Researchers found a novel genotype in a patient with a rare form of long chain fatty acid oxidation disorder (LCFAOD), as published in Molecular Genetics and Metabolism Reports.

The case report consists of a 4-year-old male patient diagnosed with erythropoietic protoporphyria due to skin changes in the physical exam. He was treated with canthaxanthin for 5 years until an assessment for ocular toxicity related to the drug showed findings inconsistent with the diagnosis, thus deciding to suspend the treatment.

The patient’s medical history remained mostly uneventful until 25 years of age, when he presented with intense myalgia following an exercise session, leading to hospital admission without further evaluation. Three years later, the symptoms worsened, and echocardiography showed dilated cardiomyopathy with reduced left ventricular ejection at 25%, diagnosing him with chronic heart failure (CHF). Treatment was initiated with beta-blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists.

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A fundus examination also revealed a dark foveal dot and posterior pole depigmentation in radial and reticular patterns. Finally, at 30 years of age, a cardiology follow-up evidenced a class 2 CHF and overall worsening of cardiac function, proposing a heart transplant.

Read more about LCFAOD etiology

In the context of a young patient with such severe disease, extensive studies were indicated and revealed elevated hydroxylated long-chain fatty acids in plasma and enzyme blockade consistent with long chain 3-hydroxyacyl-CoA dehydrogenase deficiency in fluxomic studies. Further genetic testing finally validated the diagnosis, observing a novel variation x.1108G >A, p. (Gly370Arg) located in the nicotinamide adenine dinucleotide binding domain along with the common p.(Glu510Gln) variant in the HADHA gene.

The patient-initiated dietary measures consisted of limited periods of fasting, reduced consumption of long-chain triglycerides, and medium-even-chain triglycerides supplementation. He was later replaced with triheptanoin, while also reinforcing the cardiovascular treatment scheme. At the 1 year check-up, his left ventricular ejection improved to 50%.

The case presented in this article highlights the importance of keeping LCFAOD as a differential diagnosis in the presence of findings uncharacteristic for a single disease. “This is particularly true concerning atypical presentations such as ours given that we can expect a large number of underdiagnosed mild/late-onset phenotypes, because of a very high prevalence of the particular HADHA p.(Glu510Gln) allele in the population of Northern Europe,” the authors explained.

“Our patient illustrates that in the presence of unexplained macular dystrophy and/or unexplained hypertrophic or dilated cardio-myopathy, the carnitine status and the acylcarnitines profile should be determined to exclude or confirm a beta-oxidation disorder,” they concluded. “In case of positive diagnosis, specific metabolic treatment with triheptanoin in combination with cardiovascular therapy should be considered.


Dessein A, Hebbar E, Vamecq J et al. A novel HADHA variant associated with an atypical moderate and late-onset LCHAD deficiency. Mol Genet Metab Rep. Published online March 15, 2022. doi:10.1016/j.ymgmr.2022.100860