Biotin holocarboxylase synthetase deficiency

Barry Wolf MD PhD (Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.)
Originally released February 7, 1994; last updated January 12, 2020; expires January 12, 2023

This article includes discussion of biotin holocarboxylase synthetase deficiency, biotin-responsive beta-methylcrotonylglycinuria, biotin-responsive multiple carboxylase deficiency, and holocarboxylase synthetase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


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 3 mitochondrial biotin-dependent carboxylases were described (Wolf and Feldman 1982). 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 (Gompertz et al 1971). He had metabolic ketoacidosis and elevated concentrations of urinary beta-methylcrotonic acid and beta-methylcrotonylglycine (Gompertz et al 1973). 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 3 mitochondrial carboxylases in the peripheral blood leukocytes and skin fibroblasts had deficient activity (Bartlett and Gombertz 1976; Weyler et al 1977), as did the acetyl-coenzyme A carboxylase in his fibroblasts (Feldman and Wolf 1981b). 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 (Sweetman 1981). 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 (Burri et al 1981). 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 (Wolf et al 1983). Since then, 14 patients with holocarboxylase synthetase deficiency have been reported.

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