsen AL, Behringer S, Grünert SC, Spiekerkoetter U. Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency. Front Mol Biosci. 2016;3,27:1-16.
• Sönmezışık F, Gür ES, Asıltaş B. Importance of holotranscobalamin (holotc) measurements in early diagnosis of cobalamin deficiency, especially in patients with borderline vitamin B12 concentrations. Nobel Medicus Journal. 2013;9(2):15-20.
• Shane, B. Folate status assessment history: implications for measurement of biomarkers in NHANES. Am J Clin Nutr. 2011;94(1):337S-342S.
• Wang H, Li L, Qin LL, Song Y, Vidal‐Alaball J, Liu TH (2018) Oral vitamin B 12 versus intramuscular vitamin B 12 for vitamin B 12 deficiency. Cochrane Database Syst Rev. (3):1-54.
• Koksal AO, Koksal T, Duyan Camurdan A. Sublingual spray treatment of vitamin B12 deficiency in children. Electron J Gen Med. 2022;19(4): em382.
• Regland B, Abrahamsson L, Blennow K, Gottfries CG, Wallin A. Vitamin B12 in CSF: reduced CSF/serum B12 ratio in demented men. Acta neurologica scandinavica. 1992;85(4), 276-281.
• Bender A, Hagan KE, Kingston N. The association of folate and depression: A meta-analysis. J Psychiatr Res. 2017;95:9-18.
• Rathod RS, Khaire AA, Kale AA, Joshi SR. Effect of vitamin B12 and omega-3 fatty acid supplementation on brain neurotrophins and cognition in rats: A multigeneration study. Biochimie. 2016;128:201-208.
• Zhang JC, Yao W, Hashimoto K. Brain-derived Neurotrophic Factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets. Curr Neuropharmacol. 2016;14(7):721–731.