Altered compositions of several complex lipids may be involved in the progressive neurological symptoms observed in some forms of long chain fatty acid oxidation disorder (LCFAOD) including long-chain 3-hydroxyacyl-CoA deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD).

The lipids identified in a recent hypothesis article published in the International Journal of Molecular Sciences include sphingomyelins and ceramides for LCHADD and cardiolipin for MTPD. The retinopathy and neurodegenerative symptoms commonly experienced by patients with LCHADD and MTPD despite early diagnosis and therapy initiation may be caused by the accumulation of altered versions of these complex lipids.

“The very recent reports on the altered composition of cardiolipins, [sphingomyelin] and ceramides described in the fibroblasts of LCHADD patients led us to formulate the hypothesis of a more complex multifactorial pathogenesis behind the progressive neurodegenerative symptoms in this disease also involving the complex lipids,” the author wrote.

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The proposed pathomechanism described by the author involves mitochondrial damage due to oxidative stress caused by the accumulation of long-chain hydroxy acylcarnitines and a hampered electron flow.

The accumulation of long-chain fatty acids that are unable to enter the β-oxidation cycle results in changes in the composition of mitochondrial cardiolipins. These cardiolipins have been shown to affect mitochondrial respiration and dynamics, at least in fibroblasts of patients with LCHADD.

Sphingolipids have also been observed to change in composition and shape, which can lead to the upregulation of hexosylceramides. These lipids have been shown to have detrimental effects on other neurodegenerative diseases. A previous study in LCHADD patient fibroblasts showed that cells incubated in medium-chain fatty acids did not accumulate long-chain hydroxy acylcarnitines and contributed to the restoration of sphingolipids, supporting the author’s hypothesis.

“It is unclear whether the described alterations are a consequence of oxidative stress, remodeling or to the accumulation of fatty acids rather than an unforeseen independent effect. However, they may explain why despite therapy and metabolic maintenance, the symptoms remain progressive,” the authors said.


Tucci S. An altered sphingolipid profile as a risk factor for progressive neurodegeneration in long-chain 3-hydroxyacyl-CoA deficiency (LCHADD). Int J Mol Sci. 2022;23(13):7144. doi:10.3390/ijms23137144