• Дмитро Мальцев Experimental and Clinical Medicine Institute at the O.O. Bohomolets National Medical University
Keywords: homocysteine, B vitamins, vitamin D3, folic acid, creatinine, CPK, LDH


Backgrounds. The results of recent meta-analyzes of randomized controlled clinical trials indicate an association of genetic folate deficiency with autism spectrum disorders in children.The aim of the study: to study the biochemical disorders in children with genetic deficiency of the folate cycle associated with autism spectrum disorders, to understand the mechanism of encephalopathy and immunodeficiency, as well as to find biomarkers for monitoring and targets of further therapeutic interventions to prevent and/or reduce neurotoxicity and immunosuppression..
Materials and methods. The study group (DG) consisted of 138 children diagnosed with autism spectrum disorders (DSM-IV-TR and ICD-10), who had a genetic
deficiency of the folate cycle (MTHFR C677T + MTHFR A1298C and/or MTR A2756G and/or MTRR A66G; PCR). The control group (CG) included 51 healthy children of the appropriate age and gender distribution. Biochemical profile parameters were analyzed, including serum homocysteine, vitamins B6, B12, D3, folic acid, creatinine, creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).
Results and discussion. Patients with DG are characterized by a specific pattern of biochemical disorders (p˂0.05; Z˂Z0.05). Hyperhomocysteinemia, deficiency of some B vitamins, vitamin D3 and signs of mitochondrial dysfunction are noted. An increase in the concentration of homocysteine in the serum of children DG at the time of the examination occurred in 88 %, a decrease in serum concentrations of vitamin B6 – 76 %, vitamin B12 – 79 %, vitamin D3 – 72 %, folic acid – 69 %, hypercreatininemia – in 65 %, increased serum concentrations of CPK – in 57% and LDH – in 79 % of cases. Calculations of the odds ratio (OR) and 95 % confidence interval (95 % СI) indicate that all genotypes studied are associated with a characteristic pattern of biochemical changes. The expected frequency of certain biochemical disorders in the presence of a certain genotype increases from 2 to 7 times depending on the type of biochemical indicator, type, composition and number of pathogenic polymorphic variants of folic acid cycle enzyme genes with genotype-associated patterns and cumulative effect.
Conclusions. Genetic folate deficiency associated with autism spectrum disorders in children is characterized by a specific pattern of biochemical changes that is not typical of healthy children and may be involved in the pathogenesis of immunodeficiency and encephalopathy. It can be used in the diagnostic process in screening for genetic deficiency of the folate cycle, assessing the severity of the condition and conducting clinical monitoring of children with autism spectrum disorders. These disorders can be the object of therapeutic interventions to correct the biochemical status of the patient and reduce the manifestations of immunosuppression and mental disorders.


1. Мальцев Д.В. Иммунодефицит, обусловленный генетически детерминированным нарушением фолатного цикла, у детей с расстройствами аутистического спектра // Імунологія та алергологія: наука і практика. – 2019. – № 1. – С. 4–22.
2. Мальцев Д.В. Оценка иммунного статусаNу детей с расстройством аутистическогоNспектра, ассоциированным с генетическимNдефицитом фолатного цикла // ЛікарськаNсправа. – 2018. – №1-2. – C. 11–23.
3. Мальцев Д.В. Расширенный клинико-лабораторный фенотип при генетически детермированном нарушении фолатного цикла у детей с расстройствами спектра аутизма // Международный неврологический журнал. – 2018. – №5 (99). – С. 13–25.
4. Al-Mosalem O.A., El-Ansary A., Attas O., Al-Ayadhi L. Metabolic biomarkers related to energy metabolism in Saudi autistic children // Clin. Biochem. – 2009. – Vol. 42(10-11). – P. 949–957.
5. Arab A.H., Elhawary N.A. Methylenetetrahydrofolate Reductase Gene Variants Confer Potential Vulnerability to Autism Spectrum Disorder in a Saudi Community // Neuropsychiatr. Dis. Treat. – 2019. – Vol. 15. – P. 3569–3581.
6. Belardo A., Gevi F., Zolla L. et al. The concomitant lower concentrations of vitamins B6, B9 and B12 may cause methylation deficiency in autistic children // J. Nutr. Biochem. – 2019. – Vol. 70. – P. 38–46.
7. Bhatia P., Singh N. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression // Fundam. Clin. Pharmacol. – 2015. – Vol. 29(6). – P. 522–528.
8. Chen L., Shi X.J., Liu H. et al. Oxidative stress marker aberrations in children with autism spectrum disorder: a systematic review and meta-analysis of 87 studies (N = 9109) // Transl. Psychiatry. – 2021. – Vol. 11(1). – P.15.
