Familial hypercholestrolemia

FAMILIAL HYPERCHOLESTROLEMIA
PYARI JAAN BASHEER AHMED
GROUP 8
TBILISI STATE MEDICAL UNIVERSITY

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

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

A- Xanthelasma
B – Corneal arcus
(Arcus senilis)
C - Achilles tendon
xanthomas
D - Tendon xanthomas
E - Tuberous xanthomas
F - Palmar xanthomas

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

FH Is Not a Rare Genetic Disease:
Prevalence is 2x Other Inherited Conditions
1. Genetic Alliance UK. Available at http://www.geneticalliance.org.uk/education3.htm.
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

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.

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.

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

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

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.

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.

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.

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.

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.

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

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

Familial hypercholestrolemia

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