Familial Hypercholesterolemia

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

Function of LDLR gene
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 internalization 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

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

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