HLCS – Holocarboxylase Synthetase Deficiency

Holocarboxylase synthetase deficiency is a rare autosomal recessive inborn error of biotin metabolism leading to multiple carboxylase deficiency (MCD). Affected neonates typically present with severe metabolic acidosis, lactic acidaemia, hyperammonemia, and characteristic organic aciduria. Early biotin supplementation restores carboxylase activities and prevents life-threatening decompensation (PMID:8319716, PMID:9183268).

Genetically, HLCS deficiency is caused by biallelic pathogenic variants in HLCS (HGNC:4976). Case reports and series describe at least 28 unrelated probands in a Chinese cohort (PMID:36890565) and numerous families worldwide with confirmed autosomal recessive segregation. Segregation of disease in consanguineous pedigrees and sibling pairs further supports the association.

The HLCS variant spectrum includes missense, nonsense, splice-site, and frameshift changes. A recurrent founder allele c.2182G>A (p.Gly728Ser) has been reported in Japanese patients (PMID:8541348), and the p.Leu363Arg variant is prevalent in Polynesian families (PMID:24085707). Over 100 distinct HLCS mutations have been catalogued, with hotspot and population-specific founder variants.

Clinically, patients exhibit metabolic acidosis (HP:0001942), lactic acidosis (HP:0003128), and hyperammonemia (HP:0001987), often accompanied by rash, alopecia, hypotonia, and developmental delay. Response to biotin therapy is rapid, with biochemical and clinical remission upon dosing of 10–100 mg/day, guided by kinetic studies (PMID:9686819, PMID:16231399).

Functional assays demonstrate that many HLCS mutants have elevated Km for biotin and reduced Vmax, correlating with incomplete biotin responsiveness in vitro. High-dose biotin restores enzyme activity at pharmacological concentrations, concordant with clinical outcomes (PMID:10590022, PMID:10068510).

Definitive clinical validity, strong genetic evidence, and moderate functional concordance establish HLCS deficiency as a well-characterized disorder. Newborn screening and prompt genetic testing, coupled with tailored biotin therapy, ensure favorable prognosis and normal development in most patients.

Key Take-home: Early recognition of metabolic acidosis and organic aciduria should prompt HLCS testing and immediate biotin supplementation to prevent morbidity and mortality.

References

• European journal of pediatrics • 1993 • Holocarboxylase synthetase deficiency: early diagnosis and management of a new case. PMID:8319716
• Developmental medicine and child neurology • 1997 • Resolution of subependymal cysts in neonatal holocarboxylase synthetase deficiency. PMID:9183268
• Biochimica et biophysica acta • 1995 • Molecular analysis of holocarboxylase synthetase deficiency: a missense mutation and a single base deletion are predominant in Japanese patients. PMID:8541348
• JIMD reports • 2014 • Clinical Presentation and Positive Outcome of Two Siblings with Holocarboxylase Synthetase Deficiency Caused by a Homozygous L216R Mutation. PMID:24085707
• Orphanet Journal of Rare Diseases • 2023 • Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency. PMID:36890565
• Pediatric research • 1999 • Relationship between kinetic properties of mutant enzyme and biochemical and clinical responsiveness to biotin in holocarboxylase synthetase deficiency. PMID:10590022
• Molecular genetics and metabolism • 1999 • Mechanism of biotin responsiveness in biotin-responsive multiple carboxylase deficiency. PMID:10068510

Evidence Based Scoring (AI generated)