BIOTINIDASE AND HOLOCARBOXYLASE SYNTHETASE DEFICIENCIES
Synonym: Late- and early-onset forms of multiple carboxylase deficiency
Key features
As biotin is an essential cofactor for carboxylases, there is overlap in these two autosomal recessive disorders
Cutaneous findings include alopecia, periorificial erythema and erosions (features of “nutritional dermatitis”), and sometimes flexural involvement reminiscent of seborrheic dermatitis
Metabolic acidosis occurs in both disorders
Biotinidase deficiency is associated with developmental delay, hearing loss, and seizures beginning during infancy or childhood, while patients with holocarboxylase synthetase deficiency classically develop encephalopathy and hypotonia within the first 3 months of life
Biotinidase deficiency and holocarboxylase synthetase deficiency are genetically distinct autosomal recessive disorders that result in multiple carboxylase deficiency; the former has its onset during infancy or childhood, while the latter presents during the first 3 months of life. Dermatologic features, which overlap with other forms of “nutritional dermatitis” (see Fig. 51.13), occur in >50% of patients with biotinidase deficiency and a smaller proportion of those with holocarboxylase synthetase deficiency. Characteristic skin findings include progressive alopecia and a well-demarcated dermatitis with erythema and scaling that typically begins in perioral, perianal and/or flexural regions, sometimes mimicking seborrheic dermatitis, but then can become generalized. This eruption is often eroded or fissured, and superimposed candidiasis and other secondary infections may develop.
Biotinidase deficiency, a pan-ethnic disorder with an incidence of ~1 in 60 000 births, represents a defect in biotin recycling. Patients with this disorder become functionally biotin-deficient under conditions of normal dietary biotin intake. Since biotin is an essential cofactor for the activity of carboxylases, multiple carboxylase deficiency ensues. Both cutaneous and extracutaneous manifestations usually develop between 3 months and 2 years of age but may be delayed until later childhood. Extracutaneous features include developmental delay, hearing loss, seizures, conjunctivitis, optic atrophy, myelopathy, and metabolic acidosis.
Abnormalities on urine organic acid analysis are not consistently present. The diagnosis is established by an assay of biotinidase activity in blood or molecular genetic testing; prenatal diagnosis is possible via enzymatic and molecular analyses. Considering that the highly variable manifestations may go unrecognized, biotinidase deficiency is included in the newborn screening panel of many countries, including the US. The clinical features of biotinidase deficiency are entirely preventable with administration of 5–20 mg of biotin daily.
Holocarboxylase synthetase deficiency is significantly less common than biotinidase deficiency. It represents a defect in biotinylation of the apocarboxylases, leading to a failure in synthesis of intact functional holocarboxylases. Patients typically present within the first 3 months of life with symptoms of a metabolic encephalopathy, including poor feeding, lethargy, respiratory distress, and hypotonia. Metabolic acidosis, hyperammonemia, and organic aciduria are often observed. Definitive diagnosis is established by assays of carboxylases in leukocytes or cultured skin fibroblasts, or by molecular genetic testing; prenatal diagnosis is also possible via enzymatic and molecular analyses. Most patients exhibit significant improvement when treated with 10 mg of biotin daily.