1/95. LDL-apheresis in treatment of two patients with heterozygous familial hypercholesterolemia and extremely elevated lipoprotein (a) levels.In hyperlipidemia and, in particular, elevated lipoprotein (a) [Lp(a)] levels there appears to be pronounced linkage between the development and progression of atherosclerosis. Our study concerned two Caucasian male patients with heterozygous forms of familial hypercholesterolemia and extremely high Lp(a) concentrations. Maximal diet regimens and the use of lipid lowering drugs achieved a serum total-, LDL-cholesterol and triglyceride reduction of up to 30%, but no reduction of the Lp(a) level was discernible. Both patients suffered three myocardial infarctions and several coronary angiographies with percutaneous transluminal angioplasties (PTCA) were necessary. In 1989, we commenced treatment with LDL-apheresis. At present, after 78 LDL-aphereses in the case of the 41-year-old patient (48 months, dextran sulfate adsorption, KANEKA, japan) and 38 aphereses in the case of the 35-year old patient (8 months, immunoadsorption, special Lp[a] columns, LIPOPAK, POCARD, russia), the Lp(a) has dropped an average of 53%, total cholesterol 31%, LDL-cholesterol 40% and triglycerides 42%. During this period neither mycardial infarctions nor cardiac complaints were observed. In the course of treatment, both patients experienced an improvement in general well-being and increased performance. These results are very encouraging: LDL-apheresis may be effective in the treatment of patients, the only risk factor for premature atherosclerosis being an extremely high Lp(a) concentration.- - - - - - - - - - ranking = 1keywords = gene (Clic here for more details about this article) |
2/95. Surgical excision of the tendon xanthoma in familial hypercholesterolemia--a case report.Familial hypercholesterolemia is an autosomal dominant disorder characterized by increased low-density lipoprotein cholesterol, premature atherosclerosis and tendon xanthomas. Genetic studies reveal familial hypercholesterolemia to be a dysfunction of LDL receptor gene on cell surface. Recently various mutations in the LDL receptor gene have been reported. When dna method is not available, the occurrence of tendon xanthomas, an isolated elevation of plasma cholesterol, with a normal concentration of plasma triglycerides virtually establishes the diagnosis of familial hypercholesterolemia. In this report, a 42-year-old male had tendon xanthoma at extensor surface of metacarpophalangeal joint of his right hand, olecranon of the left elbow and both knees, and Achilles tendons. The tendon xanthoma was excised for cosmetic reasons, and the wound healing was slower than average in this case. We suggest that before suture removal, wound healing must be complete. It is important that the hand surgeon recognize that tendon xanthoma is a physical sign of a potentially life-threatening disorder to the patient as well as his family, and that this disorder may respond favorably to early examination and management.- - - - - - - - - - ranking = 2keywords = gene (Clic here for more details about this article) |
3/95. Mutation -59c-->t in repeat 2 of the LDL receptor promoter: reduction in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia.The low-density lipoprotein receptor (LDLR) plays a major role in cholesterol homeostasis. Mutations in the regulatory region of the LDLR gene, although rare, have been shown to alter transcriptional activity of the gene and can cause familial hypercholesterolaemia (FH). In this study, a transition (c-->t) was identified at nucleotide position -59 within repeat 2 of the LDLR promoter in a South African FH patient of mixed ancestry. By screening 17 family members of the index case for this promoter mutation, two additional single base changes (-124c-->t and-175g-->t) were identified, located at recently described cis- acting regulatory sequences of the LDLR promoter. Both the-59c-->t and the-124c-->t transitions were identified in the normocholesterolaemic son of the index patient. Reporter plasmids containing the normal and mutant promoter fragments were constructed by directional cloning. Transcription studies using a luciferase reporter system demonstrated that the-59c-->t mutation significantly reduces promoter activity in both the presence and absence of sterols ( approximately 40% of normal activity), while the-124c-->t variant increases transcription ( approximately 160%) of the LDLR gene. The intra-familial phenotypic variability observed amongst individuals with the-59c-->t mutation can probably be ascribed to allelic interaction, suggesting that variation in the LDLR promoter region may contribute significantly to the phenotypic expression of FH-related mutations in populations where these mutations prevail.- - - - - - - - - - ranking = 3keywords = gene (Clic here for more details about this article) |
