SLC19A1 Genetic Variation Leads to Altered Thiamine Diphosphate Transport: Implications for the Risk of Developing Wernicke-Korsakoff's Syndrome.

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.

Phenotypic heterogeneity in study populations may significantly confound the results of genetic association studies on alcohol dependence.

BACKGROUND: The interpretation of genetic studies on alcohol dependence may be confounded by the co-occurrence of substance dependence, psychiatric disorders and alcohol-related comorbidities, for example, cirrhosis. Significant single-marker and haplotypic associations between polymorphisms in the zinc finger gene, ZNF699, and alcohol dependence were reported in the Irish Affected Sib Pair Study of Alcohol Dependence population, one-third of whom had co-occurring substance dependence while 80% had identified psychiatric comorbidity. The aim of this study was to explore variant ZNF699 associations with alcohol dependence while exercising controls for potential confounders. METHODS: The study population was comprised of 1449 alcohol-dependent cases and 1283 population controls; all were of British or Irish ancestry. None of the cases had a history of dependence on other substances, and the frequency of comorbid depression was low. A separate, ancestry-matched cohort of 196 opioid-dependent cases was also included. Genotyping for the four previously identified SNPs of interest in ZNF699 was performed using K-Biosciences Competitive Allele Specific PCR. RESULTS: No single-marker associations were found between polymorphisms in ZNF699 and alcohol dependence per se. A significant allelic association was found between rs7254880 in ZNF699 and alcohol-related cirrhosis (n=292), using cases with no biopsy evidence of liver disease (n=314) as controls (P=0.013). Significant allelic associations were also found between rs12460279 (P=0.028), rs7252865 (P=0.012) and rs10854142 (P=0.016) in ZNF699 and opioid dependence. CONCLUSION: Phenotypic variation in study populations may contribute towards the nonreplication of genetic association studies on alcohol dependence; controls for recognised confounding variables should be exercised whenever possible.

Genetic variants in or near ADH1B and ADH1C affect susceptibility to alcohol dependence in a British and Irish population.

Certain single nucleotide polymorphisms (SNPs) in genes encoding alcohol dehydrogenase (ADH) enzymes confer a significant protective effect against alcohol dependence syndrome (ADS) in East Asian populations. Recently, attention has focused on the role of these SNPs in determining ADS risk in European populations. To further elucidate these associations, SNPs of interest in ADH1B, ADH1C and the ADH1B/1C intergenic region were genotyped in a British and Irish population (ADS cases n = 1076: controls n = 1027) to assess their relative contribution to ADS risk. A highly significant, protective association was observed between the minor allele of rs1229984 in ADH1B and ADS risk [allelic P = 8.4 × 10(-6) , odds ratio (OR) = 0.26, 95 percent confidence interval, 0.14, 0.49]. Significant associations were also observed between ADS risk and the ADH1B/1C intergenic variant, rs1789891 [allelic P = 7.2 × 10(-5) , OR = 1.4 (1.2, 1.6)] and three non-synonymous SNPs rs698, rs1693482 and rs283413 in ADH1C. However, these associations were not completely independent; thus, while the ADH1B rs1229984 minor allele association was independent of those of the intergenic variant rs1789891 and the three ADH1C variants, the three ADH1C variants were not individually independent. In conclusion, the rare ADH1B rs1229984 mutation provides significant protection against ADS in this British and Irish population; other variants in the ADH gene cluster also alter ADS risk, although the strong linkage disequilibrium between SNPs at this location precluded clear identification of the variant(s) driving the associations.

Genetic and environmental interplay in risky drinking in adolescents: a literature review.

AIMS: The aim of the study was to review recent research on the interplay between genes, environment and epigenetic factors in risky drinking in adolescents and the impact of neurobiological determinants on early alcohol-related cognitive deficits in young people. METHODS: Narrative review. RESULTS: There is consensus that the brain and the behaviour are shaped during development by the combined effects of genes, childhood experiences, environment and hormonal variations. Epigenetic factors seem to play a role in linking the expression of genes with stress and external experiences during brain maturation and development. Evidence on the interaction between genes and environmental factors illustrates that, in adolescence, external factors play a more important role than genetic factors on the risk of developing alcohol problems later on in life. CONCLUSIONS: Adolescence is a crucial stage of brain development; intervening early and applying certain prevention programmes may halt the progression of alcohol misuse.

