Biotin deficiency due to a recessively inherited genetic defect of biotinidase, genetic defects of several carboxylases, or holocarboxylase synthetase mutations causes profound metabolic defects that can lead to permanent nervous system damage and even death. Biotinidase releases biotin from foods or from endogenous peptides. Free biotin is essential for activating 4 coenzyme A (CoA)-containing or -dependent carboxylases that have essential roles in protein catabolism, fatty acid synthesis, and gluconeogenesis. Holocarboxylase synthetase incorporates biotin into the 4 carboxylases. Biotinidase and holocarboxylase synthetase deficiency can be treated with pharmacologic doses of oral biotin.

These deficiencies are screened for in all newborns in the United States and several other countries. Biotinidase deficiency has an overall incidence of about 1:60 000 newborns. In California, biotinidase deficiency has a higher incidence in Hispanics of Mexican descent. The disorder has been found worldwide in all populations and ethnic groups.

Biotinidase deficiency can be profound or partial; profound and partial deficiencies of biotinidase are the most common forms of the multiple carboxylase-related deficiencies.

Profound biotinidase deficiency – Mean age of onset is 3.5 months; onset often occurs by 1 week of age. If untreated, patients may develop the following:

• Seizures (often myoclonic) and hypotonia
• Sensorineural deafness, ataxia and optic atrophy, and developmental delay
• Hyperventilation, respiratory stridor, and apnea
• Alopecia (rarely, trichorrhexis changes have been reported in remaining hairs)
• Perioral and periorificial eruptions than can be generalized, cutaneous Candida infections, and conjunctivitis
• Metabolic changes including keto-lactic acidosis, organic aciduria and increased ammonia levels, and hypoglycemia

Partial biotinidase deficiency – Similar symptoms but to a lesser degree, and later onset or onset only with metabolic stress such as infection.

Holocarboxylase synthetase deficiency and defects in the other carboxylases are often detected by neonatal screening programs analyzing organic acids.