Research Notes: Multiple-CoA Carboxylase Deficiency (Biotinidase Deficiency)

From Pediatrix

Background: There are four carboxylase enzymes in humans that require biotin for activity - propionyl-CoA carboxylase, 3-methylcrotonoyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase. If biotin metabolism is defective, all four carboxylases will be deficient. Biotin is covalently linked to a key lysine residue in each carboxylase by action of holocarboxylase synthetase. When the carboxylase proteins are degraded, biotinoyl-lysine is subsequently cleaved by biotinidase releasing free biotin that can be reutilized. The two defects in biotin metabolism associated with multiple carboxylase deficiency are caused by deficient activity of holocarboxylase synthetase and biotinidase. The disorders tend to present clinically at different ages, with holocarboxylase synthetase deficiency being known as early-onset (neonatal) multiple carboxylase deficiency and biotinidase deficiency referred to as late-onset multiple carboxylase deficiency. Both respond to biotin supplementation.

Clinical: Patients affected with deficient holocarboxylase synthetase usually present in the first days or weeks of life with poor feeding, lethargy, hypotonia, and seizures, sometimes progressing to coma. Generalized rash and alopecia may be present. Affected patients exhibit metabolic acidosis and mild to moderate hyperammonemia. In contrast, biotinidase deficiency, which constitutes the vast majority of patients with multiple carboxylase deficiency, typically presents after several months of life with neurocutaneous symptoms including developmental delay, hypotonia, seizures, ataxia, hearing loss, alopecia, and skin rash. In some patients, the disease can be life-threatening.

Testing: Biotinidase deficiency is readily detected by measuring the activity of the enzyme on a heel stick dried blood spot. Newborn screening using tandem mass spectrometry may reveal an elevation of C5-hydroxy acylcarnitine from the dried blood spot of a patient affected with holocarboxylase synthase deficiency. Diagnosis of holocarboxylase synthetase deficiency requires further testing. Urine organic acid analysis reveals elevations of beta-hydroxyisovaleric acid, beta-methylcrotonylglycine, and tyglylglycine. Urine may also contain metabolites seen in propionyl CoA carboxylase deficiency and beta-methylcrontonyl CoA carboxylase deficiency. Discriminating these disorders is important to ensure proper therapy is initiated.

Treatment: Treatment of patients with multiple carboxylase deficiency involves administration of high doses of biotin. An excellent and rapid clinical response to biotin is characteristic of both enzyme defects associated with multiple carboxylase deficiency. This highlights the importance of accurate and timely diagnostic evaluation of affected infants.

Because the diagnosis and therapy of multiple carboxylase deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient's physician.

Inheritance: This disorder most often follows an autosomal recessive inheritance pattern.

J Inherit Metab Dis. 2003.
Infantile mitochondrial DNA depletion syndrome associated with methylmalonic aciduria and 3-methylcrotonyl-CoA and propionyl-CoA carboxylase deficiencies in two unrelated patients: a new phenotype of mtDNA depletion syndrome.
Yano S, Li L, Le TP, Moseley K, Guedalia A, Lee J, Gonzalez I, Boles RG.
Medical Genetics, Department of Pediatrics, Children's Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.

Mitochondrial DNA (mtDNA) depletion refers to a quantitative defect in mtDNA and is heterogeneous with regard to causal genotypes and the associated clinical phenotypes. We report two unrelated infants with mtDNA depletion. A diagnosis of methylmalonic aciduria was initially raised in both on the basis of high urine methylmalonic acid and related organic acids and elevated propionylcarnitine and methylmalonylcarnitine. Carboxylase assay with skin fibroblasts revealed low propionyl-CoA and 3-methylcrotonyl-CoA carboxylase and normal pyruvate carboxylase activities. Quantitative Southern blot analysis of mitochondrial and nuclear DNA with muscle tissues revealed the patients' mtDNA to be depleted to 24% and 39% of normal controls. Our two patients showed multiple mitochondrial dysfunction including respiratory chain defects and deficiencies in the two nuclear DNA encoded carboxylases resulting in abnormal urine organic acids. To our knowledge, there is no obvious connection between the defective pathways other than their mitochondrial locations. These two cases may represent a new entity of mitochondrial disease that might be due to a defective common mechanism, such as assembly, maintenance and transport, affecting various mitochondrial enzymes and functions. Mitochondrial depletion should be considered in infants with atypical organic aciduria that may resemble methylmalonicaciduria, propionic acidaemia, or 3-methylcrotonyl-CoA carboxylase deficiency.