Cases reported "Tangier Disease"

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1/47. A point mutation in ABC1 gene in a patient with severe premature coronary heart disease and mild clinical phenotype of tangier disease.

    The proband is a 50 year-old woman born from a consanguineous marriage. She has been suffering from angina pectoris since the age of 38 and underwent coronary bypass surgery for three-vessel disease at 48. The presence of low plasma levels of total cholesterol and high density lipoprotein (HDL) cholesterol (2.4 and 0.1 mmol/l) and apo AI (<15 mg/dl), associated with corneal lesions and a mild splenomegaly suggested the diagnosis of tangier disease. However, none of the other features of tangier disease, including hepatomegaly, anemia and peripheral neuropathy, were present. The analysis of the dinucleotide microsatellites located in chromosome 9q31 region demonstrated that the proband was homozygous for the alleles of D9S53, D9S1784 and D9S1832. The mother and son of the proband, both with low levels of HDL cholesterol, shared one of the proband's haplotypes, whereas neither of these haplotypes was present in the normolipidemic proband's sister. The sequence of ATP-binding cassette transporter 1 (ABC1-1) cDNA obtained by reverse transcription-PCR (RT-PCR) of total rna isolated from cultured fibroblasts showed that the proband was homozygous for a C>T transition in exon 13, which caused a tryptophane for arginine substitution (R527W). This mutation was confirmed by direct sequencing of exon 13 amplified from genomic dna. It can be easily screened, as the nucleotide change introduces a restriction site for the enzyme Afl III. R527W substitution occurs in a highly conserved region of the NH2 cytoplasmic domain of ABC1 protein. R527W co-segregates with the low HDL phenotype in the family and was not found in 200 chromosomes from normolipidemic individuals.
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ranking = 1
keywords = lipoprotein
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2/47. Subpopulations of high density lipoproteins in homozygous and heterozygous tangier disease.

    tangier disease (TD) is characterized by severe high-density lipoproteins (HDL) deficiency, hypercatabolism of HDL constituents, impaired cellular cholesterol efflux, and mutations in the gene of ATP-binding cassette 1 (ABC-1). In the present study, we determined plasma lipid and apolipoprotein levels, and HDL subpopulations, in 110 subjects from a large TD kindred in which the proband was homozygous for an A-->C missense mutation at nucleotide 5338 of the ABC-1 transcript. In the proband HDL-C, apoA-I, and apoA-II concentrations were 2, 1, and 2 mg/dl, respectively, apoA-I was present only in prebeta(1), while apoA-II was found free of apoA-I in two distinct alpha mobility subpopulations with different sizes. The smaller size particles contained only apoA-II while the larger one contained apoA-II and apo(a). Relative to unaffected male relatives (n=30), male heterozygotes (n=21) had significant reductions (P<0.001) in plasma HDL-C (-45%), apoA-I (-34%), apoA-II (-59%), apoA-IV (-40%), Lp(a) (-62%), and apoB (-55%) concentrations, and a significant increase (P<0.05, 33%) in plasma apoC-III levels. female heterozygotes (n=11) similarly had significant reductions (P<0.001) in the concentrations of plasma HDL-C (-42%), apoA-I (-27%), apoA-II (-52%), Lp(a) (-27%), and (P<0.01) apoA-IV (-28%), apoB (-13%), and a significant increase (P<0.05) in plasma apoE levels ( 29%) as compared to unaffected female relatives (n=41). Large size HDL subpopulations, especially the two LpA-I particles: alpha(1) and prealpha(1) were dramatically reduced in both male and female heterozygotes relative to their unaffected family members. Since apoA-II decreased more than apoA-I in both male and female heterozygotes, the ratios of apoA-I/apoA-II were significantly (P<0.01) increased. The prevalence of CHD was 60% higher in the 32 heterozygotes than in the 71 unaffected relatives even though the latter group was on average 7 years older. We conclude that TD homozygotes have only prebeta(1) apoA-I-containing HDL subpopulations, while heterozygotes have HDL that is selectively depleted in the large alpha(1), prealpha(1), and alpha(2), prealpha(2) subpopulations, resulting in HDL particles that are small in size, poor in cholesterol, but relatively enriched in apoA-I compared to those of their unaffected relatives. These abnormalities appear to result in a higher risk of CHD in heterozygotes than in unaffected controls.
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ranking = 6.0045496093585
keywords = lipoprotein, deficiency
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3/47. Novel mutations in ABCA1 gene in Japanese patients with tangier disease and familial high density lipoprotein deficiency with coronary heart disease.

