Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by very high levels of LDL cholesterol due to mutations in genes that encode proteins involved in cholesterol metabolism. These mutations impair the clearance of LDL from the bloodstream and can cause premature cardiovascular disease. The main genes associated with FH encode the LDL receptor, apolipoprotein B, LDLR adaptor protein 1, and PCSK9. Mutations in these genes disrupt LDL receptor function or activity, reducing LDL uptake from the blood and elevating cholesterol levels. Treatment focuses on lowering cholesterol through medications, diet, and lifestyle changes.

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

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

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. 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

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. 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.

11. 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

13. 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

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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

20. 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