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A. Basics
B. Imaging
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01. History of Cardiology
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07. Syncope and Bradycardia
08. Ventricular Arrhythmias and Sudden Cardiac Death (SCD)
09. Device Therapy
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21. Pulmonary Circulation, Pulmonary Embolism, Right Heart Failure
22. Aortic Disease
23. Peripheral Vascular and Cerebrovascular Disease
24. Stroke
25. Interventional Cardiology
26. Cardiovascular Surgery
27. Hypertension
28. Risk Factors and Prevention
29. Rehabilitation and Sports Cardiology
30. Cardiovascular Disease in Special Populations
31. Pharmacology and Pharmacotherapy
32. Cardiovascular Nursing
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34. Public Health and Health Economics
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Update of the Portuguese Familial Hypercholesterolemia Study
Session:
Posters 1 - Écran 08 - HTA / Fármacos /Ciência Básica
Speaker:
Ana Catarina Alves
Congress:
CPC 2018
Topic:
O. Basic Science
Theme:
36. Basic Science
Subtheme:
36.2 Basic Science - Cardiac Biology and Physiology
Session Type:
Posters
FP Number:
---
Authors:
Ana Catarina Alves; Ana Medeiros; Rafael Graça; Leonor Abrantes; Joana Chora; Mafalda Bourbon
Abstract
<p>Familial hypercholesterolaemia (FH) is an inherited disorder of cholesterol metabolism characterized by defective clearance of plasma LDL that results in increased circulating LDL-cholesterol, leading to premature atherosclerosis and coronary heart disease (CHD). FH is caused mainly by mutations in <em>LDLR</em> gene but mutations in <em>APOB</em> or <em>PCSK9</em> genes are also a rare cause of FH. Portugal should have at least 20 000 cases of FH but this disorder is severely under-diagnosed in our country. Since 1999 the “Portuguese FH Study” has studied more than 1000 patients with the collaboration of clinicians countrywide. The major aim of this study is to identify and characterize the cause of hypercholesterolaemia in patients with clinical diagnosis of FH.</p> <p>Clinical criteria of FH were adapted from the Simon Broome Register (UK). Genetic diagnosis is now performed by NGS and includes <em>LDLR</em>, <em>APOB</em>, <em>PCSK9</em>, <em>LIPA</em>, <em>APOE</em> and <em>LDLRAP1</em> genes. The detected variants were confirmed by Sanger Sequencing. MLPA was also performed for <em>LDLR</em>. Functional assays were performed by generating different LDLR mutants by site-directed mutagenesis and express them in CHO–ldlA7 cells lacking endogenous expression of LDLR. To determine the effects of alterations on LDLR function, cell surface expression and binding and uptake of FITC-LDL was assessed by flow cytometry and western blot.</p> <p>A genetic defect was identified in 821 FH patients (index and relatives). We’ve identified 3 true homozygous and 8 compounds heterozygous. In our cohort 742 heterozygous patients presented a <em>LDLR</em> mutation, 51 <em>APOB</em> mutations, 11 PCSK9 mutations, 2 patients have sitosterolaemia and 4 LALD. 328 index patients have a <em>LDLR</em> variant of which 139 are different variants. From these a total of 35 produce truncated proteins with null or residual LDLR activity, for 77 variants a complete functional characterisation was performed, and for the remaining 27 variants, the functional studies are ongoing.</p> <p>These studies have allowed to confirm the diagnosis in 716 patients that are now treated according to their disease specifications. The genetic diagnosis of FH provides an unequivocal diagnosis and allows early identification of relatives at risk, allowing the implementation of appropriate treatment in early ages to decrease avoidable deaths.</p>
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