    Mutations in the ATP-binding cassette transporter 1 (ABCA1) gene have been recently identified as the molecular defect in tangier disease (TD) and familial high density lipoprotein deficiency (FHA). We here report novel mutations in the ABCA1 gene in two sisters from a Japanese family with TD who have been described previously (S. Ohtaki, H. Nakagawa, N. Kida, H. Nakamura, K. Tsuda, S. Yokoyama, T. Yamamura, S. Tajima, A. Yamamoto, atherosclerosis 49 (1983)) and a family with FHA. Both probands of TD and FHA developed coronary heart disease. sequence analysis of the ABCA1 gene from the patients with TD revealed a homozygous G to A transition at nucleotide 3805 of the cDNA resulting in the substitution of Asp 1229 with Asn in exon 27, and a C to T at nucleotide 6181 resulting in the substitution of Arg 2021 with Trp in exon 47. sequence analysis of the ABCA1 gene from the FHA patient revealed a homozygous 4 bp CGCC deletion from nucleotide 3787 to 3790 resulting in premature termination by frameshift at codon 1224. These mutations were confirmed by restriction digestion analysis, and were not found in 141 control subjects. Our findings indicate that mutations in the ABCA1 gene are associated with TD as well as FHA.
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ranking = 1577.1173295348
keywords = lipoprotein deficiency, lipoprotein, deficiency
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4/47. Phenotypic expression of familial hypobetalipoproteinemia in three kindreds with mutations of apolipoprotein B gene.

    We report the clinical phenotype in three kindreds with familial heterozygous hypobetalipoproteinemia (FHBL) carrying novel truncated apolipoprotein Bs (apoBs) of different sizes (apoB-8.15, apoB-33.4 and apoB-75.7). In D.A. kindred, we found three carriers of a C-deletion in exon 10 leading to the synthesis of apoB-8.15 not detectable in plasma. They showed steatorrhea and fatty liver. In N.L. kindred, the proband is heterozygous for a nonsense mutation in exon 26, leading to the formation of apoB-33.4. He had premature cerebrovascular disease and fatty liver; two apoB-33.4 carriers in this kindred showed only fatty liver. In B.E. kindred, the proband is heterozygous for a T-deletion in exon 26, which converts tyrosine at codon 3435 into a stop codon, resulting in apoB-75.7. The proband, a heavy alcohol drinker, had steatohepatitis, whereas his teetotaller daughter, an apoB-75.7 carrier, had no detectable fatty liver. This study suggests that: i) fatty liver invariably develops in FHBL carriers of short and medium-size truncated apoBs (< apoB-48), but its occurrence needs additional environmental factors in carriers of longer apoB forms; ii) intestinal lipid malabsorption develops only in carriers of short truncated apoBs, which are not secreted into the plasma; and iii) cerebrovascular disease due to premature atherosclerosis may occur even in FHBL subjects.
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ranking = 10
keywords = lipoprotein
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5/47. Clinical variant of tangier disease in japan: mutation of the ABCA1 gene in hypoalphalipoproteinemia with corneal lipidosis.

    Despite progress in molecular characterization, specific diagnoses of disorders belonging to a group of inherited hypoalphalipoproteinemias, i.e., apolipoprotein AI deficiency, lecithin-cholesterol acyltransferase deficiency, tangier disease (TD), and familial high-density lipoprotein (HDL) deficiency, remain difficult on a purely clinical basis. Several TD patients were recently found to be homozygous for mutations in the ABCA1 gene. We have documented here a clinical variant of TD in a Japanese patient who manifested corneal lipidosis and premature coronary artery disease as well as an almost complete absence of HDL-cholesterol, by identifying a novel homozygous ABCA1 mutation (R1680W). We propose that patients with apparently isolated HDL deficiency who are found to carry ABCA1 mutations may in fact belong to a category of TD patients whose phenotypic features are only partially expressed, and that a number of hidden clinical variants of TD might exist among other HDL deficiency patients who have escaped correct clinical diagnosis.
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ranking = 1613.7319380533
keywords = hypoalphalipoproteinemia, lipoprotein, deficiency
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6/47. Double deletions and missense mutations in the first nucleotide-binding fold of the ATP-binding cassette transporter A1 ( ABCA1) gene in Japanese patients with tangier disease.

