Cases reported "Tangier Disease"

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1/7. A novel nonsense mutation in the ABC1 gene causes a severe syringomyelia-like phenotype of tangier disease.

    tangier disease is a rare autosomal recessive disorder caused by mutations in the recently identified ATP-binding cassette transporter 1 gene (ABC1). A typical clinical manifestation of tangier disease is peripheral neuropathy. Former studies differentiated between two manifestations: the more frequent mono- or polyneuropathic form and a syringomyelia-like type. It is unknown whether specific mutations in the ABC1 gene or a particular genetic background are responsible for either of these forms. A family is presented comprising a case with a severe syringomyelia-like phenotype of tangier disease and absence of cardiovascular disease. Sequencing analysis of the ABC1 gene was performed. A new homozygous C-->T transition in exon 18 was found in the index patient. This mutation results in a stop codon at position 909 (R909X) leading to premature termination of translation. Her clinically asymptomatic daughters, her sister and one of her nieces were heterozygous. sural nerve biopsies were studied in the index patient at the age of 45 and 54 years; both revealed a severe neuropathy, characterized by a subtotal and finally complete loss of nerve fibres. The entire loss of schwann cells resulted in an extraordinary form of endoneurial sclerosis. Only rare capillaries, lipid-laden macrophages and fibroblasts had survived in the endoneurium. This case appears to be unique in respect to the underlying novel mutation in the ABC1 gene and its association with complete endoneurial sclerosis of all fascicles in the sural nerve and absence of cardiovascular disease.
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2/7. Aortic features in tangier disease and pathogenetic considerations--Part I. Fatty dots and streaks.

    Morphological studies of aortic fatty dots and streaks, and the adjacent normally appearing intima, in a 5 3/4-year-old boy who died of pneumonia, showed several hitherto unreported features. In lesions, lipid vacuoles and/or other cytoplasmic "inclusions" (ultrastructurally considered to present complex forms of lipids) were present on occasion in the endothelium but consistently involved the (intimal) smooth muscle cells (SMC). Similar changes were present in the adjacent intima, but were here less prominent and "tapered off" distally. A moderate number of macrophages also contained cytoplasmic lipids but such cells entirely free of lipid inclusions were observed, too. Most surprisingly, dilated and many cisternae of rough-surfaced endoplasmic reticulum (ER) in the SMC of lesions were associated spatially with cytoplasmic droplets and other forms of lipids. The results of these studies question the generally accepted central role of macrophages as being primarily involved in the pathogenesis of tissue changes in tangier disease. It is possible that in view of the absence or paucity of high-density lipoproteins (HDL) and alterations of (their) apo A-I and apo A-II (as well as of other lipids), the arterial SMC may be in some way involved in the metabolism of the above substances in this disorder. Support of this tentative (and highly speculative) assumption must await further work utilizing tissues and cells other than those containing macrophages and other derivatives of reticulo-endothelial system.
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3/7. tangier disease: a disorder of intracellular membrane traffic.

    The interaction of human high density lipoproteins (HDL) with isolated human monocytes from control and Tangier patients was studied in tissue culture experiments. It was observed that normal monocytes, similar to mouse peritoneal macrophages, bind HDL to a cell surface receptor, internalize the bound HDL particles, transport the internalized HDL intracellularly through the cytoplasmic compartment without significant degradation, and ultimately resecrete intact HDL. The cellular interaction of Tangier monocytes with normal HDL was markedly different from control monocytes. HDL binding to Tangier monocytes was moderately increased and cell-associated HDL radioactivity was 6- to 10-fold enhanced in Tangier monocytes. The bulk of the internalized HDL, however, was detected in secondary lysosomes. Only minor amounts of the internalized HDL were resecreted from the Tangier monocytes, and most of this was degraded. These data suggest that the cellular metabolism of HDL is abnormal in Tangier monocytes. It is postulated that tangier disease may be a disorder of intracellular membrane traffic in which HDL is diverted into the lysosomal compartment and degraded instead of being secreted through its regular transcellular route.
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4/7. Severe polyneuropathy in tangier disease mimicking syringomyelia or leprosy. Clinical, biochemical, electrophysiological, and morphological evaluation, including electron microscopy of nerve, muscle, and skin biopsies.

