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1/60. Possible induction of renal dysfunction in patients with lecithin:cholesterol acyltransferase deficiency by oxidized phosphatidylcholine in glomeruli.

    To clarify the causes of renal dysfunction in familial lecithin:cholesterol acyltransferase (LCAT) deficiency, kidney samples from 4 patients with LCAT deficiency (3 homozygotes and 1 heterozygote) were examined immunohistochemically. All of the patients exhibited corneal opacities, anemia, renal dysfunction, deficiencies in plasma high density lipoprotein and LCAT activity and mass, and an increase in the ratio of plasma unesterified cholesterol to esterified cholesterol. Renal lesions began with the deposition of lipidlike structures in the glomerular basement membrane, and these structures accumulated in the mesangium and capillary subendothelium. By electron microscopy, 2 types of distinctive structure were found in glomerular lesions: vacuole structures and cross-striated, membranelike structures. The plasma oxidized phosphatidylcholine (oxPC) -modified low density lipoprotein (LDL) levels in LCAT-deficient subjects were significantly (P<0.01) higher than those in controls (1.30 /-0.82 versus 0.42 /-0.32 ng/5 microg LDL, respectively), and a significant (P<0.01) difference was observed even after adjustment for confounding factors by an analysis of covariance. The patient with the highest plasma oxPC-modified LDL had the most membranelike structures in the glomeruli and showed the greatest renal deterioration from a young age. In glomerular lesions, although there was an abundance of apoB and apoE, oil red O-positive lipids, macrophages, apoA1, and malondialdehyde were scarce. OxPC was found extracellularly in glomerular lesions, and although its distribution differed from that of apolipoproteins, it was quite similar to that of phospholipids. In conclusion, these results indicate that oxPC in plasma and glomeruli is distinctive for patients with LCAT deficiency. Therefore, oxPC may be a factor in the deterioration of kidneys in patients with familial LCAT deficiency. ( info)

2/60. A first British case of fish-eye disease presenting at age 75 years: a double heterozygote for defined and new mutations affecting LCAT structure and expression.

    Fish-eye disease is a familial syndrome with corneal opacification, major high density lipoprotein (HDL) deficiency in plasma, significant cholesterol esterification in plasma on non-HDL lipoproteins, generally without premature coronary disease. This first British male case from unrelated British parents had infarcts when aged 49 and 73 years but was asymptomatic at age 81 years, with plasma cholesterol 4.3-7.1 mmol/litre, triglycerides 1.8-2.2 mmol/litre, HDL cholesterol < 0.1 mmol/litre, apolipoprotein a-i < 0.16 g/litre, lipoprotein(a) 0.61 g/litre. cholesterol esterification was impaired using HDL-3 and A-I proteoliposomes but not using VLDL/IDL/LDL. The findings are those of LCAT deficiency with the classic fish-eye disease defect. Most of the 22 reported cases were homozygous or heterozygous for a Thr-Ile mutation at codon 123 of the lecithin:cholesterol acyltransferase (LCAT) gene. This patient was a double heterozygote for this mutation and a second new incompletely defined mutation affecting LCAT expression as defined by reduced mass and activity in plasma. ( info)

3/60. Classical LCAT deficiency resulting from a novel homozygous dinucleotide deletion in exon 4 of the human lecithin: cholesterol acyltransferase gene causing a frameshift and stop codon at residue 144.

    Lecithin: cholesterolacyltransferase (LCAT) transacylates the fatty acid at the sn-2 position of lecithin to the 3beta-OH group of cholesterol forming lysolecithin and the majority of cholesteryl ester found in plasma. LCAT participates in the reverse cholesterol transport pathway in man where it esterifies tissue-derived cholesterol following efflux from peripheral cells into HDL. Only 38 unique mutations in the human LCAT gene have been reported worldwide. Our French female proband presented with corneal opacity and no detectable plasma LCAT activity using either endogenous or exogenous assays. Her total plasma cholesterol and HDL cholesterol were low (2.34 mmol/l and 0.184 mmol/l, respectively) with a very high cholesterol/cholesteryl ester molar ratio (10.9:1). plasma triglycerides were 0.470 mmol/l with low apo B (40.5 mg/dl), apo A-I (14.7 mg/dl), apo A-II (6.8 mg/dl) and apo E (2.1 mg/dl) levels. plasma lipoprotein analysis by ultracentrifugation showed very low HDL concentrations and a characteristic shift of the lipoprotein profile towards larger, less dense particles. No proteinuria, renal dysfunction or signs of atherosclerosis were noted at age 45. sequence analysis of her LCAT gene showed a novel homozygous TG-deletion at residues 138-139 that resulted in a frameshift causing the generation of a stop codon and premature termination of the LCAT protein at amino acid residue 144. Western blotting of the patient's plasma using a polyclonal IgY primary antibody against human LCAT failed to demonstrate the presence of a truncated LCAT protein. A 53 bp mismatched PCR primer was designed to generate an Fsp 1 restriction site in the wild type sequence of exon 4 where the mutation occurred. The 155 bp PCR product from the wild type allele produced a 103 bp and 52 bp fragment with Fsp 1 and no cleavage products with the mutant allele thus permitting rapid screening for this novel mutation. ( info)