    tangier disease (TD) is a rare autosomal recessive disease characterized by plasma high-density lipoprotein deficiency caused by an ATP-binding cassette transporter A1 ( ABCA1) gene mutation. We describe three different mutations in Japanese patients with TD. The first patient was homozygous for double deletions of 1221 bp between intron 12 and 14 and 19.9 kb between intron 16 and 31. The breakpoint sequence analyses suggest that it is a simultaneous event caused by double-loop formation through multiple Alu. The second patient was homozygous for a novel mutation of A3198C in exon 19, resulting in Asn935His. The third patient was homozygous for A3199G of exon 19 that leads to Asn935Ser, which is the same mutation found in German and Spanish families. Both Asn mutations involved Walker A motif of the first nucleotide-binding fold.
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ranking = 315.42346590695
keywords = lipoprotein deficiency, lipoprotein, deficiency
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7/47. ABCA1(alabama): a novel variant associated with HDL deficiency and premature coronary artery disease.

    The ATP-binding cassette transporter, ABCA1, is a member of the ABC superfamily of proteins involved in the active transport of substrates across cellular membranes. Recent studies have implicated mutations in ABCA1 as the cause of tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). To evaluate the molecular basis of low high density lipoprotein (HDL) in a family with premature coronary artery disease, single strand conformational polymorphism analysis was performed for all coding regions and splice site junctions of ABCA1 with the genomic dna of the proband. The proband and affected individuals were heterozygotes for C254T with proline converted to leucine (P85L). This mutation was not identified in over 400 chromosomes of healthy subjects. In the FHA kindred, family members heterozygous for the ABCA1 variant also exhibited corresponding low levels of HDL cholesterol. These data confirm recent data that a single defective allele in ABCA1 may be associated with reduced HDL cholesterol and FHA.
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ranking = 323.36003643874
keywords = hypoalphalipoproteinemia, lipoprotein, deficiency
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8/47. coronary artery bypass grafting for a patient with tangier disease.

    A 56-year-old man with tangier disease suffering from angina pectoris due to triple-vessel coronary artery disease evidenced extremely low blood high-density lipoprotein of 1 mg/dl, a specific laboratory indicator of this rare genetic disorder of lipid metabolism, considered to accompany juvenile arteriosclerosis. Because of the calcified ascending aorta, we conducted combined minimally invasive coronary artery bypass (CAB) for the left anterior descending coronary artery and percutaneous transluminal coronary angioplasty for other coronary artery lesions initially instead of conventional coronary artery bypass grafting. Angina recurred, however, due to refractory restenosis of the left circumflex coronary artery lesion. Two years later, we redid the CAB, grafting the free right internal thoracic artery from the functional left internal thoracic artery sequentially onto obtuse marginal and posterolateral coronary arteries. The patient returned to work angina-free.
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ranking = 1
keywords = lipoprotein
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9/47. Corneal opacifications in a low high density lipoprotein syndrome: suspicion of fish eye disease: a case report.

    A 49 year old patient with progressive massive bilateral corneal opacifications associated with a HDL (high-density-lipoprotein) deficiency is described. The opacifications started at the age of twenty and progressed slowly. They were found diffusely over the cornea, though more in the corneal periphery. A penetrating keratoplasty at the right eye was performed. The diagnosis of Fish eye Disease was put forward on the basis of the ophthalmological, clinical, biochemical and pathological appearance. After 2 year follow-up, the graft was clear. The final distance and near vision of the right eye was 8/10 and Snellen 1 respectively.
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ranking = 5.0045496093585
keywords = lipoprotein, deficiency
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10/47. 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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ranking = 1
keywords = lipoprotein
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