Introduction

Biotin is an essential B-complex water-soluble vitamin. It was first recognized in 1936 after its isolation from egg yolk as a yeast growth factor (Wolf & Feldman, 1982). Biotin (C10H6O3N2S) consists of a heterocyclic ring with a side chain that ends in a carboxylic acid group. In humans, biotin functions as a transport protein to four major carboxylases: pyruvate carboxylase (PC), acetyl-CoA carboxylase (ACC), propionyl-CoA carboxylase (PCC), and 3-methylcrotonyl-CoA carboxylase (MCC). It is therefore involved in critical energy pathways for gluconeogenesis, fatty acid synthesis, catabolism of branched chain amino acids, and leucine catabolism respectively. The carboxyl group of biotin links covalently to the epsilon amino group of a lysine residue of these apocarboxylases. The result is the synthesis of an active holocarboxylase. A single enzyme, holocarboxylase synthetase catalyzes these steps (Fig. 25.1). Eventual degradation of the biotin–apocarboxylase complex results in biocytin that is then regenerated as free biotin by biotinidase (Wolf & Heard, 1991). Defective activity of either enzyme therefore leads to similar metabolic anomalies.

The clinical interest in inborn errors of biotin-related disorders began with Gompertz and colleagues' (Gompertz et al., 1971) first description of a newborn with metabolic acidosis and characteristic organic aciduria (β-methylcrotonylglycinuria and β-hydroxyisovaleric aciduria). These metabolic abnormalities disappeared with initiation of biotin treatment. Clinical improvement also followed. This seminal report fueled the growing interest in understanding the biochemical basis of diseases.