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. 2025 Jul;48(4):e70060.
doi: 10.1002/jimd.70060.

Plasma Metabolomics, Lipidomics, and Acylcarnitines Are Associated With Vision and Genotype but Not With Dietary Intake in Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD)

Hak Chung  1 , Dongseok Choi  2   3 , Ashley Gregor  1 , Elaine Sim  1 , Alison Lau  4 , Danielle Black  5 , Hannah L Scanga  6 , Angela Linshinski  5 , Mark E Pennesi  3   7 , Jose-Alain Sahel  6 , Ken K Nischal  6 , Paul Yang  3 , Lesley Everett  3 , Jerry Vockley  7 , Dietrich Matern  8 , Cary O Harding  1 , Melanie B Gillingham  1   4
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Plasma Metabolomics, Lipidomics, and Acylcarnitines Are Associated With Vision and Genotype but Not With Dietary Intake in Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD)

Hak Chung et al. J Inherit Metab Dis. 2025 Jul.

Abstract

3-hydroxy acylcarnitines (3-OH-ACs) are key biomarkers for screening of long-chain 3-hydroxyacyl-CoA dehydrogenase and trifunctional protein deficiencies (LCHADD/TFPD). The utility of this biomarker for disease monitoring in identified patients remains debated, and recent suggestions have highlighted the potential use of lipidomics for diagnosis, monitoring, prognosis, and/or identification of new biomarkers. We evaluated the use of omics in LCHADD/TFPD patients by analyzing plasma acylcarnitine profiles, metabolomics, and lipidomics, combined with genotype, visual assessments, and dietary records. Fasting plasma from 39 participants with LCHADD/TFPD and 32 control subjects were analyzed through untargeted metabolomic and lipidomic analyses. In LCHADD/TFPD participants, acylcarnitine profiling, visual and retinal function assessments were performed, and 3-day diet records were collected. Relationships between acylcarnitines, metabolomics, lipidomics, along with visual outcomes and dietary intake were investigated. Plasma of LCHADD/TFPD participants exhibited elevated 3-OH-ACs, which correlated with genotype and visual outcomes. Metabolomics successfully distinguished LCHADD/TFPD from controls, and the biggest divergence was observed in lipid pathways. Metabolomic profiles tightly correlated with 3-OH-ACs, genotype, and visual outcomes. Lower concentrations of total lipids and some individual lipid species such as phosphoethanolamines (PE) were detected in LCHADD/TFPD, except for elevations in several certain triglycerides. LCHADD/TFPD participants followed a diet low in long-chain fat (LCFA) as recommended. LCFA intake did not correlate with either plasma 3-OH-ACs or metabolomics. 3-OH-ACs are strong consistent biomarkers of LCHADD/TFPD that are associated with clinical parameters of vision and genotype. We did not observe a relationship between dietary LCFA intake and 3-OH-ACs.

Keywords: 3‐hydroxy acylcarnitines; 3‐hydroxy fatty acids; fatty acid oxidation; fatty acid oxidation disorders; lipidomics; long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency; metabolomics.

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