    Polyneuropathy in tangier disease can be divided into three clinical types. The most severe form (type III) with a syringomyelia-like syndrome has been described in three cases only. Here, a fourth case of this type is presented. Because of unusual trophic disturbances even leprosy was suspected. Electrodiagnostic findings, including evoked cerebral potentials in this case, were suggestive of a generalized neuropathy with some degree of primary or secondary demyelination and implied possible impairment of central structures. sural nerve biopsy, including electron microscopy and quantitative analysis, revealed a predominant reduction of smaller myelinated and unmyelinated fibres. The main morphological feature was the abundance of abnormal non-membrane-bound vacuoles in schwann cells, mostly of the unmyelinated type, and in some endoneurial fibroblasts, macrophages and perineurial cells. There was no inverse relationship between lipid vacuoles and axons in Schwann cell complexes as suspected by others. An excess of endoneurial collagen as well as an increased fascicular area were obvious. In five skin biopsy specimens of different regions typical vacuoles were noted in schwann cells, histiocytes, nevus cells, and rarely in perineurial cells.
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5/7. Interaction of Tangier lipoproteins with cholesteryl ester-laden mouse peritoneal macrophages.

    cholesterol efflux was studied from cholesteryl esterladen mouse peritoneal macrophages in the presence of Tangier lipoproteins derived from fasting and postprandial sera of three patients homozygous for tangier disease (analphalipoproteinemia). The d greater than 1.063 g/ml fractions isolated from fasting patients and 3 hr and 18 hr after an oral fat load were all effective in cellular cholesterol removal. By contrast, the d greater than 1.063 g/ml fractions isolated 6 hr and 12 hr after fat ingestion did not affect net removal of cellular cholesterol. The d greater than 1.21 g/ml protein fractions derived from fasting as well as postprandial sera were all effective in removing cholesterol. D 1.063-1.21 g/ml fractions from fasting Tangier patients contained HDLT. In the corresponding postprandial fractions, in addition to HDLT, apoB-100- and apoB-48-containing lipoproteins were present. Furthermore, the 6 hr and 12 hr postprandial Tangier HDL fractions contained apoB-immunoreactive proteins of lower molecular weight. The abnormal activity of the elastase/alpha 1-antitrypsin proteolytic system and the abnormal fibronectin concentration we found in Tangier plasma suggests a possible relationship to the in vivo degradation of apoB. The peculiar type of membrane-bound lipid droplets in Tangier splenic macrophages points to a lipoprotein source of lipid accumulation which possibly originates from the uptake of chylomicrons or chylomicron-derived particles. It is concluded that cholesteryl ester storage in Tangier macrophages results from an imbalance of cholesterol influx and efflux. In the absence of HDL, the net increase of cholesterol caused by abnormal lipoproteins in certain postprandial states cannot be fully compensated by effective efflux and ultimately leads to macrophage cholesteryl ester accumulation.
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6/7. Massive omental reticuloendothelial cell lipid uptake in tangier disease after splenectomy.

    tangier disease is a rare, autosomal recessive condition characterized by cholesterol ester deposition in reticuloendothelial cells, abnormal chylomicron remnants, decreased low-density lipoprotein levels, and a marked deficiency of high-density lipoproteins. apolipoprotein a-i, a major protein constituent of chylomicrons and high-density lipoproteins, has been shown to be structurally and metabolically abnormal in this disease (apolipoprotein A-ITangier). A 63-year-old Tangier homozygous man is described, who underwent splenectomy because of thrombocytopenia and splenomegaly. Subsequently, a large orange mass developed at the base of the mesentery, with several smaller omental masses and thickening of the entire omentum due to infiltration with lipid-laden macrophages. splenectomy appears to predispose to such deposition, since such masses have not been observed in other Tangier homozygotes. The spleen appears to play a significant role in the removal of abnormal lipoproteins in Tangier homozygotes; therefore, splenectomy may be contraindicated in tangier disease.
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7/7. Acute presentation of Tangier polyneuropathy: a clinical and morphological study.

    We describe a patient with tangier disease and a peripheral neuropathy with an unusual acute onset. The morphological studies of sural nerve biopsy revealed both axonal degeneration and demyelination, and the fiber loss was preferentially restricted to two of ten nerve fascicles. The cytoplasm of schwann cells, fibroblasts, macrophages and pericytes were vacuolated because of the presence of numerous lipid droplets. The clinical and morphological findings are consistent with the possibility that ischemia plays a major role in causing this neuropathy.
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