Tangier Disease

Clinical characteristics: Tangier disease is characterized by severe deficiency or absence of high-density lipoprotein (HDL) in the circulation resulting in tissue accumulation of cholesteryl esters throughout the body, particularly in the reticuloendothelial system. The major clinical signs of Tangier disease include hyperplastic yellow-orange tonsils, hepatosplenomegaly, and peripheral neuropathy, which may be either relapsing-remitting or chronic progressive in nature. Rarer complications may include corneal opacities that typically do not affect vision, premature atherosclerotic coronary artery disease occurring in the sixth and seventh decades of life (not usually before age 40 years), and mild hematologic manifestations, such as mild thrombocytopenia, reticulocytosis, stomatocytosis, or hemolytic anemia. The clinical expression of Tangier disease is variable, with some affected individuals only showing biochemical perturbations.

Diagnosis/testing: The diagnosis of Tangier disease is established in a proband with absent or extremely low HDL-cholesterol and apo A-I levels and biallelic pathogenic variants in ABCA1 identified by molecular genetic testing.

Management: Treatment of manifestations: Tonsillectomy in those with airway obstruction or mass symptoms; transient bracing (such as ankle-foot orthosis) and exercise for those with peripheral neuropathy; corneal transplantation for corneal opacities that interfere with daily living; standard treatment for hepatosplenomegaly, coronary artery disease, severe thrombocytopenia, and severe hemolytic anemia.

Prevention of primary manifestations: Mitigation of cardiovascular risk factors, including improvement of plasma lipid profiles using statin therapy and a low-fat diet.

Surveillance: Assessment for hepatosplenomegaly by physical examination and imaging at each visit; neurology and ophthalmology evaluations annually; cardiovascular risk assessment of atherosclerotic plaque burden annually beginning in adulthood; complete blood count with differential as clinically indicated.

Agents/circumstances to avoid: Obesity (which makes walking more difficult); medications that are toxic or potentially toxic to those who are predisposed to the development of peripheral neuropathy; contact sports in those with hepatosplenomegaly.

Evaluation of relatives at risk: It is appropriate to measure a lipid profile (total cholesterol, HDL-cholesterol, triglyceride, and calculated LDL-cholesterol) and apo A-I concentration in at-risk sibs to identify as early as possible those who would benefit from appropriate treatment or measures to prevent disease complications.

Genetic counseling: Tangier disease is inherited in an autosomal recessive manner. Most parents are heterozygous for a pathogenic variant. At conception each sib has a 25% chance of being unaffected, a 50% chance of being a carrier (with no overt clinical manifestations, but with plasma HDL-cholesterol concentrations that are ~50% of normal), and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.