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Familial Hypercholesterolemia (familial + hypercholesterolemia)

Distribution by Scientific Domains

Medical Sciences	52%
Life Sciences	47%

Selected Abstracts

LDL-receptor mutations in Europe,

HUMAN MUTATION, Issue 6 2004
George V.Z. Dedoussis
Abstract Familial hypercholesterolemia (FH) is a clinical definition for a remarkable increase of cholesterol serum concentration, presence of xanthomas, and an autosomal dominant trait of either increased serum cholesterol or premature coronary artery disease (CAD). The identification of the low-density lipoprotein (LDL)-receptor (LDLR) as the underlying cause and its genetic characterization in FH patients revealed more insights in the trafficking of LDL, which primarily transports cholesterol to hepatic and peripheral cells. Mutations within LDLR result in hypercholesterolemia and, subsequently, cholesterol deposition in humans to a variable degree. This confirms the pathogenetic role of LDLR and also highlights the existence of additional factors in determining the phenotype. Autosomal dominant FH is caused by LDLR deficiency and defective apolipoprotein B-100 (APOB), respectively. Heterozygosity of the LDLR is relatively common (1:500). Clinical diagnosis is highly important and genetic diagnosis may be helpful, since treatment is usually effective for this otherwise fatal disease. Very recently, mutations in PCSK9 have been also shown to cause autosomal dominant hypercholesterolemia. For autosomal recessive hypercholesterolemia, mutations within the so-called ARH gene encoding a cellular adaptor protein required for LDL transport have been identified. These insights emphasize the crucial importance of LDL metabolism intra- and extracellularly in determining LDL-cholesterol serum concentration. Herein, we focus on the published European LDLR mutation data that reflect its heterogeneity and phenotypic penetrance. Hum Mutat 24:443,459, 2004. © 2004 Wiley-Liss, Inc. [source]

Homozygous familial hypercholesterolemia: Long term clinical course and plasma exchange therapy for two individual patients and review of the literature

JOURNAL OF CLINICAL APHERESIS, Issue 6 2009
Roy Beigel
Abstract Familial hypercholesterolemia (FH) is an autosomal dominant disease. Homozygous FH (HFH) manifests with severe hypercholesterolemia since birth (cholesterol levels >5,6 the upper normal limit), which, if untreated, leads to early onset accelerated atherosclerosis and premature coronary death, usually before the 2nd or 3rd decades of life. Various invasive procedures (iliocecal bypass, porto-caval shunt, liver transplant, and gene therapy) have been introduced for lowering low density lipoprotein (LDL) aiming at reducing atherosclerosis and improving survival of HFH patients. Of all the various methods, LDL apheresis has become the most attractive. Although its impressive effect on LDL-C reduction is well established, its long-term (of more than 10 year) effect on the atherosclerotic process and specifically cardiac end-points in HFH is hardly documented. We herewith report on the longest term lipophoresis so far reported in two HFH patients, each treated with plasma-exchange and LDL-apheresis for more than 20 years. The observations provide an opportunity to focus on various aspects regarding not only the procedure itself but also its effect on various clinical endpoints. By this description together with reviewing the literature, we discuss several issues, some of them are generalized while others are individualized, dealing with the approach of long term LDL apheresis in HFH. J. Clin. Apheresis 2009. © 2009 Wiley-Liss, Inc. [source]

Toll-like receptor-4 Asp299Gly polymorphism does not influence progression of atherosclerosis in patients with familial hypercholesterolemia

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 4 2004
European Journal of Clinical Investigation 2004;34:949
No abstract is available for this article. [source]

G-substrate gene promoter SNP (,1323T>C) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: Intra-familial association study in an eight-generation hyperlipidemic kindred

GERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2 2004
Yukiko Nobe
Background: Plasma lipid and lipoprotein generally reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity. Methods: In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH, to examine possible genetic modification of lipoprotein phenotype by ,modifier locus'. G-substrate (GSBS) is an endogenous substrate for cGMP-dependent protein kinase. We carried out an intrafamilial correlation analysis of modifier effect of ,1323T>C substitution in the GSBS gene among 85 LDLR-mutation carriers and 75 non-carriers. Results: In the LDLR - mutation carriers, the plasma cholesterol levels were highest among ,1323C homozygotes (mean ± SD = 454 ± 101 mg/dL), lowest among ,1323T homozygotes (mean ± SD, 307 ± 72 mg/dL) and intermediate among ,1323T/C heterozygotes (mean ± SD, 314 ± 62 mg/dL; P = 0.015). Similarly, in the LDLR-mutation carriers, the plasma triglyceride levels were highest among ,1323C homozygotes (mean ± SD, 371 ± 381 mg/dL), lowest among ,323T homozygotes (mean ± SD, 171 ± 94 mg/dL), and intermediate among ,1323T/C heterozygotes (mean ± SD, 218 ± 130 mg/dL; P = 0.003). No such gene-interactive effect was observed among non-carriers of the LDLR-mutation. Conclusion: These results indicate a significant modification of the phenotype of FH with defective LDLR allele, by GSBS-1323C allele in the kindred studied. [source]

Update of the molecular basis of familial hypercholesterolemia in The Netherlands,

HUMAN MUTATION, Issue 6 2005
Sigrid W. Fouchier
Abstract Autosomal-dominant hypercholesterolemia (ADH) has been identified as a major risk factor for coronary vascular disease (CVD) and is associated with mutations in the low-density lipoprotein receptor (LDLR) and the apolipoprotein B (APOB) gene. Since 1991 DNA samples from clinically diagnosed ADH patients have been routinely analyzed for the presence of LDLR and APOB gene mutations. As of 2001, 1,641 index patients (164 index patients per year) had been identified, while from 2001 onward a more sensitive, high-throughput system was used, resulting in the identification of 1,177 new index patients (average=294 index patients per year). Of these 1,177 index cases, 131 different causative genetic variants in the LDLR gene and six different causative mutations in the APOB gene were new for the Dutch population. Of these 131 mutations, 83 LDLR and four APOB gene mutations had not been reported before. The inclusion of all 2,818 index cases into the national screening program for familial hypercholesterolemia (FH) resulted in the identification of 7,079 relatives who carried a mutation that causes ADH. Screening of the LDLR and APOB genes in clinically diagnosed FH patients resulted in approximately 77% of the patients being identified as carriers of a causative mutation. The population of patients with ADH was divided into three genetically distinct groups: carriers of an LDLR mutation (FH), carriers of an APOB mutation (FDB), and non- LDLR/non- APOB patients (FH3). No differences were found with regard to untreated cholesterol levels, response to therapy, and onset of CVD. However, all groups were at an increased risk for CVD. Therefore, to ultimately identify all individuals with ADH, the identification of new genes and mutations in the genes that cause ADH is of crucial importance for the ongoing national program to identify patients with ADH by genetic cascade screening. Hum Mutat 26(6), 550,556, 2005. © 2005 Wiley-Liss, Inc. [source]

Molecular characterization of familial hypercholesterolemia in German and Greek patients,,

