Clinical diagnosis, treatment, and genetic analysis of adolescent onset holocarboxylase synthetase deficiency and cobalamin C deficiency: A case report and literature review

Abstract

Background

Holocarboxylase Synthetase Deficiency (HCSD) is an uncommon autosomal recessive genetic disorder that manifests with symptoms such as metabolic acidosis, lethargy, hypotonia, seizures, and persistent rashes, typically emerging during infancy. The HLCS gene has been identified as the source of pathogenic mutations associated with this condition. Cobalamin C (cblC) deficiency is another rare autosomal recessive disorder resulting from defects in cobalamin metabolism, attributable to mutations in the MMACHC gene. This disorder often leads to methylmalonic aciduria and homocystinuria and is classified into early-onset and late-onset types. The late-onset type is characterized by acute or chronic progressive neurological symptoms and behavioral disturbances. To date, there have been no documented cases worldwide of individuals diagnosed with both HCSD and cobalamin C deficiency.

Case presentation

This report details the case of an 11-year-and-9-month-old female patient from China who presented with symptoms including vomiting, altered consciousness, and a rash. Laboratory evaluations indicated the presence of metabolic acidosis, methylmalonic aciduria, and homocystinuria. Genetic analysis revealed mutations in the MMACHC gene: c.482G > A (p.R161Q) and c.567dup (p.I190Yfs∗13). Additionally, two previously unreported mutations in the HLCS gene, c.1922G > T (p.G641V) and c.1754C > T (p.P585L), were identified. She was diagnosed with Holocarboxylase Synthetase Deficiency and Cobalamin C deficiency. The child showed significant improvement following treatment with hydroxocobalamin, betaine, and biotin.

Conclusion

This article reports a case of adolescent onset HCSD and cobalamin C deficiency. Treatment with hydroxocobalamin, betaine, and biotin is effective. Two novel mutations in the HLCS gene causative for HCSD have been reported, providing a broader foundation for mutational screening and offering insights into the diagnosis and treatment of similar disorders.