Familial alpha-lipoprotein deficiency

History

The story of this condition begins in 1959 with five-year-old Teddy Laird of Tangier Island, Virginia, whose unusually large, yellow-orange tonsils were surgically removed by military doctors. Initially thought to be Niemann-Pick disease, he was referred to Dr. Louis Avioli at the National Cancer Institute.

Donald Fredrickson, suspecting a different cause, traveled with Avioli to Tangier Island in 1960. There, Teddy’s sister showed the same symptom, and examinations revealed foam cells packed with cholesterol esters not just in the tonsils but also in the bone marrow and spleen. A follow-up visit uncovered very low HDL cholesterol levels in the family, pointing to a genetic disorder.

Signs and symptoms

Homozygotes for Tangier disease develop cholesterol ester depositions, notably in the tonsils, which may appear yellow or orange and become enlarged. Deposits also occur in lymph nodes, bone marrow, liver, and spleen, often leading to hepatosplenomegaly. Neuropathy and cardiovascular disease are the most devastating developments.

Genetics

Mutations on chromosome 9q31 cause a defective ABCA1 transporter, preventing effective transport of cholesterol and phospholipids out of cells for pickup by ApoA1. This leads to HDL deficiency in circulation and toxic buildup of cholesterol in cells, causing cell death or impaired function. The condition is inherited in an autosomal recessive pattern, requiring two copies of the altered gene for the phenotype to appear.

Diagnosis

Tangier disease results in familial high-density lipoprotein deficiency. Defective ABCA1 transporters greatly reduce cholesterol transport out of cells, causing accumulation in many body tissues and reduced blood HDL levels, sometimes called hypoalphalipoproteinemia. Affected individuals have mild hypertriglyceridemia, neuropathy, and visibly orange or yellow enlarged tonsils. They often develop premature atherosclerosis with fatty deposits and scar-like tissue lining arteries, as well as splenomegaly, hepatomegaly, corneal clouding, and early-onset cardiovascular disease.

Did You Know?

• Drugs that increase serum HDL, such as niacin or gemfibrozil, do not benefit Tangier disease patients.
• The only current treatment is diet modification, with a low-fat diet reducing some symptoms, especially neuropathies.