HUMAN MUTATION, Issue 3 2004
George V. Z. Dedoussis
Abstract We used the denaturing gradient gel electrophoresis (DGGE) method to define mutations in the promoter region, the 18 exons, and their flanking intronic sequences of the low-density lipoprotein (LDL) receptor gene LDLR, causing familial hypercholesterolemia (FH) phenotype in 100 German and in 100 Greek hypercholesterolemic individuals. In addition, we tested all patients for the presence of mutations in codons 3456-3553 of the gene encoding apolipoprotein B-100 (APOB). Twenty-six aberrant DGGE patterns were identified and subsequently directly sequenced. In LDLR, two novel missense mutations (c.1957G>T/p.V653F, c.647 G>A/p.C216Y) and one novel homozygous base substitution c.1-156 C>T in the repeat 2 of the promoter region were identified among German FH patients; one novel splice site c.1060+10C>G was identified among Greek FH patients. One of the German FH patients was a carrier for the mutations c.1171G>A/p.A391T and p.V653F, and two of the Greek FH patients were compound heterozygotes for the mutations c.1150C>T/p.Q384X and c.1158C>G/p.D386E. Two German FH patients carried the mutation p.R3500Q within APOB. Comparing the mutations within the LDLR gene of the two European FH populations, the German population seems to be more heterogeneous than the Greek cohort. Further studies in progress are trying to elucidate the responsiveness to drug therapy in association with LDLR genotype and the nutritional habits of the two FH populations. © 2004 Wiley-Liss, Inc. [source]

The UMD-LDLR database: additions to the software and 490 new entries to the database,

HUMAN MUTATION, Issue 2 2002
Ludovic Villéger
Abstract Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), one of the most frequent hereditary dominant disorders. The protein defect was identified in 1973, the gene was localized by in situ hybridization in 1985, and since, a growing number of mutations have been reported. The UMD-LDLR database is customized software that has been developed to list all mutations, and also to provide means to analyze them at the nucleotide and protein levels. The database has been recently modified to fulfill the recommendations of the Nomenclature Working Group for human gene mutations. However, in the current version, both the nomenclature and usual LDLR gene mutation names are reported since the latter are more commonly used. The software has also been modified to accommodate the splicing mutations and alleles that carry two nucleotide variations. The current version of UMD-LDLR contains 840 entries, of which 490 are new entries. Point mutations account for 90% of all mutations in the LDLR gene; the remaining are mostly major rearrangements, due to the presence of Alu sequences. Three new routines have been implemented in the software, thus giving users access to 13 sorting tools. In addition to the database, a Web site containing information about polymorphisms, major rearrangements, and promoter mutations is available. Both are accessible to the scientific community (www.umd.necker.fr) and should help groups working on LDLR to check their mutations and identify new ones, and greatly facilitate the understanding of functional classes/genotype relationships and of genotype/phenotype correlations. © 2002 Wiley-Liss, Inc. [source]

Homozygous familial hypercholesterolemia: Long term clinical course and plasma exchange therapy for two individual patients and review of the literature

Effects of LDL-immunoapheresis on plasma concentrations of vitamin E and carotenoids in patients with familial hypercholesterolemia

JOURNAL OF CLINICAL APHERESIS, Issue 4 2004
Edmund Cauza
Abstract Recently very potent extracorporeal cholesterol-lowering treatment options have become available for patients with hypercholesterolemia. LDL immunoapheresis treatment selectively removes LDL and lipoprotein(a) from the circulation. Since LDL is the major carrier of lipophilic antioxidants in plasma, the purpose of the present study was to assess the effects of a single LDL apheresis treatment on plasma concentrations of tocopherols (,- and ,-tocopherol) and carotenoids (,- and ,-carotene, zeaxanthin, cryptoxanthin, canthaxanthin, lycopene, and retinol). Plasma antioxidant concentrations were determined by HPLC in 7 patients with familial hypercholesterolemia before and after LDL immunoapheresis treatment. Plasma concentrations of both ,- and ,-tocopherol and the different carotenoids were significantly reduced by LDL apheresis. However, when standardized for cholesterol to adjust for cholesterol removal, ,- and ,-tocopherol, retinol, and the more polar carotenoids lutein and zeaxanthin increased in response to apheresis treatment, while the more unpolar carotenoids such as ,-carotene and lycopene did not change. These data demonstrate that a single LDL immunoapheresis treatment affects tocopherols and individual carotenoids differently. This may be explained by differences in chemical structure and preferential association with different lipoproteins. These results further imply that tocopherols, lutein, zeaxanthin, and retinol, are associated in part with lipoproteins and other carriers such as retinol-binding protein that are not removed during apheresis treatment. J. Clin. Apheresis 19:174,179, 2004. © 2004 Wiley-Liss, Inc. [source]

