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Biotinidase releases biotin from the peptide form in which it usually exists in nature, and the free biotin is then available for attachment to apocarboxylases that act on propionyl-CoA, 3-methylcrotonyl-CoA, acetyl-CoA, and pyruvate by holocarboxylase synthetase. Deficiency of biotinidase or holocarboxylase synthetase produces multiple carboxylase deficiency; both conditions are characterized by the triad of alopecia, skin rash, and encephalopathy, and both are inherited as autosomal recessive traits.

Clinical Findings

Holocarboxylase synthetase deficiency usually causes earlier and more severe disease than biotinidase deficiency, with life-threatening ketoacidosis; alopecia; and a generalized red, scaly rash. Coma, apnea, and death often follow unless therapy is instituted. Biotinidase deficiency usually presents later in infancy with periorificial dermatitis resembling acrodermatitis enteropathica; patchy alopecia; and neurological abnormalities such as ataxia, neurosensory defects, developmental delay, and convulsions. In both conditions, the rash may be complicated by superinfection with monilia. The defect in neonatal disease is usually in holocarboxylase synthetase; in most patients with a later onset, the defect is in biotinidase. However, there is extensive overlap between the two conditions, and accurate diagnosis can be made only by enzyme assay.


Urine organic acid analysis shows increased 3-methylcrotonylglycine and 3-hydroxyisovaleric acid, often with methylcitric, 3-hydroxypropionic, and lactic acids. Acylcarnitine analysis by tandem mass spectroscopy (MS-MS) shows propionyl- and 3-hydroxyisovalerylcarnitine. Holocarboxylase synthetase deficiency can be demonstrated in fibroblasts or leukocytes; biotinidase activity can be assayed even in serum. Enzyme assay in amniocytes or demonstration of abnormal organic acids in amniotic fluid can be used for prenatal diagnosis of holocarboxylase synthetase deficiency.


Patients with multiple carboxylase deficiency are very responsive to free biotin, and doses of 5 to 20 mg/d usually reverse all the disease manifestations. Because it can cause permanent neurological sequelae and because it is so easily and effectively treated, newborn screening for biotinidase deficiency is often performed (see Chapter 134).

Biotin-responsive basal ganglia disease is a recessive disorder that presents in childhood with confusion, dysarthria, and dysphagia, and if untreated progresses to dystonia, quadriplegia, and eventual death. MRI shows bilateral central necrosis of the caudate head with variable involvement of the putamen. Although symptoms disappear within a few days of biotin administration (5–10 mg/day) and reappear within 1 month if biotin is discontinued, the defect is in a cell surface thiamine transporter that has no demonstrated involvement with biotin transport.1-4

1. Haagerup A, Andersen JB, Blichfeldt S, Christensen MF. Biotinidase deficiency: two cases of very early presentation. Dev Med Child Neurol. 1997;39:832.  [PubMed: 9433861]
2. Touma E, Suormala T, Baumgartner ER, et al. Holocarboxylase synthetase deficiency: report of a case with onset in late infancy. J Inherited Metab Dis. 1999;22:115.  [PubMed: 10234606]
3. Wolf B, Pomponio RJ, Norrgard KJ, et al. Delayed-onset profound biotinidase deficiency. J Pediatr. 1998;132:362.  ...

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