Carboxylase Deficiency

Key Features

• Isolated pyruvate carboxylase deficiency presents with lactic acidosis and hyperammonemia in early infancy

• Even if biochemically stabilized, the neurologic outcome is dismal

• Isolated 3-methylcrotonyl-CoA carboxylase deficiency

  • Frequently recognized on newborn screening using acylcarnitine analysis

  • Usually a benign condition that sometimes causes symptoms of acidosis and neurologic depression

Clinical Findings

• Holocarboxylase synthetase deficiency usually presents in neonates with hypotonia, skin problems, and massive acidosis

• Biotinidase deficiency presents later with a syndrome of ataxia, seizures, seborrhea, and alopecia

• Mental retardation, hearing loss, and optic nerve atrophy can develop in untreated patients

• Newborn screening is justified because the neurologic sequelae of the disorder in many patients are preventable if treated early

Diagnosis

• Diagnosis should be considered in patients with typical symptoms or in those with primary lactic acidosis

• Urine organic acids are usually but not always abnormal

• Diagnosis is made by enzyme assay of carboxylase activities in fibroblasts or leucocytes

• Biotinidase can be assayed in serum

• Holocarboxylase synthetase can be assayed in leukocytes or fibroblasts

Treatment

• Oral administration of pharmacologic doses of biotin reverses the organic aciduria within days and the clinical symptoms within days to weeks

• Hearing loss can occur in patients with profound biotinidase deficiency despite treatment