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Familial

Hypercholesterolemia

Gourav KumarM.Sc. Biotech second sem 2

207

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Cholesterol is one of the body's fats (lipids).

Cholesterol and another lipid, triglyceride, are

important building blocks in the structure of cells

and are also used in making hormones Vit D and

producing energy.

WAT IS CHOLESTEROL

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DESIRABLE

CHOLESTEROL LEVEL

Desirable

Less than 200mg/dL

Borderline high risk 200

239 mg/dL

High risk 240 mg/dL and

over

So the less cholesterol i.e less then 200mg/dl

reduse chance for cardiac arrest

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LOWDENSITY LIPOPROTEINS

It is also called bad cholesterol

The cholesterol from LDL is the main

source of damaging and blockage in thearteries.

Thus, the more LDL-cholesterol youhave in your blood greater the chancesfor heart diseases.

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HIGHDENSITY LIPOPROTEINS

HDL carry cholesterol from other parts of the

body back to the liver through blood, which leads

to its removal from the body. So HDL help in

cholesterol reducing from the walls of the

arteries.

Average HDL

FOR MEN45mg/dl

FOR WOMEN

55mg/dl

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Symptoms of Hyper CholesterolemiaHigh cholesterol rarely causes symptoms. It is

usually detected during a regular blood test thatmeasures cholesterol level. So diagnosis of below

character gives clue for HYPERCHOLESTEROLEMIA:-

ARTERIOSCLEROSIS

CORONARY ARTERYBLOCK

STROKE

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What is Hypercholestermia

Hypercholesterolemia is a high level of

cholesterol in the blood that can cause plaqueto form and build up leading to blockages in

the arteries (arteriosclerosis), increasing the

risk for heart attack, stroke, circulationproblems, and death.

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TYPES OF FH

I. HOMOZYGOUS FH

II. HETEROZYGOUS FH

III. Apo-B-100 associated

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HOMOZYGOUS FH

CHILDRENS

SYMPTOMS:-

1. Peripheral vascular disease

2. Cerebrovascular disease

3. Aortic stenosis

4. Tendonitis

Because they are obligate heterozygous

hypercholesterolemics, both parents must have

severe elevations in LDLc.

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ADULTS

Most patients do not survive beyond age 30years unless treated with liver transplantation

or ileal bypass surgery to lower their LDLc

levels.

Their family history should be positive for

severe hypercholesterolemia and premature

CAD in both parental family lines.

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It is an autosomal dominant diseasecharacterized by elevated plasma

concentration of LDL cholesterol (LDL-

C) ,depends 95 percent on age and

sex.

HETEROZYGOUS FH

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WHOhas estimated that

HtFH

is properlydiagnosed in only about 15% of affected

patients.

As many as 30% of patients do not survive in

their first myocardial infarction :-

so early detection ofHtFH therefore has the

potential to save many lives and prevent early

morbidities related to CAD.

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It is the primary apolipoprotien of low density

lipoprotiens, which is responsible for carrying

cholesterol to tissue.

LDL-LDLR complex formation is mediated by

apolipoprotein B-100.

The levels of APOB are a better indicator of

heart disease risk than total cholesterol or LDL.

Apolipoprotein B

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Familial hypercholesterolemia is

caused by a gene defect on

chromosome 19. The defect makes the

body unable to remove LDL cholesterol

from the bloodstream. .

The condition is typically passed

down through families in an autosomal

dominant manner. An individual who

inherits one copy of the gene isconsidered "heterozygous."

CAUSES

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In rare cases, a child may inherit the

gene from both parents. Individuals whoinherit both genes are considered

"homozygous." Homozygous familial

hypercholesterolemia is much moresevere.

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The clinical characteristics of FH include:-

Elevated concentrations of plasma LDL.

Deposition ofLDL-cholesterol in the arteries

called ATHEROMAS.

Deposition ofLDL-cholesterol in tendons and

skin called XANTHOMAS.

CLINICAL FEATURE OF

FH

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XANTHOMAS, ARCUS CORNEA and

ATHEROSCLEROSIS will develop duringchildhood in HOMOZYGOTES.