9. El-Ansary A., Hassan Wail M., Daghestani M. et al. Preliminary evaluation of a novel ninebiomarker profile for the prediction of autism spectrum disorder // PLoS One. – 2020. – Vol. 15(1). – e0227626.
10. Frustaci A., Neri M., Cesario A. et al. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses // Free Radic. Biol. Med. – 2012. – Vol. 52(10). – P. 2128–2141.
11. Gevi F., Belardo A., Zolla L. A metabolomics approach to investigate urine levels of neurotransmitters and related metabolites in autistic children // Biochim. Biophys. Acta Mol. Basis. Dis. – 2020. – Vol. 1866(10). – P. 165859.
12. Guo B.Q., Li H.B., Ding S.B. et al. Blood homocysteine levels in children with autism spectrum disorder: An updated systematic review and meta-analysis // Psychiatry Res. – 2020. – Vol. 291. – P. 113283.
13. Haghiri R., Mashayekhi F., Bidabadi E., Salehi Z. Analysis of methionine synthase (rs1805087) gene polymorphism in autism patients in Northern Iran // Acta Neurobiol. Exp. (Wars). – 2016. – Vol. 76(4). – P. 318–323.
14. Li B., Xu Y., Zhang X. et al. The effect of vitamin D supplementation in treatment of children with autism spectrum disorder: a systematic review and meta-analysis of randomized controlled trials // Nutr. Neurosci. – 2020. – Vol. 7. – P. 1–11.
15. Li Y., Qiu S., Shi J. et al. Association between MTHFR C677T/A1298C and susceptibility to Nautism spectrum disorders: a meta-analysis // BMC Pediatr. 2020. – Vol. 20(1). – P. 449.
16. Li Y.J., Li Y.M., Xiang D.X. et al. Supplement intervention associated with nutritional deficiencies in autism spectrum disorders: a systematic review // Eur. J. Nutr. – 2018. – Vol. 57(7). – P. 2571–2582.
17. Lv M.N., Zhang H., Shu Y. et al. The neonatal levels of TSB, NSE and CK-BB in autism spectrum disorder from Southern China // Transl. Neurosci. – 2016. – Vol. 7(1). – P. 6–11.
18. Mead J., Ashwood P. Evidence supporting an altered immune response in ASD // Immunol. Lett. – 2015. – Vol. 163(1). – P. 49-55.
19. Melamed I.R., Heffron M., Testori A, Lipe K. A pilot study of high-dose intravenous immunoglobulin 5% for autism: Impact on autism spectrum and markers of neuroinflammation // Autism Res. – 2018. – Vol. 11(3). – P. 421– 433
20. Mohammad N.S., Shruti P.S., Bharathi V. et al. Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders // Psychiatr. Genet. – 2016. – Vol. 26(6). – P. 281–286.
21. Noriega D.B., Savelkoul H.F. Immune dysregulation in autism spectrum disorder // Eur. J. Pediatr. – 2014. – Vol. 173(1). – P. 33–43.
22. Pu D., Shen Y., Wu J. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis // Autism Res. – 2013. – Vol. 6(5). – P. 384–392.
23. Rai V. Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility // Metab. Brain Dis. – 2016. – Vol. 31(4). – P. 727–735.
24. Rai V. Strong Association of C677T Polymorphism of Methylenetetrahydrofolate Reductase Gene With Nosyndromic Cleft Lip/ Palate (nsCL/P) // Indian. J. Clin. Biochem. – 2018. – Vol. 33(1). – P. 5–15.
25. Sadeghiyeh T., Dastgheib S.A., Mirzaee-Khoramabadi K. et al. Association of MTHFR 677C>T and 1298A>C polymorphisms with susceptibility to autism: A systematic review and meta-analysis // Asian J Psychiatr. – 2019. – Vol. 46. – P. 54–61.
26. Wan L., Li Y., Zhang Z., Sun Z. et al. Methylenetetrahydrofolate reductase and psychiatric diseases // Transl. Psychiatry. – 2018. – Vol. 8(1). – P. 242.
27. Wang Z., Ding R., Wang J. et al. The Association between Vitamin D Status and Autism Spectrum Disorder (ASD): A Systematic Review and Meta-Analysis // Nutrients. – 2020. – Vol. 13(1). – E86.
28. Yektaş Ç., Alpay M., Tufan A.E. et al. Comparison of serum B12, folate and homocysteine concentrations in children with autism spectrum disorder or attention deficit hyperactivity disorder and healthy controls // Neuropsychiatr. Dis. Treat. – 2019. – Vol. 15. – P. 2213–2219.
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