Extended clinical and laboratory phenotype in genetically determined folate cycle deficiency in children with autism spectrum disorders

D.V. Maltsev


Background. The genetic deficiency of folate cycle enzymes is considered today as one of the common causes of autism spectrum disorders in children, but the relationship between the genetic components of failures and clinical phenotype was not characterized enough. There is some evidence of immune system involvement in the pathogenesis, including association with immunodeficiencies, cases of autism after neuroinfections and autoimmune encephalitis, the effectiveness of immunotherapy. The purpose was to evaluate the extended clinical and laboratory phenotype in patients with autism spectrum disorders associated with genetically determined deficiency of folate cycle. Materials and methods. A prospective, controlled, single­center study included 78 children diagnosed with autism spectrum disorders and/or cerebral palsy. These were patients from different regions of Ukraine, aged 2 to 10 years, 47 boys and 31 girls. Control group consisted of 34 healthy children with the same age and gender distribution. The identification of gene polymorphisms of folate cycle by polymerase chain reaction, a comprehensive immunological study, diagnosis of infection (polymerase chain reaction, serological tests, microbiological method), determination of biomarkers (biochemical methods) were performed. In order to establish the significant differences of the results, Student’s T­test was used with the calculation of confidence coefficient p (parametric test) and the number of Z signs by Urbach (nonparametric). To study the relationship between polymorphisms of folate cycle genes and the immune status, the Pearson’s chi­squared test (χ2) was used. Results. The deficiency of NK­ and/or NKT­cells was observed in the study group in 91 % of cases, while among healthy children from the control group, similar immunophenotype occurred only in 27 % of cases, and usually there was a slight decrease in the number of cells (p < 0.05; Z < Z0.05). Deficiency of NK­ and NKT­cells was closely associated with the presence of polymorphisms in the genes of folate cycle enzymes (χ2 = 51.1; p = 0.01), as well as demonstrated less pronounced but statistically significant correlation with myeloperoxidase deficiency (p = 0.05). An abnormally reduced resistance to viral agents was shown: lymphotropic herpesviruses, measles and rubella, rotavirus, which can be explained by the immune deficiency. Associated extensive clinical phenotype is characterized that include, in addition to autistic disorders, other immunodependent lesions: chronic viral infections, mesial temporal sclerosis and mesial temporal lobe epilepsy (46 %), PANDAS (27 %), movement disorders (20 %), allergy (32 %) and bowel syndrome (88 %). Leukoencephalopathy, especially that involving periventricular areas of the parietal lobes, associated with neuroinfections and autoimmune reactions, was the main form of damage to the central nervous system (96 %). Conclusions. It is reasonable to talk about the extended clinical and laboratory phenotype in children with genetic folate cycle deficiency associated with autism spectrum disorders that requires a multidisciplinary approach to the management of patients with the mandatory assistance of a clinical immunologist.


folate cycle; polymorphisms; NK-cells; immunodeficiency; autism


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