Tangier

Genetic disorders of HDL metabolism have also resulted in greater understanding of the molecular regulation of HDL metabolism. Nonsense or missense mutations in apoA-I can result in substantially reduced HDL-C levels due to rapid catabolism of structurally abnormal or truncated apoA-I proteins. Tangier disease is a rare autosomal codominant disorder characterized by markedly low HDL-C and apoA-I levels and caused... 

Famiiiai aipha-iipoprotein deficiency Tangier disease Fish-eye disease Apo-A-i deficiencies All have low or near absence of HDL. Tendency toward hypertriacylglycerolemia as a result of absence of apo C-ll, causing inactive LPL. Low LDL levels. Atherosclerosis in the elderly. 

Horne, R.J. Pelly. 2007. Geological transect of the Meguma Terrane from centre Musquodoboit to Tangier. Nova Scotia Department Natural Resources, Report of Activities 2001, 71-89. 

HDLt is the only detectable high density lipoprotein in Tangier homozygotes HDL and HDLt are detectable in Tangier heterozygotes (L6)... 

F7. Fredrickson, D. S., Gotto, A. M., and Levy, R. I., Familial lipoprotein deficiency. In The Metabolic Basis of Inherited Disease (Abetalipoproteinemia, Hypo-betalipoproteinemia, and Tangier s Disease). (J. B. Stanbur, ed.), 3rd Ed., pp. 493-530. McGraw-Hill, New York, 1972. 

K4. Kocen, R. S., Lloyd, J. K., Lascelles, P. T., Fosbrooke, A. S., and Williams, D., Familial alpha-lipoprotein deficiency (Tangier disease) with neurological abnormalities. Lancet 1, 1341 (1967). 

Rare genetic disorders, including Tangier disease and LCAT (lecithin cholesterol acyltransferase) deficiency, are associated with extremely low levels of HDL. Familial hypoalphalipoproteinemia is a more common disorder with levels of HDL cholesterol usually below 35 mg/dL in men and 45 mg/dL in women. These patients tend to have premature atherosclerosis, and the low HDL may be the only identified risk factor. Management should include special attention to avoidance or treatment of other risk factors. Niacin increases HDL in many of these patients. Reductase inhibitors and fibric acid derivatives exert lesser effects. 

The findings of virtual HDL deficiency and low levels of apoA-I are not sufficient for the diagnosis of Tangier disease, which ultimately requires ABCA1 gene sequence... 

The more widely accepted test is the cholesterol efflux assay on cultivated skin fibroblasts. After equilibration with radiolabeled cholesterol, fibroblasts are incubated with albumin in the presence or absence of lipid-free apoA-I. ApoA-I substantially increases cholesterol efflux from normal cells but not from Tangier cells [11, 30]. 

Nondenaturing two-dimensional electrophoresis and subsequent anti-apoA-I im-munoblotting of normal plasma helps to discriminate a bulk of HDL, which has electrophoretic alpha mobility (a-HDL), from a quantitatively minor proportion, which has electrophoretic pre-jS-mobility (pre/fi-HDL). In plasma from Tangier patients the latter particle is the only apoA-I containing lipoprotein [4, 26]. 

In the presence of lipid-free apoA-I, ABCA1 mediates cholesterol efflux from many cells including skin fibroblasts. This opens the possibility to test the activity of ABCA1 in cultivated skin fibroblasts of patients who are suspected to suffer from Tangier disease. 

Parallel analysis of control skin fibroblasts from normolipidemic donors and, ideally from patients with established diagnosis of Tangier disease, is needed. In addition,... 

ApoA-I-mediated cholesterol efflux from fibroblasts of homozygous Tangier patients is reduced by more than 90% compared to normal control fibroblasts. Heterozygous carriers show significantly reduced cholesterol efflux from fibroblasts compared to unaffected family members. 

Interpretation of the HDL subclass pattern is achieved according to von Eckard-stein and colleagues [25, 26]. In normolipidemic plasma, the majority of apoA-I HDL is found in particles with electrophoretic -mobility (a-LpA-I) and a minor part (about 5%) in a particle with pre-/Tmobility (pre/fi-LpA-I). In Tangier disease, plasma a-LpA-I is absent and residual amounts of apoA-I reside in pre/fi-LpA-I (Fig. 5.2.10). 

Fig. 5.2.10 Nondenaturing two-dimensional electrophoresis with agarose gel electrophoresis in the first dimension and gradient polyacrylamide gel electrophoresis in the second dimension combined with anti-apolipoprotein AI (apoA-I) immunoblotting differentiates apoA-I-contain-ing lipoproteins by charge (pre-/ l-LpA-I versus a-LpA-I) and size (HDL2 versus HDL3). In normal plasma the major part of the HDL pool is formed by a-LpA-I, a smaller by pre-/ l-LpA-I (left picture). In the plasma from Tangier patients only some pre-/ l-LpA-I particles are present (right picture)...

Residual amounts of apoA-I are exclusively present in pre-/VLpA-I, which in nor-molipidemic plasma accounts for less than 5% of total apoA-I. The -migrating a-LpA-I, which in normolipidemic plasma represents the bulk of HDL, is absent from Tangier disease plasma. 

Assmann G, von Eckardstein A, Brewer HJ (2000) Familial analphalipoproteinemia tangier Disease. In Scriver C, Beaudet A, Sly E, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York, McGraw-Hill, pp 2937-2960... 

Asztalos BE, Brousseau ME, McNamara JR, Horvath KV, Roheim PS, Schaefer EJ (2001) Subpopulations of high density lipoproteins in homozygous and heterozygous Tangier disease. Atherosclerosis 156 217-225... 

Francis GA, Knopp RH, Oram JF (1995) Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier disease. J Clin Invest 96 78-87... 

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