Thiamine deficiency (TD) is accepted as the cause of
beriberi because of its action in the metabolism of simple
carbohydrates, mainly as the rate limiting cofactor for the
dehydrogenases of
pyruvate and
alpha-ketoglutarate, both being critical to the action of the citric acid cycle.
Transketolase, dependent on
thiamine and
magnesium, occurs twice in the oxidative
pentose pathway, important in production of reducing equivalents.
Thiamine is also a cofactor in the
dehydrogenase complex in the degradation of the
branched chain amino acids,
leucine,
isoleucine and
valine. In spite of these well accepted facts, the overall clinical effects of TD are still poorly understood. Because of the discovery of 2-hydroxyacyl-CoA
lyase (HACL1) as the first peroxisomal
enzyme in mammals found to be dependent on
thiamine pyrophosphate (TPP) and the ability of
thiamine to bind with
prion protein, these factors should improve our clinical approach to TD. HACL1 has two important roles in alpha oxidation, the degradation of
phytanic acid and shortening of 2-hydroxy long-chain
fatty acids so that they can be degraded further by beta oxidation. The downstream effects of a lack of efficiency in this
enzyme would be expected to be critical in normal brain metabolism. Although TD has been shown experimentally to produce reversible damage to mitochondria and there are many other causes of
mitochondrial dysfunction, finding TD as the potential biochemical lesion would help in differential diagnosis. Stresses imposed by
infection,
head injury or inoculation can initiate intermittent
cerebellar ataxia in
thiamine deficiency/dependency. Medication or
vaccine reactions appear to be more easily initiated in the more intelligent individuals when asymptomatic marginal
malnutrition exists. Erythrocyte
transketolase testing has shown that
thiamine deficiency is widespread. It is hypothesized that the massive consumption of empty calories, particularly those derived from
carbohydrate and fat, results in a high calorie/
thiamine ratio as a major cause of disease. Because mild to moderate TD results in pseudo
hypoxia in the limbic system and brainstem, emotional and stress reflexes of the autonomic nervous system are stimulated and exaggerated, producing symptoms often diagnosed as psychosomatic disease. If the biochemical lesion is recognized at this stage, the symptoms are easily reversible. If not, and the
malnutrition continues, neurodegeneration follows and results in a variety of chronic
brain diseases. Results from acceptance of the hypothesis could be tested by performing erythrocyte
transketolase tests to pick out those with TD and supplementing the affected individuals with the appropriate dietary supplements.