The role of genetic predisposing factors in developing fetal toxicity of ethanol is continued. During the past year we have studied the transketolase abnormality in cultured fibroblasts from a diabetic patient who developed Wernicke's encephalopathy when treated with tolazamide, a hypoglycemic agent. Additionally, three diabetic kindreds without any history of Wernicke's encephalopathy and four normal controls were also studied. We found that the patient with tolazamide induced Wernicke's encephalopathy and one of the three diabetic kindreds had abnormal Km of transketolase for TPP similar to the ones found previously in post-alcoholic Wernicke's-Korsakoff syndrome. These data suggest that transketolase abnormality is prevalent in the population and the individuals with this abnormality may be predisposed to developing thiamine deficiency syndromes either by drugs that increase thiamine utilization or by ethanol abuse. To investigate whether or not this enzyme abnormality is associated with FAS we studied 2 cultured amniotic fluid cell lines where the neonates were diagnosed to have FAS by several criteria. Three control amniotic fluid cell lines from normal pregnancies were also investigated. Preliminary results suggest that both amniotic cell lines with FAS pregnancies have abnormal transketolase enzyme as suggested by the determination of Km of this enzyme for TPP and compared to control values. Studies in progress will investigate the cells from more FAS, normal control pregnancies as well as cells derived from pregnancies where mother had a history of alcohol abuse but the baby was unaffected. In a related study we have investigated the transketolase enzyme kinetics in fibroblasts from ten members representing three generations of an Amish Family. The results show a pattern of autosomal recessive type of inheritance of the abormality as previously speculated by McKusick. We have recruited three patients with FAS in our clinical protocol to search for a genetic factor(s) in FAS as well as to study the pathophysiology of this common disorder.
