Tangier disease is a rare, inherited metabolic condition that disrupts the body’s ability to process cholesterol and certain fats. This disruption leads to a severe reduction of high-density lipoprotein (HDL), or “good cholesterol,” in the bloodstream. HDL’s function is to transport excess cholesterol from the body’s tissues back to the liver for removal. Without sufficient HDL, cholesterol accumulates in various cells and tissues throughout the body, leading to a range of health issues.
Cause and Genetics
Tangier disease is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene. This gene provides instructions for creating the ABCA1 protein, which transports cholesterol and phospholipids out of cells. Once outside, these lipids are picked up by apolipoprotein A-I (ApoA-I) to form HDL particles, initiating reverse cholesterol transport.
In individuals with Tangier disease, mutations prevent the ABCA1 protein from functioning correctly. This traps cholesterol and phospholipids inside cells, particularly scavenger cells known as macrophages. This cellular trapping prevents the formation of HDL, causing its levels in the blood to become extremely low and leading to the deposition of fats in various body tissues. The condition was named after Tangier Island, Virginia, where the first cases were identified.
The disease is inherited in an autosomal recessive pattern, meaning an individual must inherit two mutated copies of the gene, one from each parent. Individuals who inherit only one mutated copy are known as carriers. Carriers do not show the full symptoms but do exhibit reduced HDL levels, often around 50% of the normal concentration, which can be identified through blood tests.
Signs and Symptoms
The most distinctive sign of Tangier disease is the appearance of the tonsils, which become significantly enlarged and take on a characteristic yellow or orange hue from cholesterol ester accumulation. While this feature is prominent in children and adolescents, the effects of cholesterol deposition are systemic.
Fatty deposits also affect the reticuloendothelial system, a network of cells that clears cellular debris. This commonly leads to hepatosplenomegaly, the enlargement of the liver and spleen, and can also cause enlarged lymph nodes. These enlarged organs are often asymptomatic but serve as a clinical indicator of the lipid storage issue.
A more serious consequence of the disease is peripheral neuropathy, which affects over half of the individuals diagnosed. This nerve damage is caused by lipids accumulating in the protective myelin sheath around nerve cells, disrupting their signals. The neuropathy can manifest as a relapsing-remitting pattern of weakness or numbness, or as a more progressive sensory and motor impairment. Some individuals may also experience clouding of the cornea, though this rarely impacts vision.
Diagnosis Process
Diagnosing Tangier disease often begins with observing its clinical signs, particularly enlarged, orange-colored tonsils and an enlarged spleen or liver. These symptoms prompt a physician to order a specialized blood test called a lipid panel.
A lipid panel provides the primary biochemical evidence for the condition. In a patient with Tangier disease, the test reveals a distinct profile:
- Virtually absent or extremely low levels of HDL cholesterol, often below 5 mg/dL
- A severe deficiency of apolipoprotein A-I (ApoA-I)
- Low levels of low-density lipoprotein (LDL) cholesterol
- Normal or slightly elevated triglycerides
While the lipid panel is highly suggestive, a definitive diagnosis requires molecular genetic testing to identify mutations in both copies of the ABCA1 gene. If genetic testing is unavailable, a biopsy of affected tissue like the tonsils can be performed. These tissue samples will show the presence of “foam cells”—macrophages laden with cholesterol esters—which supports the diagnosis.
Management and Treatment
There is no cure for Tangier disease that can correct the underlying genetic defect. Therefore, management focuses on mitigating symptoms and reducing the long-term risk of complications like premature cardiovascular disease. The buildup of cholesterol in artery walls can lead to atherosclerosis, increasing the chances of heart attacks and strokes later in life.
The primary management strategy is lifestyle and dietary modification. Patients are advised to follow a heart-healthy, low-fat diet with strict limits on saturated and trans fats. This approach aims to reduce the lipids circulating in the body, which can lessen the rate of cholesterol accumulation. Regular cardiovascular screening is recommended to track the development of atherosclerosis.
Specific symptoms are treated as they arise. For instance, if the tonsils become so enlarged that they obstruct breathing or swallowing, a tonsillectomy may be performed, but this only addresses the localized symptom. Similarly, bracing or physical therapy may be used for peripheral neuropathy. While medications like statins might manage a patient’s cardiovascular risk, they do not resolve the HDL deficiency.