Different forms of long chain fatty acid oxidation disorders (LCFAODs) result in varied lipidomic profiles, according to a recent presentation at the International Network for Fatty Acid Oxidation Research and Management (INFORM) Virtual Conference.

Dr. Sara Tucci. Credit: INFORM

The presenter, Dr. Sara Tucci, Head of the Laboratory for Clinical Biochemistry and Metabolism for Pediatrics at the University of Freiberg Medical Center in Germany, showed data that suggested that carnitine palmitoyltransferase II (CPTII), very long-chain acyl-CoA dehydrogenase (VLCAD), and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency disorders all resulted in different fatty acid profiles.

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The study showed that fibroblast cells taken from LCFAOD patients result in a deep remodeling of the acyl residues of mitochondrial cardiolipins that affect both the chain length and amount of desaturation causing the altered lipidomic profiles.

CPTII and LCHAD deficiencies both had profiles with higher amounts of shorter cardiolipins compared to healthy control cells while LCHAD and VLCAD deficiencies had fewer longer cardiolipins compared to controls.

The LCFAOD cells were also observed to express abnormal phosphatidylcholine (PC) to phosphatidylethanolamine (PE) ratios. This information, combined with increased levels of plasmalogens and lysophospholipids, lends evidence to support the theory of inflammation causing the symptoms of LCFAODs.

“This finding is of particular relevance since abnormalities of this [PC/PE] ratio influence energy metabolism and are associated with progression of several diseases. Specifically, the increased ratio in LCHAD fibroblasts is consistent with a deregulated mitochondrial biogenesis as previously described in the use of fibroblast cell lines,” Dr. Tucci said.

“One of the proposed pathophysiologic mechanisms associated with the higher ratio is the inhibition of the calcium transport activity of the SERCA protein contributing to protein misfolding and endoplasmic reticulum stress with consequences also on muscle contraction,” she added.

Cells taken from patients with LCHAD deficiency also exhibited disturbed sphingolipid metabolic flow which decreased the ratios of sphingomyelin to ceramide and sphingomyelin to hexosylceramide. These ratios indicate an altered flow that favored the creation of hexosylceramide rather than sphingomyelin.

These changes may contribute to the neuropathic phenotype sometimes observed in patients with LCHAD and mitochondrial trifunctional protein (MTP) deficiencies as the release of ceramide from sphingomyelin is known to be specifically detrimental to neurons and oligodendrocytes, according to Dr. Tucci. The elevation of hexosylceramide levels has also been implicated in other neurodegenerative diseases, as well.

“It is possible that the oxidative stress due to accumulating toxic hydroxy acid in LCHAD and MTP induces mitochondrial damage with the subsequent activation of the sphingomyelin/ceramide pathway involved in the development of peripheral neuropathy in these diseases,” she explained.

Dr. Tucci also presented results showing that the addition of medium chain fatty acids restores the metabolic flow in LCHAD deficiency cells to favor the production of sphingomyelin rather than hexosylceramide.

During the study, fibroblast cells were collected from 7 healthy control, 6 VLCAD patients, 3 LCHAD, and 2 CPTII patients. Dr. Tucci highlighted that all of the results were observed in fibroblasts and more research is needed to extrapolate the findings.


Disease specific lipid signature in fibroblasts of long-chain fatty acid oxidation disorders. Presented at: International Network for Fatty Acid Oxidation Research and Management (INFORM) Virtual Meeting: October 28, 2021; Virtual.