Approximately 10% of detoxified alcoholics are severely impaired as a result of alcoholism-associated chronic organic mental disorders, i.e., alcohol amnestic disorder (commonly called Wernicke-Korsakoff [W-K] syndrome or Korsakoff's psychosis [KP]) or dementia associated with alcoholism [DAA]. Although the relative contributions of ethanol neurotoxicity and thiamine deficiency (a frequent complication of alcoholism) in the pathogenesis of alcoholic organic brain disorders remain controversial, the importance of thiamine, deficiency, particularly in the etiology of W-K syndrome, is well established. We have demonstrated that transketolase derived from fibroblasts has reduced affinity for its cofactor thiamine pyrophosphate [TPP] in alcoholic patients with W-K syndrome (Michaelis-Menten constant [KM] four times higher than normal) and in familial alcoholics and their alcohol-naive sons (KM twice normal). It is hypothesized that the transketolase phenotype with reduced affinity for TPP may represent a genetic susceptibility to thiamine deficiency disease, and consequently, a risk factor for alcoholic brain damage. Using 1) two cDNA clones which we have isolated and shown to correspond to the human transketolase gene and 2) cell lines from our previous studies, we propose to elucidate the gene structure and organization of human transketolase; determine the primary structure of the coding regions for normal individuals with low KM form(s) of the enzyme and for W-K patients with high KM form(s); and prepare probes which can distinguish between the gene(s) encoding low KM form(s) of transketolase and the gene(s) encoding high KM form(s). In a prospective study using these gene probes, we will determine whether the abnormal (high KM) genotype(s) are more frequent in chronic alcoholics with KP than in those with DAA or in those without significant neuropsychological impairment. The relation of transketolase genotype to the pattern of cognitive impairment. The relation of transketolase genotype to the pattern of cognitive impairment in individual patients will be explored using the results of a neuropsychological test battery designed to obtain a global assessment of cognitive skills and an in-depth examination of memory functions. The identified patients would serve as probands for future pedigree studies to evaluate the association between transketolase genotype and alcoholic organic brain disease and to determine the mode of inheritance of transketolase.