Time to act on the inadequate management of Wernicke's encephalopathy in the UK.

Wernicke's encephalopathy (WE) is a serious medical emergency whose pathogenesis is well understood and reviewed in this paper. Summarizing the evidence for its prophylaxis and management, the authors suggest that, in the UK, there is evidence that many patients identified as being at risk of WE currently do not receive appropriate treatment, despite the availability (not universal) of guidelines and protocols.

The Korsakoff syndrome: clinical aspects, psychology and treatment.

AIMS: The Korsakoff syndrome is a preventable memory disorder that usually emerges (although not always) in the aftermath of an episode of Wernicke's encephalopathy. The present paper reviews the clinical and scientific literature on this disorder. METHODS: A systematic review of the clinical and scientific literature on Wernicke's encephalopathy and the alcoholic Korsakoff syndrome. RESULTS: The Korsakoff syndrome is most commonly associated with chronic alcohol misuse, and some heavy drinkers may have a genetic predisposition to developing the syndrome. The characteristic neuropathology includes neuronal loss, micro-haemorrhages and gliosis in the paraventricular and peri-aqueductal grey matter. Lesions in the mammillary bodies, the mammillo-thalamic tract and the anterior thalamus may be more important to memory dysfunction than lesions in the medial dorsal nucleus of the thalamus. Episodic memory is severely affected in the Korsakoff syndrome, and the learning of new semantic memories is variably affected. 'Implicit' aspects of memory are preserved. These patients are often first encountered in general hospital settings where they can occupy acute medical beds for lengthy periods. Abstinence is the cornerstone of any rehabilitation programme. Korsakoff patients are capable of new learning, particularly if they live in a calm and well-structured environment and if new information is cued. There are few long-term follow-up studies, but these patients are reported to have a normal life expectancy if they remain abstinent from alcohol. CONCLUSIONS: Although we now have substantial knowledge about the nature of this disorder, scientific questions (e.g. regarding the underlying genetics) remain. More particularly, there is a dearth of appropriate long-term care facilities for these patients, given that empirical research has shown that good practice has beneficial effects.

Molecular genetics of alcohol-related brain damage.

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.

Wernicke's encephalopathy revisited. Translation of the case history section of the original manuscript by Carl Wernicke 'Lehrbuch der Gehirnkrankheiten fur Aerzte and Studirende' (1881) with a commentary.

AIMS: A translation into English of the case history section of Carl Wernicke's original manuscript of 1881, with a discussion on its relevance for clinicians today. METHODS: A copy of Carl Wernicke's original German text was obtained by one of the authors (CCHC) and translated into English from the old German by a professional translator. RESULTS: The translation was subsequently agreed by native German speaking referees, and minor changes made. CONCLUSIONS: The authors studied the translation in detail and concluded that Wernicke's description had stood the test of time. The diagnosis of Wernicke's Encephalopathy remains a clinical one.

Wernicke's encephalopathy: 'Plus ça change, plus c'est la même chose'.

AIMS: To develop clinical guidelines to identify individuals who misuse alcohol and are at risk of developing Wernicke's Encephalopathy (WE). METHOD: Non-systematic literature review of studies which includes a careful clinical record of the development of signs and symptoms of thiamine deficiency and in which the diagnosis of WE has been confirmed at autopsy. RESULTS: The review of the clinical findings in cases of WE, diagnosed at autopsy, shows a consistent pattern of signs and symptoms. The pattern appears to be similar regardless of whether the thiamine deficiency is related to nutritional problems alone or associated with alcohol misuse. CONCLUSIONS: The assessment of the degree of thiamine deficiency and the diagnosis of WE remain a clinical evaluation, and guidelines are suggested to help the clinician. Since neurotoxicity due to the metabolism of excessive alcohol in patients with chronic and severe alcohol dependence may be an important factor in determining long-term outcome of treatment, this must form part of the overall evaluation.

