Wernicke-Korsakoff Syndrome

Clinical Features

Coy et al. (1996) noted that thiamine deficiency is associated with 2 neurologic disorders, beriberi and Wernicke-Korsakoff syndrome. Beriberi is caused by lack of dietary thiamine and its symptoms include myocardial failure, reversible by thiamine treatment. Wernicke-Korsakoff syndrome is characterized by acute encephalopathy followed by chronic impairment of short-term memory. Early treatment with high doses of thiamine stabilizes the disease, yet thiamine deficiency is not sufficient to cause the syndrome.

Biochemical Features

Blass and Gibson (1977) found that transketolase (606781) in fibroblasts from patients with Wernicke-Korsakoff syndrome bound thiamine pyrophosphate less avidly than normal. The abnormality persisted through serial passages in cell culture in the presence of excess thiamine and no ethanol.

Nixon et al. (1984) studied red cell transketolase by 2 techniques. Apparent Km values for the cofactor thiamine diphosphate were similar for patients and controls. However, isoelectric focusing separated red cell transketolase into different isozymes characterized by pI values in the range 6.6 to 9.2. The isozyme pattern found in 39 of 42 patients with Wernicke-Korsakoff syndrome was present in only 8 of 36 controls.

Using isoelectric focusing of human erythrocyte transketolase to reexamine the isoenzyme patterns on which the results of Nixon et al. (1984) were based, Kaufmann et al. (1987) concluded that the method used 'does not permit the distinction of transketolase variants, that would allow to postulate a genetic polymorphism....' In comparing the nucleotide sequence of the transketolase coding region in fibroblasts derived from 2 Wernicke-Korsakoff patients with that of 2 nonalcoholic controls, Abedinia et al. (1992) could find no differences.

Inheritance

Patients with Wernicke-Korsakoff syndrome appear to have an inborn error of metabolism that is clinically important only when the diet is inadequate in thiamine. Probably this means that the Wernicke-Korsakoff syndrome is a recessive disorder, presumably autosomal recessive. Two of the patients with the syndrome whose cells were studied by Blass and Gibson (1977) were female. Mukherjee et al. (1987) confirmed the observation of Blass and Gibson (1977) in 3 Wernicke-Korsakoff patients. Furthermore, they reported a similar transketolase abnormality in familial chronic alcoholic males and in their sons who did not have any history of alcohol abuse. Leigh et al. (1981) found an anomaly of the enzyme transketolase in both of monozygotic twins: one with Wernicke-Korsakoff syndrome and one 'normal.' The role of environmental factors in 'bringing out' the defect was nicely demonstrated.

Population Genetics

Studies of a nonalcoholic Amish family suggested that the transketolase abnormality may occur in nonalcoholic populations and that it is present in both male and female sibs. This might be expected with autosomal recessive inheritance. Europeans are more vulnerable to this syndrome than are Asians (and probably Africans) on the same thiamine-deficient diet. The syndrome is said to be rare in American blacks.

Molecular Genetics

In comparing the nucleotide sequence of the transketolase coding region in fibroblasts derived from 2 Wernicke-Korsakoff patients with that of 2 nonalcoholic controls, Abedinia et al. (1992) could find no differences.

A variant transketolase enzyme has been proposed to be associated with Wernicke-Korsakoff syndrome; however, no mutations have been found in the transketolase gene cloned from these patients (McCool et al., 1993).

Coy et al. (1996) raised the possibility that variation in the X-linked TKTL1 gene (300044) is responsible for the genetic predisposition to the development of Wernicke-Korsakoff syndrome.