4/95. Familial hypercholesterolemia. Acceptor splice site (G-->C) mutation in intron 7 of the LDL-R gene: alternate rna editing causes exon 8 skipping or a premature stop codon in exon 8. LDL-R(honduras-1) [LDL-R1061(-1) G-->C].Familial hypercholesterolemia (FH) is an autosomal dominant lipoprotein disorder caused by defects in the low density lipoprotein (LDL) receptor (R) gene. We report a novel mutation of the LDL-R gene in a 38-year-old man with homozygous FH from the province of Trujilo in Northern honduras. The patient presented with tendinous xanthomas over the extensor tendons as well as xanthelasmas at sites of surgical scars. He was diagnosed with severe coronary artery disease requiring revascularization at age 29. After an unsuccessful course of treatment with simvastatin, the patient has been treated with plasma apheresis and macromolecular plasma filtration bi-monthly. Haplotyping of the LDL-R gene revealed homozygosity for the rare 'J' allele and a loss of the EcoRV restriction cleavage site in exon 8. Single stranded conformational polymorphism of exons 3, 6, 7, 9, 10 and 8 reveals an abnormal migration pattern in exon 8. Direct sequencing of the promoter region, exons 1, 4, 8 and 13 revealed two RFLP's and a novel mutation in intron 7. This mutation consists of G-->C transposition at the acceptor splice site of exon 8 at the last nucleotide of intron 7 [LDL-R1061(-1)G-->C]. Reverse transcriptase (RT) PCR amplification of RNA from monocytes obtained from the patient reveals a decrease in LDL-R mRNA (52% of control) and skipping of exon 8 (approximately 38%, as assessed by densitometric scanning of the amplified fragments) to form a new RNA transcript that includes exons 7 and 9 without frameshift. Alternative rna editing leads to a new cryptic acceptor splice site 17 bp downstream in exon 8 producing a frameshift mutation and a predicted premature stop codon 1138 bp from the transcriptional start site (approxiamtely 62%). Western blotting analysis using a monoclonal antibody (C7) directed at the amino terminus of the LDL-R protein reveals a marked reduction in LDL-R protein expressed in monocytes obtained from the patient. We conclude that LDL-R1061(-1)G-->C is a novel mutation of the LDL-R gene that results in marked decrease in LDL-R mRNA levels and protein expression by two alternate rna editing mechanisms, that cause skipping of exon 8 or the use of a novel cryptic acceptor splice site in exon 8 with a frameshift and premature stop codon. The patient continues to do well on selective plasma filtration but developed bilateral severe carotid artery disease requiring surgical intervention.- - - - - - - - - - ranking = 8keywords = gene (Clic here for more details about this article) |
5/95. Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia.Familial hypercholesterolemia (FH) is characterized by a raised concentration of LDL in plasma that results in a significantly increased risk of premature atherosclerosis. In FH, impaired removal of LDL from the circulation results from inherited mutations in the LDL receptor gene or, more rarely, in the gene for apo B, the ligand for the LDL receptor. We have identified two unrelated clinically homozygous FH patients whose cells exhibit no measurable degradation of LDL in culture. Extensive analysis of dna and mRNA revealed no defect in the LDL receptor, and alleles of the LDL receptor or apo B genes do not cosegregate with hypercholesterolemia in these families. FACS((R)) analysis of binding and uptake of fluorescent LDL or anti-LDL receptor antibodies showed that LDL receptors are on the cell surface and bind LDL normally, but fail to be internalized, suggesting that some component of endocytosis through clathrin-coated pits is defective. Internalization of the transferrin receptor occurs normally, suggesting that the defective gene product may interact specifically with the LDL receptor internalization signal. Identification of the defective gene will aid genetic diagnosis of other hypercholesterolemic patients and elucidate the mechanism by which LDL receptors are internalized.- - - - - - - - - - ranking = 6keywords = gene (Clic here for more details about this article) |
