Trifunctional protein (TFP) deficiency, a type of long-chain fatty acid oxidation disorder (LCFAOD), is associated with a disruption in cardiolipin deacylation and/or remodeling, according to study results presented by Eduardo Vieira Neto, MD, PhD, at the 2022 lecture series of the International Network for Fatty Acid Oxidation Research and Management (INFORM).

Cardiolipin is an important component of the inner mitochondrial membrane that plays a crucial role in the structure of the mitochondrial cristae.

The disruption in cardiolipin remodeling, Dr. Neto said, can be attributed to a deficit in the function of monolysocardiolipin acyltransferase, which plays a key role in the remodeling of monolysocardiolipins into cardiolipin.


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More than 50 mutations in genes coding for the TFP have been identified in patients. Here, the researchers analyzed 4 patients (2 men and 2 women) with TFP deficiency and 1 man with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, another type of LCFAOD.

Read more about the different types of LCFAOD and their etiology.

Three of the patients had hypoglycemia, hypotonia, and motor delays. All patients had rhabdomyolysis and all patients with TFP deficiency had muscle weakness. Two patients had cardiomyopathy that was reversed with treatment and 3 patients had peripheral neuropathy. None of them had retinopathy. 

Cell culture experiments showed that the levels of cardiolipins were lower in cells obtained from patients compared to those from controls, whereas the levels of monolysocardiolipins were higher.

Dr. Neto, a clinical pathologist and medical geneticist, also showed that LCHAD affects the catalytic site of the dehydrogenase and monolysocardiolipin acyltransferase enzymes, causing significant impairment in mitochondrial bioenergetics.

Finally, a history of maternal HELLP syndrome, which was known to affect 2 of the 5 patients analyzed, correlated with high levels of C16-OH after a palmitate load to the cells, Dr. Neto reported. Maternal HELLP syndrome is a life-threatening complication during pregnancy that is considered to be a variant of preeclampsia.

Reference

Neto EV. Mitochondrial bioenergetics and cardiolipin remodeling deregulation in mitochondrial trifunctional protein deficiency. Lecture presented as part of International Network for Fatty Acid Oxidation Research and Management (INFORM) 2022 lecture series: March 28, 2022; Virtual.