Clinical Problems Relating to Biotin

Experience with biotin-related clinical problems in man has led to a rekindling of interest in biotin, its role in nutrition, and its place in biochemistry. The clinical manifestations of deficient activity of biotin are very striking indeed. Their features include an unforgettable cutaneous eruption, alopecia totalis and the development of severe metabolic acidosis that in the untreated state is lethal. Later manifestations focus on the central nervous system, and progressive ataxia may become incapacitating. Despite this dramatic presentation, most clinicians have never seen such a patient. Clinical recognition may not be rapid, and most known patients have been described very recently. Requirements for biotin in human nutrition and optimum concentrations in the blood, particularly in early infancy, are not known with great security. Nevertheless, clinical deficiency of biotin has rarely been encountered. We described a young mentally retarded boy who developed a deficiency of biotin because of a nutritional supplement made from raw eggs that had gradually become his entire caloric intake. ’ The recognition of a syndrome of biotin deficiency in young infants receiving total parenteral alimentation was an important observation. *,’ Its description has led to the widespread incorporation of biotin into the formulations used, and this should eliminate the occurrence of this disorder. Most clinical experience with biotin-related problems has been with genetically determined disorders in which there is multiple carboxylase deficiency. It is now clear that there are at least two distinct disorders, a young infantile or neonatal disease that is caused by deficiency of holocarboxylase synthetase4 and a slightly more indolent late infantile disease that is caused by deficiency of biotinidase. ’ An infant with holocarboxylase synthetase deficiency may die in an overwhelming acidotic episode before there has been time to develop a cutaneous eruption, and alopecia is not so quickly recognized as abnormal a t this age, although skin lesions are a usual component of the clinical picture in this disease. The patient with biotinidase deficiency may appear with a dermatologic picture that suggests a diagnosis of acrodermatitis enteropathica and neurologic symptoms may be prominent. In both disorders, there is usually a characteristic organic aciduria in which the excretion of the leucine metabolites, 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, are associated with the excretion of the isoleucine metabolites, 3-hydroxypropionic acid and methylcitric acid, and massive excretion of lactic acid. However, Wolf’ has reported some patients with biotinidase deficiency in whom organic aciduria was not demonstrated. The diagnosis is made usually on the basis of the finding of the characteristic metabolites on organic acid analysis of the urine. Quantitative assessment of the actual levels excreted can be of considerable help in elucidating the pattern. For instance, an isolated mass spectrum may appear to be that of tiglylglycine or of 3-methylcrotonylglycine, suggesting a diagnosis of propionic acidemia instead of multiple carboxylase deficiency. However, the level of excretion of tiglylglycine in propionic acidemia is that of a minor metabolite. The mcurrence of a major peak with this structure would