Tangier Disease in Severely Progressive Coronary and Peripheral Artery Disease
A 37-year-old man was first referred to our lipid clinic in December 2007 for plasma lipid alteration. He presented with large, orange tonsils (Figure 1) and hepatosplenomegaly. There was no evidence of corneal opacities nor of other ocular abnormalities, and there were no nervous system abnormalities as assessed by sensitive and motor electromyography.
Hematologic abnormalities included thrombocytopenia and erythrocytes with altered morphology (stomatocytes; Figure 2) and function (decreased osmotic resistance). Serum levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were 58, 184, and 4 mg/dL, respectively; plasma apolipoprotein A-I concentrations were very low (3.9 mg/dL); and apolipoprotein A-II plasma levels were 1.7 mg/dL.
The patient’s father (58 years of age) had serum levels of total cholesterol, HDL cholesterol, and apolipoprotein A-I of 127, 25, and 99.5 mg/dL, respectively. Moreover, he had a history of premature severe coronary disease since 37 years of age that had been treated with repeated surgical revascularization.
Our patient began having exertional chest pain in March 2006 at 35 years of age. His ECG stress test was positive for myocardial ischemia, so a coronary angiogram was performed. The test revealed severe atherosclerosis in 2 vessels, 95% stenosis in the mid portion of the right coronary artery with 75% stenosis at the crux and 95% stenosis in the proximal portion of the left anterior descending coronary artery, continuing on to 2 other 50% stenoses (Figure 3).
The patient was treated by percutaneous coronary angiography and stenting of the right coronary artery, mid portion, and crux and the left anterior descending coronary artery. The procedure was complicated by an episode of ventricular fibrillation, which was treated with DC shock.
Ten days later, the patient underwent percutaneous transluminal angioplasty and stenting because of occlusion of the right external common iliac–femoral arteries. Nine months later, he experienced restenosis in the paclitaxel-eluting stent in the proximal left anterior descending coronary artery and was treated with a rapamycin-eluting stent.
At 10 months, on medical consultation, he was referred to coronary angiography because the ECG stress tested positive for myocardial ischemia. Angiography showed a critical stenosis at the left main coronary; he was referred for coronary artery bypass graft surgery.
The man was diagnosed with Tangier disease on the basis of the occurrence of the typical pathognomonic triad: HDL deficiency (confirmed in 2-dimensional electrophoresis in which a virtual absence of α-lipoproteins is observed; Figure 4), low plasma cholesterol concentration associated with normal (or even elevated) triglyceride levels, and hyperplastic orange tonsils.1 Because of an ABCA-1 cellular receptor defect, maturation of lipid-rich HDL in Tangier disease cannot take place, so apolipoprotein A-I and A-II are subjected to enhanced catabolism. In this patient, the investigation of the specific gene variant is ongoing.
Besides the pathognomonic findings given above, this case was characterized by other classic signs of Tangier disease such as thrombocytopenia and stomatocytes. The reduced cholesterol-to-phosphatidylcholine ratio in the erythrocytes membrane is considered to be the origin of the morphological anomaly—leading to the smiling pattern—and the functional changes as the decreased osmotic resistance of erythrocytes.
However, the most prominent aspect of this clinical phenotype was the very early and severe atherosclerotic cardiovascular disease that manifested at 35 years of age in the proband and at 37 years of age in the father (who, as heterozygous, should have been clinically silent).
This case underlines the need for a deeper understanding of the relation between cellular cholesterol efflux (in this case, abolished) and the processes of atherogenesis.2