Inborn errors biotin

MetabolicaUy, biotin is of central importance in lipogenesis, gluconeogen-esis, and the catabolism of branched-chain (and other) amino acids. There are two well-characterized biotin-responsive inborn errors of metabolism, which are fatal if untreated holocarboxylase synthetase deficiency and biotinidase deficiency. In addition, biotin induces a number of enzymes, including glu-cokinase and other key enzymes of glycolysis. Biotinylation of histones may be important in regulation of the cell cycle. 

Biotin deficiency results from a number of inborn errors of metabolism, and biotin quantitation therefore represents a general screening method for these diseases. Recently, a new method was proposed for biotin quantitation in serum. The method has been called an ELLSA, and relies on the following competitive reaction ... 

Propionyl-CoA is an intermediary product in the metabo-hsm of four essential amino acids (isoleucine, valine, threonine, and methionine), the aliphatic side-chain of cholesterol, pyrimidines (uracd and thymine), and the final product of the [3-oxidation of odd-chain fatty acids. Under normal circumstances, propionyl-CoA first is converted by a biotin-dependent carboxylase to methylmalonyi-CoA, then to succinyl-CoA by an adenosylcobalamin-dependent mutase, leading to oxidation in the tricarboxylic acid cycle. Primary or secondary defects of these two enzymes were among the first organic acidurias to be discovered, and their natural history has been characterized perhaps better than any other inborn error of organic acid metabolism. 

Inborn errors of metabolism may be due to propionyl-CoA carboxylase deficiency, defects in biotin transport or metabolism, methylmalonyl-CoA mutase deficiency, or defects in adenosylcobalamin synthesis. The former two defects result in propionic acidemia, the latter two in methylmalonic acidemia. All cause metabolic acidosis and developmental retardation. Organic acidemias often exhibit hyperammonemia, mimicking ureagenesis disorders, because they inhibit the formation of N-acetylglutamate, an obligatory cofactor for carbamoyl phosphate synthase (Chapter 17). Some of these disorders can be partly corrected by administration of pharmacological doses of the vitamin involved (Chapter 38). Dietary protein restriction is therapeutically useful (since propionate is primarily derived from amino acids). Propionic and methylmalonyl acidemia (and aciduria) results from vitamin B12 deficiency (e.g., pernicious anemia Chapter 38). 

Description. Also known as vitamin Bg or H, this vitamin is of great importance for the biochemistry of the human organism. Biotin is the cofactor for a small group of enzymes that catalyze carboxyla-tion, decarboxylation, and transcarboxylation reactions in carbohydrate and fatty acid metabolism. Deficiency of this vitamin is rare in humans, but can be induced in special circumstances in individuals with inborn errors of biotin metabolism, in individuals taking certain medications, and in some women during pregnancy. ... 

Prior to 1981, human biotin deficiency had been reported only in children with inborn errors of intermediary metabolism or in individuals ingesting excessive intakes of raw egg white or experimental diets which excluded biotin (Tanaka, 1981). Since then, there have been several case reports of TPN-associated biotin deficiency (Mock et al, 1981 Kien et al, 1981 Gillis et al., 1982). The children in these reports all suffered from gastrointestinal abnormalities and had received biotin-free, or deficient, parenteral formulations for extended time periods with little or no oral intake. It appears that patients with altered intestinal flora secondary to antibiotic treatment, diminished gut motility, or abnormal intestinal anatomy, are at risk of deficiency on long-term biotin-free TPN. 

Biotin deficiency may be caused by inborn errors on other proteins involved in biotin homeostasis biotidinase, the sodium-dependent multivitamin transporter and holocarboxylase synthetase (Zempleni et al. 2008). A congenital deficiency of either of these proteins may create impairments in essential metabolisms, causing clinical signs with various intensities. 

Daily doses up to 200 mg orally and up to 20 mg intravenously have been given to treat biotin-responsive inborn errors of metabolism and acquired biotin deficiency. Toxicity has not been reported. 

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