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Familial hypercholestrolemia


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It is genetical disorder which is caused by mutation in genes and blood cholestrol level is high.

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Familial hypercholestrolemia

  2. 2. INTRODUCTION  Familial hypercholesterolemia (FH) have raised cholesterol levels in blood with a significant risk of developing early CAD.  FH is an autosomal dominant disorder occurs in 1 in 500 individuals.  Usually due to mutations in LDL receptor gene that result in decreased clearance of LDL particles from plasma  Other mutations include those in the Apo B ,ARH and PCSK9 genes
  3. 3. CLINICAL MANIFESTATIONS • High cholesterol level in blood. • Heterozygotes may have premature cardiovascular disease at the age of 30 to 40. • homozygous may cause severe cardiovascular disease in childhood. • Accompanied by cholesterol deposition in tendons and skin (xanthomas) and in the eyes
  4. 4. A- Xanthelasma B – Corneal arcus (Arcus senilis) C - Achilles tendon xanthomas D - Tendon xanthomas E - Tuberous xanthomas F - Palmar xanthomas
  5. 5. PLASMA CHOLESTEROL LEVEL IN NORMAL AND FH INDIVIDUALS  NORMAL – 150 – 200 mg/dl  FH HETEROZYTOGE – 200 – 500 mg/dl  FH HOMOZYGOTES – 600 – 1000 mg/ dl
  6. 6. FH Is Not a Rare Genetic Disease: Prevalence is 2x Other Inherited Conditions 1. Genetic Alliance UK. Available at 2. Streetly A, et al. J Clin Path. 2010;63:626-629. Neuro- fibromatosis Frequency per 1,000 Births of Common Genetic Disorders1 2FH 2.0
  7. 7. Function of LDLR gene  The LDLR gene is located on 19p13.2  The LDLR gene provides instructions for making a protein called low density lipoprotein receptor  This receptor binds to particles called low-density lipoproteins, which are the primary carriers of cholesterol in the blood.  They are particularly abundant in the liver, which is the organ responsible for removing most excess cholesterol from the body.
  8. 8. Mutation in LDLR gene  Mutations in the LDLR gene cause FH  More than 1,000 mutations have been identified in this gene.  Some genetic changes reduce the no. of low-density lipoprotein receptor and other mutations disrupt the receptor's ability to remove low-density lipoproteins from the blood.  As a result, people with mutations in the LDLR gene have very high blood cholesterol levels.  The excess cholesterol circulates through the bloodstream, is deposited abnormally in tissues such as the skin, tendons.  And also arteries that supply blood to the heart (coronary arteries) results in heart attack.
  9. 9. CLASSES OF MUTATION IN LDLR  Class 1 mutations affect the synthesis of the receptor in the endoplasmic reticulum (ER).  Class 2 mutations prevent proper transport to the Golgi body needed for modifications to the receptor  Class 3 mutations stop the binding of LDL to the receptor..  Class 4 mutations inhibit the internalisation of the receptor-ligand complex  Class 5 mutations give rise to receptors that cannot recycle properly. This leads to a relatively mild phenotype as receptors are still present on the cell surface  Class 6 Failure to localize receptor to the basolateral domain
  10. 10. Function of APOE gene  The APOB gene is located on 2p24-p23  The APOB gene provides instructions for making two versions of the apolipoprotein B protein, a short version called apolipoprotein B-48 and a longer version known as apolipoprotein B-100.  Both of these proteins are components of lipoproteins.  Apolipoprotein B-48 is produced in the intestine, where it is a building block of a type of lipoprotein called a chylomicron.  Apolipoprotein B-100, which is produced in the liver, is a component of several other types of lipoproteins
  11. 11. Mutation in APOE gene  At least five mutations in the APOB gene are known to cause a form of inherited hypercholesterolemia.  Each mutation that causes this condition changes a single amino acid in a critical region of apolipoprotein B-100.  The altered protein prevents low-density lipoproteins from effectively binding to their receptors on the surface of cells.  As a result, fewer low-density lipoproteins are removed from the blood, and cholesterol levels are much higher than normal.
  12. 12. Function of LDLRAP1 Gene  The LDLRAP1 gene is located on 1p36-p35.  The LDLRAP1 gene is also known as ARH( Autosomal recessive hypercholesterolemia)  The LDLRAP1 gene provides instructions for making a protein LDLRAP1 that helps remove cholesterol from the bloodstream.  The LDLRAP1 protein interacts with a protein called a low-density lipoprotein receptor.  The LDLRAP1 protein appears to play a critical role in moving these receptors, together with their attached low-density lipoproteins, from the cell surface to the interior of the cell.
  13. 13. Mutation in LDLRAP1 gene  More than 10 mutations in the LDLRAP1 gene have been shown to cause a form of inherited high cholesterol called ARH  These mutations lead to the production of an abnormally small, nonfunctional version of the LDLRAP1 protein or prevent cells from making any of this protein.  Without the LDLRAP1 protein, LDL receptors are unable to remove LDL’s from the bloodstream effective.  The receptors can still bind normally to low-density lipoproteins, but not properly transported into cells . As a result,more low-density lipoproteins remain in the blood.
  14. 14. FUNCTION OF PCSK9 GENE  The PCSK9 protein appears to control the number of low-density lipoprotein receptors, which are proteins on the surface of cell  the PCSK9 protein helps control blood cholesterol levels by breaking down low-density lipoprotein receptors before they reach the cell surface.
  15. 15. Mutation GAIN OF FUNCTION: The mutations responsible for hypercholesterolemia as "gain-of-function" because they appear to enhance the activity of the PCSK9 protein or give the protein a new, atypical function. Altered protein may cause these receptors to be broken down more quickly than usual. With fewer receptors to remove low LOSS OF FUNCTION: Loss-of-function mutations in the PCSK9 gene appear to be more common than gain-of-function mutations, which are responsible for hypercholesterolemia. Loss-of-function mutations in the PCSK9 gene lead to an increase in the number of low-density lipoprotein receptors on the surface of liver cells.
  16. 16. The 4 Genes Associated with FH Mutant Gene Product Pattern of Inheritance Prevalence Effect of Disease- Causing Mutations Typical LDL Cholesterol Level (Normal Adults: ~120 mg/dL) LDL receptor AD (19p13.2) HTZs: 1/500 HMZs: 1/106 Loss of function HTZs: 350 HMZs: 700 Apo B-100 AD (2p24) HTZs: 1/1000* HMZs: 1/106* Loss of function HTZs: 270 HMZs: 320 ARH adaptor Pr. AR (1p36-p35) Very rare† Loss of function HMZs: 470 PCSK9 protease AD (1p34.1-p32 ) Very rare Gain of function HTZs: 225
  17. 17. TREATMENT  Heterozygous FH is normally treated with statins-drugs that lower cholesterol level  Bile acid sequestrants (hypolipidemic agents), Ezetimibe, Fibrates (such as gemfibrozil or fenofibrate) and nicotinic acid  Also other hypolipidemic agents that lower cholesterol levels.  Homozygous FH often does not respond to regular medical therapy and may require LDL-apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.  Dietary reduction of cholesterol, and healthy lifestyle