Holocarboxylase synthetase deficiency: pathogenesis, clinical features, diagnosis, treatment, and research prospects

Holocarboxylase Synthetase Deficiency (HLCSD) is a rare autosomal recessive inborn error of metabolism caused by biallelic mutations in the HLCS gene. The encoded enzyme, holocarboxylase synthetase (HLCS), plays a critical role in biotin metabolism by activating five essential carboxylases, including pyruvate carboxylase (PC) and propionyl-CoA carboxylase (PCC), thereby regulating key processes such as gluconeogenesis, fatty acid synthesis, and branched-chain amino acid catabolism [1, 14]. HLCS dysfunction leads to the accumulation of toxic metabolites (e.g., 3-hydroxyisovaleric acid, methylcitric acid), resulting in severe manifestations like metabolic acidosis and hyperammonemia [6]. This review systematically consolidates current knowledge on the molecular mechanisms, clinical spectrum, diagnostic approaches, and therapeutic strategies for HLCSD. It critically addresses core controversies, including genotype-phenotype correlations and variability in biotin treatment response, and proposes a multidimensional "gene-enzyme activity-metabolic phenotype-treatment response" framework. Studies confirm that early diagnosis via newborn screening, coupled with standardized biotin supplementation, achieves biochemical normalization and clinical symptom resolution in over 85% of patients and reduces the risk of neurological sequelae [10, 33, 35]. However, biotin-unresponsive cases and rare phenotypes present ongoing diagnostic and therapeutic challenges, necessitating further exploration of novel interventions to advance the precision medicine approach for HLCSD. What is Known: • Holocarboxylase synthetase defi ciency (HLCSD) is a rare autosomal recessive metabolic disorder caused by HLCSbiallelic mutations, and biotin supplementation is the mainstream treatment for most patients. • Distinct population-specifi c HLCS mutation hotspots exist, and residual enzyme activity is closely correlated with disease severity and age of onset. What is New: • A multidimensional framework of gene-enzyme activity-metabolic phenotype-treatment response was proposed tointerpret phenotypic heterogeneity and variable biotin responsiveness in HLCSD. • This review systematically summarized rare clinical phenotypes, diagnostic pitfalls, emerging detection technologies and novel therapeutic directions including gene therapy and epigenetic intervention.