Multiple carboxylase deficiency

Multiple carboxylase deficiency (MCD) is a rare inherited metabolic disorder in which the activity of biotin-dependent carboxylases — pyruvate carboxylase, propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylase — is impaired. There are two main forms: the neonatal (early-onset) form caused by deficiency of holocarboxylase synthetase (HLCS), the enzyme that attaches biotin to the carboxylases, and the juvenile (late-onset) form caused by deficiency of biotinidase, the enzyme responsible for recycling biotin from biocytin. Both forms are also collectively referred to as biotin-responsive multiple carboxylase deficiency. The condition affects multiple body systems. Key clinical features include metabolic acidosis, organic aciduria, seizures, hypotonia, skin rash (including eczema and alopecia), feeding difficulties, lethargy, and developmental delay. In the holocarboxylase synthetase deficiency form, symptoms typically present in the neonatal period with life-threatening metabolic crises including lactic acidosis, hyperammonemia, and ketoacidosis. In biotinidase deficiency, onset is usually later in infancy or early childhood, and patients may additionally develop hearing loss, optic atrophy, and recurrent infections due to immune dysfunction. Treatment for both forms involves oral biotin supplementation, which is highly effective when initiated early. Pharmacological doses of biotin (typically 5–20 mg/day) can reverse or prevent most symptoms, particularly in biotinidase deficiency. Early diagnosis through newborn screening programs has significantly improved outcomes. Without treatment, the disease can lead to coma, intellectual disability, and death. Patients with holocarboxylase synthetase deficiency may require higher doses of biotin and may have a more variable response to treatment. Lifelong biotin supplementation is necessary for both forms.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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