**2. Global ABCA1 Deficiency: Tangier Disease**

Tangier disease (TD) is a rare autosomal recessive disease caused by homozygous or compound heterozygous loss of function variants in both alleles of the *ABCA1* gene (OMIM #205400). TD is characterized by severe deficiency or absence of circulating HDL-C particles and accumulation of cholesteryl-esters in cells throughout the body, particularly in the reticuloendothelial system [7,8]. The major clinical signs of TD are very low HDL-C levels (<5 mg/dL), hyperplastic yellow orange tonsils and hepatosplenomegaly; while peripheral neuropathy occurs in approximately 50%, and premature coronary heart disease (CHD), occurs in 30 to 50% of TD patients [9–11]. Carriers of a single *ABCA1* mutation (heterozygotes) have variable reductions in plasma HDL-C levels and a variable increased risk for CHD [12]. Other less frequent symptoms include corneal opacity and hematologic manifestations, such as thrombocytopenia, altered platelet morphology and function, mild bleeding tendency, reticulocytosis, stomatocytosis and hemolytic anemia [13].

Macrophages and other cells from TD patients are overloaded with cholesterol (foam cells) because the ABCA1-mediated efflux of cellular free (unesterified) cholesterol and phospholipids to ApoA-I is defective [14]. These foam cells play a crucial role in the pathogenesis of atherosclerosis and CHD. However, it is not clear why not all TD patients

develop premature CHD. A review of 185 TD cases reported that 51% of patients aged 40 to 65 years had premature CHD and suggested that reduced low-density lipoproteincholesterol (LDL-C) levels in TD patients provide cardiovascular protection, while TD patients with normal LDL-C levels are likely to develop premature CHD [10]. A more recent review reported angina in 24.8%, and other vascular diseases in 21.8% of TD cases. Patients with CHD had a higher mean age, and while total cholesterol and LDL-C levels were higher in CHD than in non-CHD TD patients, the differences were only statistically significant in women [15]. The presence of small-dense LDL-C particles in some TD patients are also thought contribute to the development of CHD [10,15].
