Consequences of Biotin Deficiency

Biotin carboxylases and relationship with intermediate metabolism. Alternative pathways responsible of organic acids accumulation (dashed arrows) take place with deficient carboxylases (black bars) as a consequence of biotin deficiency. ACCl and ACC2 acetyl-CoA carboxylase 1 and acetyl-CoA carboxylase 2 PC pyruvate carboxylase PCC pro-pionyl CoA carboxylase MCC methylcrotonyl CoA carboxylase. 

Biotin (vitamin H) is an unusual vitamin because it can be synthesized by bacteria that live in the intestine. Consequently, biotin does not have to be included in our diet and deficiencies are rare. Biotin deficiencies, however, can be found in people who maintain a diet high in raw eggs. Egg whites contain a protein (avidin) that binds biotin tightly and thereby prevents it from acting as a coenzyme. When eggs are cooked, avidin is denatured, and the denatured protein does not bind biotin. Biotin is attached to its enzyme by forming an amide with the amino group of a lysine side chain. 

Reduced activities of carboxylase enzymes can cause a metabolic block of certain substrates and a use of alternative pathways for catabolism. Therefore, 3-hydroxyisovaleric acid and 3-methylcrotonyl glycine are formed consequently to a shunt of 3-methylcrotonyl carboxylase counterbalancing its activity decrease. Marginal biotin deficiency experimentally induced by 20 days of free biotin diets in human increased 3-hydroxyisovaleric acid excretion in urine above the upper limit of normal. The normal urinary excretion of 3-hydroxyisovaleric acid in healthy adults is 112 38 pmol per 24 hours (Mock et al. 1997). This suggests that 3-hydroxyisovaleric acid urinary excretion is a good indicator of marginal biotin deficiency. 

Biotin adheres very tightly to a specific protein of egg white, avidin, and consequently is inactivated by it. Large doses of raw egg white fed to animals are able to evoke biotin deficiency. A similar phenomenon is seen occasionally in man. Avidin is denatured and inactivated by heat. 

Since this first case report, some 12 patients who have shown features of 3-methylcrotonyl-CoA carboxylase deficiency have been reported in the literature. The majority (7) of these patients appear to have multiple carboxylase deficiencies probably due to holocarboxylase synthetase deficiency and are responsive to D-biotin therapy. Early diagnosis is essential in order to avoid the possible fatal consequences of the diseases. The number of cases now reported permit some degree of classification, but the degree of heterogeneity of presentation necessitates their description in some detail and the important features are given below. 

Biotinidase deficiency is an autosomal recessive disorder with an estimated incidence of 1 in 72,000-126,0(X). Many newborn-screening programs of genetic diseases include testing for this enzyme. Prompt treatment with oral biotin administration of 5-20 mg/d in affected infants will prevent clinical consequences. If the treatment is delayed, neurological manifestations (e.g., hearing loss and optic atrophy) and developmental delay occur and may not revert to normal. 

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