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Maternal thiamine deficiency is prevalent in low- and middle-income countries. Thiamine-responsive pulmonary hypertension (TRPHTN) in exclusively breastfed infants is reported in India. Thiamine transporter gene (ThTR) variations have not been studied. This study compared the presentation of exclusively breastfed infants with respiratory distress diagnosed as TRPHTN or acute respiratory infection (ARI). We investigated pathogenic variations in the SLC19A2 and SLC19A3 ThTr genes in a representative sample. Observational study. Tertiary care pediatric unit of a teaching hospital in southern India. Data collection was prospective. We included exclusively breastfed infants between 1 and 6 months of age with respiratory distress. Infants with PHTN in echocardiography and lactic acidosis (LA) received thiamine. TRPHTN was diagnosed based on response within 72 h. Infants with fever, chest findings, and positive microbiology were managed as ARI. The ThTr genes were sequenced and analyzed. Chi-square and stratified analysis were done to determine TRPHTN risk. Forty infants with TRPHTN and 42 with ARI were included. The median pulmonary arterial pressure in the TRPHTN group was 51.5 mmHg. Mild PHTN was seen in 65%, moderate in 22.5%, and severe in 12.5%. Cardiac failure (P < .001), stridor and aphonia (P < .001), encephalopathy (P = .024), LA (P < .001), and PHTN (P <.001) facilitated the diagnosis. The adjusted risk was 17.3 (95% confidence interval 7.8-38.3; P <.001). The ThTR sequencing showed wild-type genotypes. TRPHTN has a distinct, identifiable presentation. Lactate and pulmonary pressure estimations are useful investigations in thiamine deficiency endemic areas. We could not demonstrate a genetic variation that determines susceptibility., (© The Author(s) [2024]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Wernicke-Korsakoff syndrome (WKS) is commonly associated with chronic alcohol misuse, a condition known to have multiple detrimental effects on thiamine metabolism. This study was conducted to identify genetic variants that may contribute to the development of WKS in individuals with alcohol dependence syndrome through alteration of thiamine transport into cells., Methods: Exome sequencing data from a panel of genes related to alcohol metabolism and thiamine pathways were analysed in a discovery cohort of 29 individuals with WKS to identify possible genetic risk variants associated with its development. Variant frequencies in this discovery cohort were compared with European frequencies in the Genome Aggregation Database browser, and those present at significantly higher frequencies were genotyped in an additional cohort of 87 alcohol-dependent cases with WKS and 197 alcohol-dependent cognitively intact controls., Results: Thirty non-synonymous variants were identified in the discovery cohort and, after filtering, 23 were taken forward and genotyped in the case-control cohort. Of these SLC19A1:rs1051266:G was nominally associated with WKS. SLC19A1 encodes the reduced folate carrier, a major transporter for physiological folate in plasma; rs1051266 is reported to impact folate transport. Thiamine pyrophosphate (TPP) efflux was significantly decreased in HEK293 cells, stably transfected with rs1051266:G, under thiamine deficient conditions when compared with the efflux from cells transfected with rs1051266:A (P = 5.7 × 10-11)., Conclusion: This study provides evidence for the role of genetic variation in the SLC19A1 gene, which may contribute to the development of WKS in vivo through modulation of TPP transport in cells., (© The Author(s) 2022. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Aims: In the scientific literature it has been repeatedly hypothesized that there is a heritable susceptibility to thiamine deficiency comparable to other hereditary metabolic disorders. The aim of this paper is to review the most recent knowledge on the genetic susceptibility to the development of alcohol-related Wernicke-Korsakoff syndrome (WKS)., Methods: A literature review was carried out looking at the molecular genetics studies performed in alcohol-dependent patients affected by WKS., Results: A genetic component in the pathogenesis of WKS has been postulated since the late seventies. Since then, very few genetic studies have been carried out on candidate genes such as thiamine-dependent enzymes, alcohol-metabolizing enzymes and GABA receptors. The findings are controversial and not conclusive. Several authors reported the important role of the thiamine transporters in the pathogenesis of the thiamine deficiency disorders. Our findings on SLC19A2 and SLC19A3 suggest a potential role of these two genes in the pathophysiology of alcohol-related thiamine deficiency but further studies need to be carried out., Conclusions: The WKS may be a very complex, multifactorial disorder where the interaction of multiple genes and environment plays an important role in the pathogenesis. However, it is still plausible that megaphenic gene effects are responsible for WKS susceptibility and the thiamine transport genes are good candidates for having such a role. Further genetic studies are definitely needed to investigate the association with candidate genes or linkage with hot spot areas.

It was found that the activity of the marker thiamine-dependent enzyme, transketolase (TK), was decreased (down to 61-79% of control) in blood, liver and brain of inbred rats following a 6-month consumption of 15% ethanol as their only source of drinking fluid. After ethanol withdrawal, the enzyme activity was gradually restored, but did not reach the control values until 1 month following cessation of alcohol consumption. Moreover, in rats preferring ethanol, the decrease of TK activity was more pronounced than in water-preferring rats. Another experiment showed that thiamine deficiency induced by the thiamine antagonist, oxythiamine (200 mg/kg), led to a prolonged increase of the preferential intake of ethanol solutions in inbred rats. Significantly lower liver TK activities and thiamine pyrophosphate content were found in Finnish AA line rats as opposed to ANA line rats which had been obtained by selective outbreeding for high and low voluntary alcohol intake, respectively. Significantly lower TK activity was also found in the whole brain (89%), cerebellum (79%) and pons-medulla oblongata (87%) of AA rats as compared to ANA animals. Our own findings and the literature data confirm the hypothesis that thiamine deficiency can be both predisposing to and a consequence of, increased alcohol consumption.