6/95. liver transplantation in patients with homozygotic familial hypercholesterolemia previously treated by end-to-side portocaval shunt and ileal bypass.Familial hypercholesterolemia is the result of mutations in the gene that encodes the synthesis of the cellular receptor for low density lipoprotein (LDL). In the homozygous form of the disease (HFHC), cellular LDL receptors either do not form, or, when present, cannot bond LDL and mediate its cellular uptake LDL, and the cholesterol that it transports accumulate in plasma, producing severe premature atherosclerosis and death from coronary artery disease usually before the age of 20. Currently, the only effective treatment is liver transplantation, which, alone or in association with medications, normalizes plasma cholesterol levels. The authors report the cases of 2 siblings with HFHC who underwent portocaval shunt at the ages of 2.5 and 1.5 years, respectively. Portocaval shunt produced an immediate, but insufficient decrease in cholesterol (by 40% and 35%, respectively), leaving them with cholesterol concentrations of about 500 mg/dL. One year later they each underwent ileal bypass without obtaining any significant response. liver transplantation at the ages of 18 and 16 years, respectively, reduced plasma cholesterol concentrations to 129 and 225 mg/dL, respectively. The earlier operations seriously increased the technical difficulty of liver transplantation and did not produce a favorable effect on the natural course of the disease, so portocaval shunt and ileal bypass are not indicated in HFHC, not even for the purpose of delaying liver transplantation.- - - - - - - - - - ranking = 1keywords = gene (Clic here for more details about this article) |
7/95. FH-Freiburg: a novel missense mutation (C317Y) in growth factor repeat A of the low density lipoprotein receptor gene in a German patient with homozygous familial hypercholesterolemia.We describe the characterization of a novel mutation in the low density lipoprotein receptor (LDL-R) gene in a patient with true homozygous familial hypercholesterolemia (FH). The combined use of denaturing gradient gel electrophoresis (DGGE) and sequencing of genomic dna revealed a guanine to adenine base substitution at nucleotide position 1013 of the LDL-R cDNA. This point mutation results in a change from cysteine to tyrosine at amino acid residue 317 of repeat A of the epidermal growth factor (EGF) precursor homology domain. Binding, uptake and degradation of iodinated LDL in skin fibroblasts from the homozygous patient were less than 10% of normal. In contrast, binding, uptake and degradation of iodinated VLDL was reduced by only 60, 30, and 38%, respectively. Incubation of the patient's fibroblasts in the presence of cholesterol diminished the residual binding of VLDL by 50%, suggesting that the loss of the highly conserved cysteine at position 317 results in a LDL-R that fails to bind LDL, but retains some ability to bind VLDL by interacting with the apolipoprotein E. Both parents were heterozygous for the C317Y mutation. Interestingly, however, the father presented with markedly elevated levels of triglycerides and VLDL cholesterol, whereas his LDL cholesterol was unexpectedly low. The mother of the index patient had only slightly elevated LDL cholesterol. These observations testify to the biological complexity of genotype-environment interactions in individuals carrying mutations at the LDL-R locus and indicate that genetic analysis importantly complements the clinical and biochemical diagnosis of patients with hyperlipidemia.- - - - - - - - - - ranking = 6keywords = gene (Clic here for more details about this article) |
