Hyperhomocysteinemia in late-onset MADD: high prevalence and exacerbation of lipid deposition

Abstract Background Hyperhomocysteinemia (HHcy) is common in patients with late-onset multiple acyl-CoA dehydrogenase deficiency (MADD), but its role in disease progression remains unclear. This study aimed to investigate the prevalence of HHcy in late-onset MADD and explore its impact on lipid metabolism. Methods We conducted a meta-analysis of three studies including 43 patients to assess the prevalence and serum levels of homocysteine (Hcy). Additionally, we used a HEK293 cell model carrying a homozygous c.917G > A mutation in electron transfer flavoprotein dehydrogenase ( ETFDH) to evaluate the effects of Hcy on lipid accumulation and fatty acid oxidation. Results The meta-analysis revealed a high prevalence of HHcy (91%, 95% CI: 86–95%) and significantly elevated serum Hcy levels (50.21 µmol/L, 95% CI: 23.07–77.35). In vitro experiments showed that Hcy treatment significantly increased intracellular triglyceride (TG) levels, upregulated acetyl-CoA carboxylase 2 (ACC2) expression at both mRNA and protein levels, and elevated malonyl-CoA levels, indicating inhibition of fatty acid oxidation. Conclusion HHcy is highly prevalent in late-onset MADD and may exacerbate lipid deposition, potentially through the modulation of ACC2 expression. These findings suggest that HHcy may play a role as an environmental factor associated with the pathogenesis of late-onset MADD, and vitamin therapy to lower Hcy levels may be an adjuvant intervention strategy for late-onset MADD patients with comorbid HHcy.