Researchers highlighted the importance of recognizing thermo-sensitive forms of mitochondrial trifunctional protein (MTP) deficiencies seen in various long chain fatty acid oxidation disorders (LCFAODs) and published their results in the Journal of Inherited Metabolic Disease.

The study published by Schwantje et al described 5 cases of LCFAODs, 4 MTP deficiencies, and 1 long-chain ketoacyl-CoA thiolase (LCKAT) deficiency. All patients, aged 2 to 10 years, presented with myopathic symptoms followed by an episode of fever or exercise. The initial evaluation revealed normal or slightly increased long-chain acylcarnitine plasma levels in all cases, and 4 also had some degree of retinopathy or neuropathy. All patients underwent genetic testing, identifying HADHB mutations and hence diagnosing them with LCFAOD.

“Performing metabolic screening during symptomatic episodes may therefore increase the chance to find abnormalities and reduce the diagnostic delay,” the authors said.


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“However, we found that acylcarnitine concentrations may also be normal or only minimally increased when patients have symptoms, implicating that normal metabolic screening does not rule out the presence of MTP deficiency. This increases the risk of missing the diagnosis. Therefore, genetic screening early in the diagnostic trajectory may be useful.”

Read more about LCFAOD etiology

Recalling MTP, long-chain hydroxyacyl-CoA dehydrogenase (LCHAD), and LCKAT deficiencies are variants of enzyme dysfunctions that are sensitive to temperature changes. The triggering events (fever and exercise) of the reported cases are no surprise. Regardless, the molecular and clinical variations that temperature shifts may generate in LCFAOD have not yet been fully described.

When studying in vitro fibroblasts from the skin of the patients, both LCHAD and LCKAT activity barely decreased at 37 °C while the long-chain fatty acid β-oxidation (lcFAO)-flux remained normal. Conversely, by increasing 3 °C, both enzymes’ activity and lcFAO-fluxes significantly deteriorated. These results likely happen in vivo since dietary measures such as long-chain triglyceride restriction, enriched carbohydrate meals, and supplementation with medium-chain triglycerides are effective preventive and therapeutic strategies during febrile episodes.

“This case series shows that thermo-sensitive MTP deficiency is a potentially severe and disabling, but at least partly treatable condition,” the authors concluded. “The beneficial treatment effects emphasize the need of early recognition of thermo-sensitive MTP deficiencies and thermo-sensitive forms of inborn errors of metabolism in general.”

Reference

Schwantje M, Ebberink M, Doolaard M, et al. Thermo‐sensitive mitochondrial trifunctional protein deficiency presenting with episodic myopathy. J Inherit Metab Dis. Published online April 11, 2022. doi:10.1002/jimd.12503