Holocarboxylase synthetase deficiency prevents biotinylation of holocarboxylase and results in metabolic acidosis, marked tachypnea, hypotonia, vomiting and seizures

Most patients become symptomatic early in life. The blood pH is typically quite low, often less than 7, and the blood lactate is high. Many infants also have hyperammonemia. Quantitation of urinary organic acids typically shows a marked ketoaciduria with excretion of lactate, 3-methylcrotonylglycine, tiglylglycine, 3-hydroxypropionate, methylcitrate and 3-hydroxyisovalerate, inter alia. If the disorder is not treated promptly, patients can develop a skin rash, alopecia and varying degrees of psychomotor retardation. Direct assay of holocarboxylase synthetase in fibroblasts is possible. Antenatal diagnosis is feasible, either by determination of enzyme activity or by quantitation of organic acids in the amniotic fluid.

Biotinidase deficiency prevents recycling of biotin and often causes developmental retardation, hypotonia, seizures, cerebellar signs, alopecia, dermatitis and conjunctivitis

Hearing loss is common. Quantitation of the urinary organic acids shows increased excretion of lactate, 3-hydroxyisovalerate, methylcitrate and 3-hydroxypropionate; however, these are not invariant findings, and the measurement of biotinidase activity in fibroblasts or peripheral blood cells may be necessary. Biotinidase activity in the serum of affected children usually is <10% that of control values. Antenatal diagnosis is possible.

Pathological lesions in the brain include cystic changes and demyelination. The cerebellum is especially vulnerable. A few patients have manifested changes suggesting meningoencephalitis. Virtually all patients respond favorably to oral biotin at a dose of 10 to 40 mg daily. Many of the clinical findings are reversible, even including some of the neurological abnormalities, although the hearing loss tends to persist.