Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a rare inherited disorder of mitochondrial fatty acid beta-oxidation. It is caused by mutations in the HADHA gene, which encodes the alpha subunit of the mitochondrial trifunctional protein (MTP). This enzyme is essential for breaking down long-chain fatty acids into energy, particularly during periods of fasting or increased energy demand. When LCHAD is deficient, the body cannot properly metabolize long-chain fatty acids, leading to a dangerous accumulation of toxic intermediates and an energy deficit in key organs. The condition primarily affects the heart, liver, skeletal muscles, and nervous system. Key clinical features include hypoketotic hypoglycemia (low blood sugar without appropriate ketone production), hepatopathy (liver dysfunction that can progress to liver failure), cardiomyopathy, hypotonia, rhabdomyolysis, and metabolic crises that can be life-threatening, often triggered by fasting, illness, or physical exertion. A distinctive long-term complication is pigmentary retinopathy, which can lead to progressive vision loss. Peripheral neuropathy may also develop over time. Notably, mothers carrying an affected fetus may develop HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) or acute fatty liver of pregnancy during the third trimester. LCHAD deficiency is typically identified through newborn screening programs that detect elevated long-chain hydroxylated acylcarnitines (particularly C16-OH and C18:1-OH) in dried blood spots. Treatment centers on dietary management, including avoidance of fasting, restriction of long-chain fatty acid intake, and supplementation with medium-chain triglycerides (MCT) as an alternative energy source. Carnitine supplementation may be considered, and essential fatty acid supplementation (such as DHA) is often recommended to support retinal health. Emergency protocols during illness are critical to prevent metabolic decompensation. With early diagnosis and careful management, outcomes have improved significantly, though long-term complications such as retinopathy and neuropathy may still occur.

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