4/60. Hypocomplementemic type II membranoproliferative glomerulonephritis in a male patient with familial lecithin-cholesterol acyltransferase deficiency due to two different allelic mutations.

    patients with familial lecithin-cholesterol acyltransferase (LCAT) deficiency very often show progressive glomerulosclerosis with evolution to end-stage disease. High levels of an abnormal lipoprotein (lipoprotein X) cause glomerular capillary endothelial damage. The ultrastructural study of renal biopsy specimens shows characteristic glomerular deposits of membrane-like, cross-striated structures and vacuole structures. The gene encoding for LCAT has been mapped to chromosome 16q22.1, and several mutations of this gene cause LCAT deficiency which is inherited as an autosomal recessive trait and which is characterized by corneal opacities, normochromic normocytic anemia, and renal dysfunction. Herein we report clinical features and renal histological findings concerning a 24-year-old male patient with classical familial LCAT deficiency due to two different allelic mutations: a nonsense mutation inherited from the father and a missense mutation inherited from the mother. Moreover, the patient showed glomerular histological lesions and an immunofluorescent glomerular pattern typical of hypocomplementemic membranoproliferative type II glomerulonephritis (dense-deposit disease). The nature of electron-dense material that characterizes dense-deposit disease is still unknown, but there are suggestions that some chemical modifications might occur in the renal basement membranes. Therefore, this clinical case might induce to consider possible relations between disorders of the lipoprotein metabolism and renal dense-deposit disease. ( info)

5/60. Marked atherosclerosis in a patient with familiar lecithin: cholesterol acyltransferase deficiency associated with end-stage renal disease and diabetes mellitus.

    Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare genetic disorder of the lipid metabolism caused by the absence of LCAT activity in plasma. It is not generally accompanied by atherosclerosis in spite of low high-density lipoprotein cholesterol levels nor by diabetes mellitus. However, reports of long-term follow-up or autopsy findings are rare, and the true incidence of atherosclerosis in LCAT deficiency is not clear. We report on the long-term observation of a patient with familial LCAT deficiency who developed renal failure, diabetes mellitus, and marked atherosclerosis. The patient died of sepsis from foot ulcers 7 years after starting hemodialysis and 13 years after the diagnosis. Marked atherosclerosis characterized by medial calcification in small arteries was observed at autopsy. The genesis of the atherosclerosis seemed to be on the basis of a combination of factors. ( info)

6/60. A normal rate of cellular cholesterol removal can be mediated by plasma from a patient with familial lecithin-cholesterol acyltransferase (LCAT) deficiency.

    Lecithin-cholesterol acyltransferase (LCAT) is the major enzyme involved in the esterification of cholesterol in circulating plasma lipoproteins. In the present study, we describe the molecular defects in the LCAT gene and in lipoprotein metabolism of a 34-year-old patient presenting with features of classic familial LCAT deficiency. dna sequencing revealed two separate point mutations in exon 3 of the patient's LCAT gene: a C to A substitution converting Tyr(83) to a Stop and a C to T transition converting an Arg(99) to a Cys. digestion of patient PCR-amplified dna with the restriction enzymes AccI and AciI established that the patient was a compound heterozygote for both mutations. in vitro expression of LCAT (Arg(99)-->Cys) in human embryonic kidney-293 cells demonstrated reduced expression, as well as reduced secretion and/or increased intracellular degradation of the mutant enzyme with significantly decreased alpha-LCAT specific activity, thus, establishing the functional significance of the LCAT (Arg(99)-->Cys) mutation. The plasma cholesterol esterification rate (CER, 2 /-0.3 nmol/ml/h), alpha-LCAT activity (2.9 /-0.1 nmol/ml/h) and LCAT concentration (0.3 /-0.1 microg/ml) were 2.9%, 2.3% and 6.1% that of normal subjects, respectively. Analysis of the patient's plasma lipid profile revealed reduced plasma concentrations of total cholesterol (111 /-0.5 mg/dl), HDL cholesterol (1.6 /-0.2 mg/dl), apolipoprotein (apo) A-I (52 /-4 mg/dl) and apo A-II (11 /-0.5 mg/dl). Nevertheless, for the first time, we demonstrate that the LCAT-deficient plasma is as efficient as control plasma in cholesterol efflux experiments performed with [(3)H]-cholesterol loaded fibroblasts. This result could explain the absence of premature atherosclerosis in this LCAT-deficient patient. ( info)

7/60. Alterations in erythrocyte membrane lipid and its fragility in a patient with familial lecithin:cholesterol acyltrasferase (LCAT) deficiency.

