Apolipoprotein A-I deficiency

Apolipoprotein A-I (apo A-I) deficiency is a rare inherited disorder of lipoprotein metabolism caused by mutations in the APOA1 gene, which encodes the major protein component of high-density lipoprotein (HDL) cholesterol. This condition is also known as familial hypoalphalipoproteinemia or analphalipoproteinemia when HDL is completely absent. Apo A-I plays a critical role in reverse cholesterol transport — the process by which excess cholesterol is removed from tissues and transported to the liver for excretion. When apo A-I is deficient or absent, HDL cholesterol levels are markedly reduced or undetectable, leading to impaired cholesterol clearance from the body. The disease primarily affects the cardiovascular system, the eyes, and the skin. Patients are at significantly increased risk for premature coronary artery disease and atherosclerosis, often presenting with symptomatic cardiovascular events in early adulthood. Corneal opacification (corneal clouding) is a hallmark feature and may develop in childhood or early adulthood, potentially impairing vision. Some patients also develop xanthomas — yellowish deposits of cholesterol in the skin and tendons — due to abnormal lipid accumulation. In certain variants, amyloidosis affecting the kidneys, liver, or other organs has been reported, caused by deposition of amyloid fibrils derived from mutant apo A-I protein. There is currently no specific curative therapy for apo A-I deficiency. Management focuses on aggressive cardiovascular risk reduction, including lifestyle modifications (diet, exercise, smoking cessation) and lipid-lowering medications such as statins. Corneal transplantation may be considered for significant visual impairment due to corneal opacities. Regular cardiovascular monitoring and screening for complications such as amyloidosis are recommended. Research into HDL-targeted therapies and apo A-I replacement strategies is ongoing but remains largely investigational.

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