Familial hypercholesterolaemia: A pressing issue for European health care

Brice, Philippa; Burton, Hilary; Edwards, Christopher; Humphries, Steve E.; Aitman, Timothy J.

doi:10.1016/j.atherosclerosis.2013.09.019

Cited by 27 publications

(18 citation statements)

References 22 publications

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“…The early and definitive identification of FH is important to improve patient prognosis by the implementation of adequate treatment to prevent premature CHD, especially effective in younger individuals. [37] and, would also save large amounts of money to health services [38].…”

Section: Discussionmentioning

confidence: 99%

Advantages and Versatility of Fluorescence-Based Methodology to Characterize the Functionality of LDLR and Class Mutation Assignment

et al. 2014

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Familial hypercholesterolemia (FH) is a common autosomal codominant disease with a frequency of 1∶500 individuals in its heterozygous form. The genetic basis of FH is most commonly mutations within the LDLR gene. Assessing the pathogenicity of LDLR variants is particularly important to give a patient a definitive diagnosis of FH. Current studies of LDLR activity ex vivo are based on the analysis of 125I-labeled lipoproteins (reference method) or fluorescent-labelled LDL. The main purpose of this study was to compare the effectiveness of these two methods to assess LDLR functionality in order to validate a functional assay to analyse LDLR mutations. LDLR activity of different variants has been studied by flow cytometry using FITC-labelled LDL and compared with studies performed previously with 125I-labeled lipoproteins. Flow cytometry results are in full agreement with the data obtained by the 125I methodology. Additionally confocal microscopy allowed the assignment of different class mutation to the variants assayed. Use of fluorescence yielded similar results than 125I-labeled lipoproteins concerning LDLR activity determination, and also allows class mutation classification. The use of FITC-labelled LDL is easier in handling and disposal, cheaper than radioactivity and can be routinely performed by any group doing LDLR functional validations.

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Section: Discussionmentioning

confidence: 99%

Advantages and Versatility of Fluorescence-Based Methodology to Characterize the Functionality of LDLR and Class Mutation Assignment

et al. 2014

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“…In most European countries, and probably also in Germany, FH is diagnosed in only 15% of cases, typically not until after a heart attack has occurred at an early age or following multiple myocardial infarctions in a family (7,8). There are no studies investigating the prevalence rate in a representative German sample.…”

mentioning

confidence: 92%

Familial Hypercholesterolemia

Klose¹,

Laufs

März

et al. 2014

Deutsches Ärzteblatt International

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“…[14][15][16] Despite the knowledge of causal genes and the obvious advantages of early therapy only 1-15% of FH cases are diagnosed in most European countries. 17 Notable exceptions are Norway (43%) and the Netherlands (71%), in which national screening programs had been initiated. 1,18,19 There are several reasons why FH is vastly under-diagnosed.…”

Section: Introductionmentioning

confidence: 99%

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

et al. 2015

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Familial hypercholesterolemia (FH) is an oligogenic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDLC) levels. Variants in four genes have been reported to cause the classical autosomal-dominant form of the disease. FH is largely under-diagnosed in European countries. As FH increases the risk for coronary artery disease (CAD) and myocardial infarction (MI), it might be specifically overlooked in the large number of such patients. Here, we systematically examined the frequency of potential FH-causing variants by exome sequencing in 255 German patients with premature MI and a positive family history for CAD. We further performed co-segregation analyses in an average of 5.5 family members per MI patient. In total, we identified 11 potential disease-causing variants that co-segregate within the families, that is, 5% of patients with premature MI and positive CAD family history had FH. Eight variants were previously reported as disease-causing and three are novel (LDLR.c.811G4A p.(V271I)), PCSK9.c.610G4A (p. (D204N)) and STAP1.c.139A4G (p. (T47A))). Co-segregation analyses identified multiple additional family members carrying one of these FH variants and the clinical phenotype of either FH (n = 2) or FH and premature CAD (n = 15). However, exome sequencing also revealed that some variants in FH genes, which have been reported to cause FH, do not co-segregate with FH. The data reveal that a large proportion of FH patients escape the diagnosis, even when they have premature MI. Hence, systematic molecular-genetic screening for FH in such patients may reveal a substantial number of cases and thereby allow a timely LDLC-lowering in both FH/MI patients as well as their variantcarrying family members.

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Familial hypercholesterolaemia: A pressing issue for European health care

Cited by 27 publications

References 22 publications

Advantages and Versatility of Fluorescence-Based Methodology to Characterize the Functionality of LDLR and Class Mutation Assignment

Advantages and Versatility of Fluorescence-Based Methodology to Characterize the Functionality of LDLR and Class Mutation Assignment

Familial Hypercholesterolemia

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

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