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  • Updated 11.30.2023
  • Released 02.07.1994
  • Expires For CME 11.30.2026

Biotin holocarboxylase synthetase deficiency



The author explains that a child with biotin holocarboxylase synthetase deficiency who is homozygous for the L216R mutation, which is usually associated with a poor outcome even with biotin supplementation, can potentially do better clinically if diagnosed early and treated with a daily dose of as much as 1.2 mg of biotin.

Key points

• Biotin holocarboxylase synthetase deficiency, a rare inherited metabolic disorder, usually presents during infancy with neurologic symptoms, metabolic acidosis, hyperammonemia, and organic aciduria.

• Biotin holocarboxylase synthetase deficiency can usually be treated successfully with pharmacological doses of the vitamin biotin.

• Although children with biotin holocarboxylase synthetase deficiency may be identified by tandem mass spectroscopy on newborn screening, many affected individuals are initially diagnosed by the characteristic organic aciduria when they are symptomatic.

• Although most children with biotin holocarboxylase synthetase deficiency respond to biotin therapy, the degree of response appears to correlate with the characteristics of the defective enzyme; some individuals require considerably larger doses of biotin than others.

Historical note and terminology

During the 1970s, inherited isolated deficiencies of the three mitochondrial biotin-dependent carboxylases were described (86). The carboxylases include (1) pyruvate carboxylase, which converts pyruvate to oxaloacetate, the initial step of gluconeogenesis; (2) propionyl-coenzyme A carboxylase, which catabolizes several branch-chain amino acids and odd-chain fatty acids; and (3) beta-methylcrotonyl-coenzyme A carboxylase, which is involved in the catabolic pathway of leucine. Each deficiency is due specifically to a structural abnormality in its respective enzyme; the activities of the other carboxylases are normal. Children with these disorders usually develop neurologic symptoms and metabolic compromise. Each disorder is treated by dietary restrictions, but fails to respond to pharmacological doses of biotin.

Some children who exhibited symptoms similar to those seen in isolated carboxylase deficiencies responded to biotin therapy. In 1971, the first patient diagnosed with such a disorder was reported as having biotin-responsive beta-methylcrotonylglycinuria (25). He had metabolic ketoacidosis and elevated concentrations of urinary beta-methylcrotonic acid and beta-methylcrotonylglycine (24). Subsequently, beta-hydroxyisovaleric acid and triglycine were demonstrated in the urine. Several days after starting oral biotin, the patient's symptoms resolved and the urinary metabolites cleared. All three mitochondrial carboxylases in the peripheral blood leukocytes and skin fibroblasts had deficient activity (06; 82), as did the acetyl-coenzyme A carboxylase in his fibroblasts (20). These findings prompted the diagnosis of "multiple carboxylase deficiency."

By 1980, additional patients with multiple or combined carboxylase deficiencies were reported. Initially, depending on the age of onset of symptoms, these patients were classified as having either the early-onset (neonatal) or late-onset (infantile or juvenile) forms of multiple carboxylase deficiency (71). Most of the reported patients with the early-onset form of the disorder were shown to have deficient holocarboxylase synthetase activity, with markedly elevated Michaelis constants of biotin for the enzyme (10). In 1983, it was shown that the primary biochemical defect in most patients with late-onset multiple carboxylase deficiency was deficient activity of serum biotinidase (87). Since then, 14 patients with holocarboxylase synthetase deficiency have been reported.

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