Untargeted Metabolomic and Lipidomic Profiling Reveals Distinct Biochemical Patterns in Treated Biotinidase Deficiency

Biotinidase deficiency is an autosomal recessive disorder that disrupts biotin recycling and multiple carboxylase-dependent pathways. Early and continuous biotin therapy prevents major clinical manifestations, but its long-term biochemical effects remain unclear. This study applied untargeted metabolomic and lipidomic profiling in 54 pediatric patients with genetically confirmed BD receiving regular biotin supplementation and 30 age- and sex-matched controls. Multivariate analyses and pathway enrichment revealed distinct biochemical signatures involving amino acid, energy, and lipid metabolism. Reduced levels of serine, glycine, threonine, and tricarboxylic acid cycle intermediates suggested modified mitochondrial flux, while octopine, exhibiting an approximately 11-fold increase, was the metabolite best able to discriminate between the groups. Lipidomic profiling indicated elevations in sphingolipids, phosphatidylcholines, long-chain fatty acids, and acylcarnitines, consistent with systemic lipid remodeling. These coordinated alterations imply metabolic adaptations to sustained biotin exposure rather than ongoing pathology. Octopine and selected lipid species may represent biochemical indicators of this adaptive state. Overall, the findings highlight that clinically stable children with Biotinidase deficiency exhibit unique metabolic and lipidomic patterns reflecting long-term compensatory mechanisms, underscoring the value of combined omics approaches for understanding disease-specific homeostasis and informing personalized follow-up strategies.