Diseases 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. 

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... 

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,... 

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). 

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... 

In familial HDL deficiency, HDL levels are very low they are almost undetectable in Tangier disease. Both genetic disorders are the result of mutations in the ABC1 protein. Cholesterol-depleted HDL cannot take up cholesterol from cells that lack ABC1 protein, and... 

A brief review of three papers in this journal issue that establish mutations in ABC1 as the cause of Tangier disease and familial HDL deficiency. 

Tangier disease is a rare autosomal recessive disorder characterized by the near absence of plasma HDL and the storage of esterified cholesterol in foam cells in many tissues. Clinical features include enlarged orange-colored tonsils, splenomegaly and a relapsing sensory-motor neuropathy. The clincial aspects of Tangier disease have been reviewed elsewhere (H24, S10). 

Schaefer et al. performed kinetic studies with radioiodinated apoA-I and apoA-II in two patients with homozygous Tangier disease (S5). ApoA-I was removed from the circulation faster than apoA-II, but both were catabolized much faster than in normal subjects. After the plasma HDL concentration was increased by HDL infusion in one of the Tangier patients, a repeat kinetic study showed that increasing HDL concentration may have influenced the initial removal of HDL tracer from the circulation, but not the final slope of the plasma radioactivity removal curve (S5). 

The consensus of these studies is that the underlying defect in Tangier disease is faulty conversion of pro-apoA-I to mature apoA-I, either because of a defect in converting enzyme activity or a specific structural defect in Tangier apoA-I, although this hypothesis still awaits direct confirmation. 

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