Hyperhomocysteinemia in men and women of married couples with reproductive disorders. What is the difference?

Hyperhomocysteinemia (HHcy) is an autosomal recessive inherited metabolic disease caused by variations in folate metabolism genes, characterized by impaired methionine metabolism and accumulation of homocysteine (Hcy) in the blood serum. It was shown that men usually have higher plasma Hcy levels than women, but have not yet assessed the leading factors of these differences, which is important for the development of personalized protocols for the prevention of folate metabolism disorders in couples with reproductive disorders. This study aimed to analyze the effect of intergenic and gene-factor interactions on the risk of developing HHcy in men and women of married couples with reproductive disorders. In our study were involved 206 married Caucasian couples (206 males and 206 females) from central regions of Ukraine with early pregnancy losses in the anamnesis. We found that the incidence of HHcy in men was significantly higher than in women. Gender differences in folic acid and vitamin B12 levels were identified. The best predictors of HHcy in men (MTRR (A66G), MTHFR (C677T), MTR (A2756G), vitamin B12 level) and in women (MTHFR (C677T), MTR (A2756G), vitamin B12 level) were selected by binary logistic regression. There was no significant difference in the distribution of genotypes by the studied gene variants when comparing men and women with HHcy. Our findings demonstrate that there is a gender difference in the development of HHcy. This difference is caused by intergenic interaction and by environmental factors, in particular, nutrition and vitamins consumption.

Betaine consumption as a new clinical approach to treatment and prophylaxis of folate-related pathologies.

The most important pathway in the development of folate-related pathologies is an increase in the level of homocysteine (HC). HC, a cytotoxic and neurotoxic amino acid (when its level is ≥12 µmol/L), is 1 of the most widely studied compounds in cardiology, neurobiology, oncology, and embryology for the last 20 years. Given its toxicity, the processes of endogenous detoxification of HC are of particular interest to medicine. To date, the most studied pathway is that of remethylation (the conversion of HC to methionine), with the participation of B12- and B9-dependent methionine synthase. Less studied is remethylation with the participation of the choline derivatives betaine and betaine-HC-S-methyltransferase (BHMT). Therefore, the aim of this review was to conduct a theoretical analysis of available information regarding the contribution of betaine metabolism, its enzyme, and its genetic polymorphism to folate metabolism disturbances, and the development of folate-related pathologies. This review emphasizes the potential clinical significance of 2 factors that can influence the remethylation reaction of HC: the use of betaine and identifying the BHMT gene variants and their impact on the risk for developing certain folate-related pathologies, and treatment options. Moreover, with a high level of methylation of the BHMT gene and in the presence of its low-function variants (eg, rs3733890), it is necessary to use betaine as an additional methyl donor, especially during folate therapy. More clinical research is needed to identify the effects of the different BHMT gene variants on the individual risk for folate-related pathologies to better assess the clinical significance, the need for genetic testing, and betaine consumption.

The analysis of using a panel of the most common variants in the PAH gene for the newborn screening in Ukraine.

Phenylketonuria (PKU) is hyperphenylalaninemia that develops due to a deficiency of the phenylalanine hydroxylase enzyme (PAH). Identification of variants in the PAH gene is necessary for verification of the diagnosis, choice of treatment tactics, detection of heterozygous carriers. The aim of the study was to analyze the effectiveness of identification of selected pathological variants in the PAH gene during the newborn screening program. This study relied on the results of the examination of 257 patients (138 boys and 119 girls) with hyperphenylalaninemia from different regions of Ukraine. Genotyping was performed on nine pathogenic variants in PAH gene: I65T, R261Q, G272*, R252W, R261*, R408W, IVS12 + 1G > A, Y414C, IVS10-11G > A. According to the results of the study, variants R408W (AF = 52.7%), R252W (AF = 3.5%) and Y414C (AF = 1.8%) were the most common. More than half of the examined patients (51.7%) had a compound genotype with a major variant of R408W in one allele. Approximately a quarter of the examined patients (26.8%) had the R408W/R408W genotype. In 12.1% of patients, the applied panel of variants of the РАН gene did not allow us to identify the pathogenic variant in any allele. We conclude that the selected panel allowed us to identify the presence of variants in 87.9% of patients with PKU. The panel of genetic testing in the PAH gene for the newborns that we used for the study allows accurate prediction of some phenotypes for therapy planning. But in-depth analysis of pathological gene variants may be necessary for unclear and difficult cases of the disease, and for genetic counseling of patients families.