8/95. Long-term (14 years) effect of LDL apheresis on obstructive changes in aortocoronary saphenous-vein bypass grafts in a case of heterozygous familial hypercholesterolemia with the LDL receptor proline664 to leucine mutation.A 61-year-old Japanese woman with heterozygous familial hypercholesterolemia (FH), type 2 diabetes mellitus and coronary artery disease underwent coronary artery bypass grafting (CABG) utilizing a saphenous vein graft at the age of 46, in June 1984, 6 months before low density lipoprotein (LDL) apheresis was started. She had received LDL apheresis every two weeks, along with combined drug treatment since the age of 47 (December 1984). She had bilateral xanthelasma and achilles tendon xanthomas. Her fasting baseline serum total cholesterol and triglyceride level were 464 mg/dl and 57 mg/dl, respectively at the age of 47 when she visited our hospital for the first time. Analysis of the genomic dna from the patient revealed heterozygous amino acid substitution of Leu for Pro664 in the LDL receptor gene. She was diagnosed as type 2 diabetes mellitus at the age of 53. Combined treatment in the steady state yielded a pretreatment LDL cholesterol level of 230 /-14 mg/dl and a posttreatment level of 57 /-7.6. All grafts were widely patent after as long as 14 years since CABG, suggesting that LDL apheresis combined with drug therapy is highly effective in preventing the occlusion of bypass grafts in a patient with heterozygous FH and type 2 diabetes mellitus.- - - - - - - - - - ranking = 1keywords = gene (Clic here for more details about this article) |
9/95. R3531C mutation in the apolipoprotein B gene is not sufficient to cause hypercholesterolemia.Familial hypercholesterolemia and familial ligand-defective apolipoprotein b-100 (FDB) are dominantly inherited disorders leading to impaired low-density lipoprotein receptor (LDLR) and apolipoprotein b-100 (APOB) interaction, plasma LDL elevation, and hypercholesterolemia. We previously identified the first French FDB-R3531C proband, a woman with very high total cholesterol, in a group of type IIa hypercholesterolemic families. We report here the investigation of her family at large that revealed the total absence of cosegregation with hypercholesterolemia. Six of the 10 subjects heterozygous for the R3531C mutation had plasma cholesterol lower than the 97.5th percentile for their age and gender, and mean cholesterol levels were not significantly different between affected and unaffected persons. Furthermore, 2 family members with similar high LDL-cholesterol levels were not carriers of the R3531C substitution, suggesting the implication of another mutation. Segregation analysis of the LDLR gene revealed statistically significant genetic linkage with hypercholesterolemia, and analysis of the proband LDLR gene led to the identification of the 664 proline to leucine defective mutation and its detection in all 6 hypercholesterolemic-related members of this family. Therefore, our results show that the family presents with familial hypercholesterolemia and give evidence that the R3531C substitution in the APOB gene is not an allelic variant leading to FDB. Furthermore, thorough analysis of our data suggests that the APOB-R3531C mutation enhances the hypercholesterolemic effect of the LDLR-P664L defect, suggesting that it is a susceptibility mutation.- - - - - - - - - - ranking = 8keywords = gene (Clic here for more details about this article) |
10/95. Role of orthotopic liver transplant in the treatment of homozygous familial hypercholesterolemia.Homozygous familial hypercholesterolemia is an inherited metabolic disease that leads to decreased catabolism of low-density lipoprotein cholesterol. As a result coronary artery disease ensues by the first or second decade. Because most low-density lipoprotein receptors (50-75%) are located in the liver, liver transplantation has been introduced as a therapeutic option in this disorder. AIMS: To report our experience in the treatment of homozygous familial hypercholesterolemia with ortothopic liver transplantation. We evaluated metabolic results and patient survival. METHOD: We treated two affected siblings. One of them received a sequenced heart-liver transplantation because of cardiac failure due to severe coronary disease. RESULTS: The operative and postoperative course was favourable in both patients, with a decrease in cholesterol levels to normal values. Four years later both were alive and both had normal liver and heart functions. Neither patient needed cholesterol-lowering drugs, and the disease had not progressed. CONCLUSIONS: As shown by our results and those reported by others, liver transplantation is the treatment of choice for homozygous familial hypercholesterolemia until gene therapy becomes a viable option. Transplantation should be done before of cardiovascular complications develop.- - - - - - - - - - ranking = 3963.6715112641keywords = gene therapy, gene (Clic here for more details about this article) |
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