The importance of alcohol misuse, malnutrition and genetic susceptibility on brain growth and plasticity.

The "dyad: alcoholic mother and foetus" is a very complex entity in which several elements such as genes, metabolism, diet, drugs and social habits play a role at different stages in the development of the fetal brain damage. The literature on the effects of alcohol consumption on the developing brain is extensive but very few evidences have been reported regarding the combined neurotoxic effects of poor nutrition and alcohol consumption. The consequences of ethanol intake alone or combined with poor maternal nutrition appear to be severe and life-long. Alcohol exerts its neurotoxic effects on the developing brain directly by acting on fetal brain tissues, and indirectly either by interfering with placental physiology or by impairing the mother's physiology. Alcohol misuse in pregnancy is also frequently associated with other conditions that can potentially increase the brain damage such as poor nutrition and smoking. This article reviews the effects of poor nutrition and alcohol misuse during pregnancy on the development of the fetal brain and discusses the cumulative effects of these two environmental factors and their interaction with maternal and fetal genetic make-ups.

The treatment of patients at risk of developing Wernicke's encephalopathy in the community.

AIM: To review the process of identifying alcohol-dependent patients at risk of developing Wernicke's encephalopathy (WE) in the community, and prophylactic treatment options. METHODS: Non-systematic literature review of the diagnosis of thiamine deficiency and of its treatment in the community. The role of supplementation of beer and bread with thiamine was evaluated. RESULTS: The diagnosis of thiamine deficiency is not always made, and treatment apparently may sometimes be inadequate. CONCLUSIONS: Alcohol-dependent patients in the community who are at risk of developing WE should be given thiamine 250 mg, intramuscularly, daily for 3-5 days as part of a community detoxification programme. Further work is essential to determine the optimum dose of thiamine required to prevent permanent brain damage (Korsakoff's Psychosis). Neurotoxicity, due to the metabolism of excessive alcohol in patients with chronic and severe alcohol dependence, must be considered as an important factor in determining the long-term outcome of treatment.

The natural history and pathophysiology of Wernicke's Encephalopathy and Korsakoff's Psychosis.

AIMS: To identify the early clinical indications of thiamine deficiency and to understand the factors involved in the development of the amnesic state in alcohol-dependent individuals with thiamine deficiency. It is hoped that this will highlight the need for clinicians to treat alcohol-dependent patients prophylactically with parenteral thiamine and thus prevent the development of Korsakoff's Psychosis (KP). METHOD: We have reviewed the natural history and pathophysiology of Wernicke's Encephalopathy (WE) in both human and animal studies together with any contributory factors that may predispose the individual to thiamine deficiency. A further understanding of these problems is provided by recent studies into the metabolic consequences of thiamine deficiency and alcohol misuse. CONCLUSIONS: Where WE is due to thiamine deficiency alone (i.e. in the absence of alcohol misuse) KP rarely supervenes following thiamine replacement therapy. Successful treatment or prophylaxis of WE in alcohol dependence probably depends on a number of inter-related issues and is not simply a matter of early and adequate thiamine treatment. If sufficient alcohol-related neurotoxicity has occurred by the time of diagnosis, then this may be the more important or limiting factor with respect to the long-term outcome. This possible obstacle to complete recovery should not prevent every attempt being made to provide the patient with optimum brain thiamine replacement.

The Royal College of Physicians report on alcohol: guidelines for managing Wernicke's encephalopathy in the accident and Emergency Department.

The Royal College of Physicians (London) recently published its latest report on alcohol misuse entitled 'Alcohol - Can the NHS Afford It?'. Part of this document, encompassing our views, has made specific recommendations for the management of patients in the Accident and Emergency (A&E) Department who may possibly have, or are at risk of developing, Wernicke's encephalopathy. Patients showing evidence of chronic alcohol misuse and suspected of having a poor diet should be treated at the outset with B vitamins intravenously or intramuscularly, especially when the clinical signs are initially masked by drunkenness at presentation to the A&E Department. This commentary offers a review of the scientific foundations on which these recommendations have been made.