Mitochondrial trifunctional protein deficiency

Mitochondrial trifunctional protein (MTP) deficiency is a rare inherited disorder of mitochondrial fatty acid beta-oxidation. It is caused by pathogenic variants in the HADHA or HADHB genes, which encode the alpha and beta subunits of the mitochondrial trifunctional protein complex, respectively. This enzyme complex is responsible for three of the four steps in the mitochondrial long-chain fatty acid beta-oxidation spiral: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain 3-ketoacyl-CoA thiolase activities. MTP deficiency involves deficiency of all three enzymatic activities, distinguishing it from isolated LCHAD deficiency, which affects only one activity of the alpha subunit. The disease primarily affects the heart, skeletal muscles, liver, and nervous system. It presents in a clinical spectrum ranging from a severe neonatal form to milder later-onset phenotypes. The severe neonatal form is characterized by cardiomyopathy, hypoglycemia, metabolic acidosis, liver dysfunction, and early death. An infantile-onset hepatic form features recurrent hypoketotic hypoglycemia, hepatomegaly, liver failure, and hypotonia, often triggered by fasting or illness. A milder, later-onset myopathic form presents primarily with episodic rhabdomyolysis, skeletal myopathy, and peripheral neuropathy. Pigmentary retinopathy is a distinctive feature that may occur across phenotypes. Mothers carrying an affected fetus may develop HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) or acute fatty liver of pregnancy. Treatment is primarily supportive and dietary. Management includes avoidance of fasting, a diet restricted in long-chain fatty acids supplemented with medium-chain triglycerides (MCT oil), and essential fatty acid supplementation. Carnitine supplementation may be considered. During acute metabolic crises, intravenous glucose administration is critical. Newborn screening using tandem mass spectrometry can identify affected individuals through elevated long-chain acylcarnitine species, enabling early intervention. Despite treatment, long-term complications including cardiomyopathy, neuropathy, and retinopathy may still develop. Prognosis varies significantly depending on the severity of the phenotype and the timeliness of diagnosis and management.

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