LCHAD Deficiency as a Model of Carnitine-Mediated Lipotoxicity: A Clinical Case with Therapeutic Carnitine Reduction

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a severe inherited disorder of mitochondrial β-oxidation. The transport of toxic long-chain fatty acids (LCFA) into mitochondria is mediated by the carnitine shuttle, making free carnitine a potential therapeutic target. We present a clinical case of a female child (age at study onset: 1.5 years) with a homozygous c.1528G>C mutation in the HADHA gene, managed with meldonium (a carnitine synthesis inhibitor) to achieve therapeutic carnitine reduction. Over 15 months of monitoring, hydroxyacylcarnitines decreased from 0.78 to 0.03 µmol/L (C16-OH) when free carnitine was maintained at 7–8 µmol/L. A critical threshold was identified: free carnitine levels above 8–9 µmol/L were associated with an increase in toxic hydroxyacylcarnitines. The patient remained clinically stable, including during severe influenza with fever up to 39.4°C. A persistent predominance of sebacic acid (C10) with a ratio C10 >> C8 > C6 was observed in urinary dicarboxylic acids, consistent with dominant peroxisomal β-oxidation. A riboflavin supplementation trial (24 mg/day for one month) did not alter the dicarboxylic acid profile, indicating that the peroxisomal pathway operates at kinetic maximum rather than cofactor limitation. Following these findings, we revised our earlier thesis of complete TFP non-functionality, demonstrating minimal but clinically insignificant residual activity. We propose that LCHAD represents a model of carnitine-mediated lipotoxicity with implications extending to metabolic syndrome and type 2 diabetes.