Defective HLCS causes multiple carboxylase deficiency

Defects in HLCS causes holocarboxylase synthetase deficiency (HLCS deficiency aka early onset multiple carboxylase deficiency; MIM:253270). HLCS deficiency is an autosomal recessive disorder whereby deficient HLCS activity results in reduced activity of all five biotin-dependent carboxylases. Symptoms include metabolic acidosis, organic aciduria, lethargy, hypotonia, convulsions and dermatitis. Patients can present symptoms shortly after birth to up to early childhood and will be prescribed oral biotin supplements, typically 10-20 mg daily. Two classes of HLCS deficiency have been reported depending on whether patients respond to biotin therapy. Most patients respond favourably to treatment and show complete reversal of biochemical and clinical symptoms. Here mutations in the HLCS active site cause a reduced affinity for biotin that can be overcome by pharmacological doses of the vitamin. Patients who display incomplete responsiveness to biotin therapy have a poor long-term prognosis. Here mutations that reside outside of the enzyme's active site have no effect on biotin binding but do compromise the protein-protein interaction between the HLCS and its substrates, resulting in reduced biotinylation of all five carboxylases thus reducing their enzymatic activity.

Summary from Reactome (R-HSA-3371599), read 2026-09-23.