Hypercholesterolemia and inflammation in atherogenesis: Two sides of the same coin

MOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 11 2005
Daniel SteinbergArticle first published online: 3 NOV 200
Abstract An abundance of experimental, clinical, and epidemiologic data capped by stunning interventional results with the statins has established hypercholesterolemia as a major causative factor in atherogenesis. In familial hypercholesterolemia and in animal models it is a sufficient cause. Some degree of hypercholesterolemia, perhaps 30,50 mg/dL, may even be a necessary cause. It is equally clear that from the very beginning atherogenesis has a strong inflammatory component, i. e., it is characterized by penetration of monocytes and of T-cells into the developing lesion. These cells, through the secretion of cytokines and growth factors, through immune responses, and through complex cross-talk with elements of the artery wall modulate the growth of the lesion and affect its stability. But inflammation has to occur in response to something. What is that something? What is the "injury" in "response-to-injury"? The case will be made that oxidized lipids in oxidized LDL or generated in response to prooxidative changes in the cells of the artery wall should be considered a plausible candidate. There is no need to consider hypercholesterolemia and inflammation as alternative hypotheses. Both are very much involved. Optimal intervention and prevention will probably require attention to both. [source]

Natural History of a Giant Coronary Aneurysm With Spontaneous Dissection

CLINICAL CARDIOLOGY, Issue 12 2009
Alberto Bouzas-Mosquera MD
Primary spontaneous coronary artery dissection may appear in young women during the peripartum period or as a result of atherosclerosis. We present a patient with familial hypercholesterolemia who developed a giant aneurysm of the right coronary artery in the setting of atherosclerotic spontaneous coronary dissection over an 8 year period. This report illustrates the association between spontaneous coronary artery dissection and subsequent coronary aneurysm formation. Copyright © 2009 Wiley Periodicals, Inc. [source]

Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing

CLINICAL GENETICS, Issue 6 2008
JC Defesche
In a large group of patients with the clinical phenotype of familial hypercholesterolemia, such as elevated low-density lipoprotein (LDL) cholesterol and premature atherosclerosis, but without functional mutations in the genes coding for the LDL receptor and apolipoprotein B, we examined the effect of 128 seemingly neutral exonic and intronic DNA variants, discovered by routine sequencing of these genes. Two variants, G186G and R385R, were found to be associated with altered splicing. The nucleotide change leading to G186G resulted in the generation of new 3,-splice donor site in exon 4 and R385R was associated with a new 5,-splice acceptor site in exon 9 of the LDL receptor gene. Splicing of these alternate splice sites leads to an in-frame 75-base pair deletion in a stable mRNA of exon 4 in case of G186G and R385R resulted in a 31-base pair frame-shift deletion in exon 9 and non-sense-mediated mRNA decay. [source]

Plasma exchange and heart,liver transplantation in a patient with homozygous familial hypercholesterolemia

CLINICAL TRANSPLANTATION, Issue 6 2001
Jon Offstad
A female patient born in 1950 underwent plasma exchange and concomitant drug therapy for 20 yr due to homozygous familial hypercholesterolemia. Plasma exchange reduced total cholesterol levels from 25,30 mmol/L (967,1160 mg/dL) before treatment to 9.5 mmol/L (363 mg/dL) with regression of xanthomas and no side effects of long-term treatment. Due to end-stage calcific left ventricular outflow tract obstruction not amenable to standard valve reconstructive surgery, a combined heart,liver transplantation was successfully performed in 1996. She is without symptoms and living a normal life 4 yr after transplantation. Total cholesterol value is normal (4.7 mmol/L [182 mg/dL]) using a moderate dose of statins. Selective coronary angiography is without signs of graft vascular disease and the liver function is normal. [source]