Fatty acid oxidation and ketogenesis disorder with hypertrophic cardiomyopathy

Fatty acid oxidation and ketogenesis disorder with hypertrophic cardiomyopathy (Orphanet code 217591) is a clinical grouping within the broader category of inherited fatty acid oxidation disorders (FAODs) that specifically present with hypertrophic cardiomyopathy (HCM) as a prominent feature. These disorders result from defects in the enzymes or transport proteins required for the breakdown (beta-oxidation) of fatty acids in the mitochondria, which serves as a critical energy source particularly for the heart and skeletal muscles. When fatty acid oxidation is impaired, the heart muscle may become abnormally thickened (hypertrophic cardiomyopathy) due to the accumulation of lipid intermediates and energy deficiency within cardiac cells. Several specific genetic conditions can present under this clinical umbrella, including very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, mitochondrial trifunctional protein (MTP) deficiency, and carnitine-acylcarnitine translocase deficiency, among others. Key symptoms typically include hypertrophic cardiomyopathy, hypoglycemia (particularly hypoketotic hypoglycemia during fasting or illness), skeletal muscle weakness, hepatomegaly, lethargy, and in severe cases, life-threatening cardiac arrhythmias or cardiac failure. Metabolic crises can be triggered by prolonged fasting, intercurrent illness, or increased energy demands. Management focuses on avoidance of prolonged fasting, dietary modification with restriction of long-chain fatty acids and supplementation with medium-chain triglycerides (MCT), and carnitine supplementation in selected cases. Emergency protocols during metabolic crises include intravenous glucose administration to prevent catabolism. Early detection through newborn screening programs using tandem mass spectrometry has significantly improved outcomes for many of these conditions. Cardiac management may include standard heart failure therapies and close monitoring by a cardiologist. Despite treatment advances, prognosis varies depending on the specific underlying enzyme deficiency and the severity of cardiac involvement.

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