    Lecithin:cholesterol acyltrasferase (LCAT) plays a key role in the cholesterol metabolism-mediated esterification of free cholesterol into the cholesterol ester in normal plasma. Familial LCAT deficiency is frequently associated with anemia. Using biochemical and physiological techniques, the erythrocytes of this patient were investigated to gain an insight into the relationship between the abnormalities of lipid metabolism and erythrocyte membrane fragility. Abnormal erythrocytes, so-called Target cells and/or Knizocytes, were observed at 20% in our patient's erythrocytes. Moreover, the mean corpuscular volume of the patient's cells was 7% greater than that of a normal individual. In the membrane lipids of the patient's erythrocytes, cholesterol and phosphatidylcholine increased, and phosphatidylethanolamine decreased. The electron spin resonance technique with a fatty acid spin probe showed that the membrane fluidity was more elevated than that of normal cells in spite of the increase in cholesterol content and the cholesterol/phospholipid ratio of the membrane of patient's erythrocytes. The patient's abnormally shaped erythrocytes were less deformed than those of the normal individual under high shear stress. The partial depletion of membrane cholesterol from the patient's erythrocytes was demonstrated by incubation with normal plasma with LCAT activity. The increment of transformed erythrocytes during the incubation could be prevented by cholesterol depletion from the patient's erythrocyte membrane. These findings indicate that normochromic anemia of the patient might be caused by erythrocyte fragility resulting from decreased deformity and/or abnormal shape of the cells due to abnormal lipid composition in the membrane. ( info)

8/60. Histopathology of corneal changes in lecithin-cholesterol acyltransferase deficiency.

    PURPOSE: Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare entity. This dyslipoproteinemia may lead to corneal opacity, renal failure, and arteriosclerosis. methods: Presentation of a 66-year-old man with bilateral corneal opacification due to LCAT deficiency caused by a single-nucleotide exchange in codon 123 of gene. An extracapsular cataract extraction combined with full-thickness corneal transplantation was performed. The corneal specimen was analyzed by light and transmission electron microscopy. RESULTS: All stromal layers showed extracellular vacuoles with acid mucopolysaccharide contents measuring up to 2.5 microm. Amyloid deposits measuring up to 12 microm in diameter were detected in the stroma and especially predescemetally. CONCLUSION: To our knowledge, this is the first histologic description of secondary amyloidosis in a full-thickness corneal specimen with LCAT deficiency. The disease is associated with anemia, proteinuria, a lack of plasma high-density lipoprotein, and the presence of target cells. Bilateral corneal opacification is a characteristic of the disease and may allow early detection of homozygous LCAT deficiency by the ophthalmologist. ( info)

9/60. corneal opacity in LCAT disease.

    Deficiency of lecithin:cholesterol acyltransferase, LCAT disease, is one of the dyslipoproteinemias with characteristic lipid deposits in the cornea. The present report documents the clinicopathologic abnormalities of one case in which a full-thickness corneal specimen was obtained at the time of corneal transplantation. The characteristic clinical abnormality was a progressive corneal opacification with a peripheral arcus that extended into the sclera. The pathologic abnormality consisted of vacuoles prevalent in the anterior corneal stroma by light microscopy and containing extracellular, membranous deposits by electron microscopy. These observations confirm and supplement the previous six pathologic reports of corneal changes in LCAT disease and demonstrate, for the first time, histopathologic evidence of unesterified cholesterol in the corneal stroma of LCAT disease. ( info)

10/60. Cardiac surgery for a patient with familial lecithin: cholesterol acyltransferase deficiency.

    A 62-year-old female with familial lecithin: cholesterol acyltransferase (LCAT) deficiency was subjected to cardiac surgery consisting of mitral valve repair, tricuspid valve annuloplasty, and left atrium plication, under cardiopulmonary bypass. Familial LCAT deficiency is a very rare disease with clinical features including corneal opacity, hemolytic anemia, and renal failure. Our patient manifests partial LCAT activity and no renal failure. patients with LCAT deficiency have fragile red blood cells, renal dysfunction, and disturbed metabolism of platelet-activating factor. To date, no record of cardiac surgery on patients with LCAT deficiency has been reported. Thus, we present the result of this experience to share what we learned about this complicated and rare disease. ( info)
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