Biotin and biotin-responsive disorders

OVERVIEW OF THE BIOTIN CYCLE AND BIOTIN-RESPONSIVE DISORDERS In 1971, a child with a deficiency of β-methylcrotonyl-coenzyme A (COA) carboxylase (MCC), a biotin-dependent enzyme, was described who improved clinically and metabolically following administration of the water-soluble B vitamin, biotin. Individuals who improved with biotin therapy were considered biotin-responsive. Further study revealed that this child also had deficient activity of propionyl-CoA carboxylase (PCC), another biotin-dependent carboxylase. Subsequently, other children were reported who had biochemical profiles consistent with deficiencies of all three mitochondrial carboxylases – PCC, MCC, and pyruvate carboxylase (PC) – or multiple carboxylase deficiency (MCD). All children with MCD have improved when treated with pharmacological doses of biotin. These biotin-responsive MCD disorders were subsequently classified into three groups based on their underlying genetic defects: biotin holocarboxylase synthetase (HCS) deficiency (Online Mendelian Inheritance in Man [OMIM] 253260), biotinidase deficiency (OMIM 253260), and, most recently, biotin-responsive basal ganglia disease (OMIM 607483), In 1971, a child with a deficiency of β-methylcrotonyl-coenzyme A (COA) carboxylase (MCC), a biotin-dependent enzyme, was described who improved clinically and metabolically following administration of the water-soluble B vitamin, biotin. Individuals who improved with biotin therapy were considered biotin-responsive. Further study revealed that this child also had deficient activity of propionyl-CoA carboxylase (PCC), another biotin-dependent carboxylase. Subsequently, other children were reported who had biochemical profiles consistent with deficiencies of all three mitochondrial carboxylases – PCC, MCC, and pyruvate carboxylase (PC) – or multiple carboxylase deficiency (MCD). All children with MCD have improved when treated with pharmacological doses of biotin. These biotin-responsive MCD disorders were subsequently classified into three groups based on their underlying genetic defects: biotin holocarboxylase synthetase (HCS) deficiency (Online Mendelian Inheritance in Man [OMIM] 253260), biotinidase deficiency (OMIM 253260), and, most recently, biotin-responsive basal ganglia disease (OMIM 607483). To gain a better understanding of these biotin-responsive disorders, it is important to consider the metabolism of biotin. Humans cannot synthesize biotin. Although biotin is widely found in the diet, it is not readily found in the free, unbound form. As shown in Figure 4-1, only free biotin, not bound to protein or other moieties, enters the biotin pool through intestinal absorption. Although biotin is synthesized by flora in the large intestine, it does not contribute to the biotin pool because the usual site of absorption of biotin is in the sterile duodenum.