Shown in the Table below are representative

values of various plasma lipids in normal,

heterozygote FH and homozygote FHindividuals.

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Genotyp

e Age, yrs

Total

Choleste

rol

(mg/dl)

LDL

(mg/dl)

HDL

(mg/dl)

Triglycer

ides(mg/dl)

Normal 1-19 175 30 110 25 55 15 60 25

Heterozy

gotes1-19 300 60 240 60 45 10 80 50

Homozy

gotes1-19

680

170

625

16035 10 100 50

Normal >20 200 40 125 30 55 15 80 30

Heterozy

gotes>20 380 80 300 80 45 15 150 75

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GENETICS OF FAMILIAL

HYPERCHOLESTROLEMIA

Till now there have been over 700 different

mutations identified in FH patients.

Through diagnostic 45 different

polymorphisms in the LDLR gene have been

identified through RFLP/SSCP.

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Class 1 Mutations:

Multiple molecular mechanisms have been

shown to result in the null mutations that

comprise the class 1 FH family.

The alterations include deletions that

eliminate the LDLR gene promoter. In addition,frameshift, nonsense and splicing mutations

cause the null phenotype.

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Class 2 Mutations:

Class 2A mutations result in an LDLR proteinthat fails to be transported out of the ER.

Class 2B mutations are "leaky" in that some of

the newly synthesized LDLR protein istransported to the Golgi but at a reduced rate

compared to wild-type.

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Class 3 Mutations:

Most of the class 3 alleles result from in-

frame rearrangements in the cysteine-rich

repeats of the LDL-binding domain or in the EGF

precursor domain.

To accurately distinguish class 3 and class 2B

alleles at the functional level it is necessary toisolate fibroblasts from the patient and do in

vitro ligand-binding assays.

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Class 4 Mutations:

MUTATION INCYTOPLASMIC

DOMAIN

MUTATION INMEMBRANE-

SPANNING DOMAIN

SUBCLASS

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Class 5 Mutations:

Deletion or alteration of the EGF precursor

homology domain results in class 5 alleles.

The total percentage of FH alleles that are of

the class 5 type may be underestimated

because the class 5 mutations can produce a

phenotype that somewhat resembles that of

class 3 mutations (i.e. deficient LDL binding).

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Mutations in the APOB, LDLR, LDLRAP1, and PCSK9genes cause hypercholesterolemia.

APOB

It provides instructions for making two

versions of the apolipoprotein B protein, a short

version called APOB-48 and a longer version

known as APOB-100.

Both of these proteins are components of

lipoproteins, which carry fats and fat-like

substances (such as cholesterol) in the blood.

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Apolipoprotein B-48 is produced in the

intestine, where it is a building block of a

type of lipoprotein called a chylomicrons.

Chylomicrons are also necessary for the

absorption of certain fat-soluble vitaminssuch as vitamin E and vitamin A.

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Cytogenetic Location: 2p24-p23

Molecular Location on chromosome 2: base pairs 21,077,805 to21,120,449

The APOB gene is located on the short (p) arm ofchromosome 2

between positions 24 and 23.

More precisely, the APOB gene is located from base pair21,077,805 to base pair 21,120,449 on chromosome 2.

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LDLR

low density lipoprotein receptor.

The LDLR gene provides instructions for

making a protein called a low-density lipoprotein

receptor.T

his receptor binds to low-densitylipoproteins (LDLs), which are the primary

carriers of cholesterol in the blood.

LDLR sit on the outer surface of many types ofcells, where they pick up LDL circulating in the

bloodstream and transport them into the cell.

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Once inside the cell, the low-density

lipoprotein is broken down to release

cholesterol. The cholesterol is then used by

the cell, stored, or removed from the body.

After low-density lipoprotein receptors dropoff their cargo, they are recycled back to the

cell surface to pick up more low-density

lipoproteins.

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Cytogenetic Location: 19p13.3

Molecular Location on chromosome 19: base pairs 11,061,131

to 11,105,489

The LDLR gene is located on the short (p) arm ofchromosome19 at position 13.3.

More precisely, the LDLR gene is located from base pair11,061,131 to base pair 11,105,489 on chromosome 19.

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LDLRAP1

low density lipoprotein receptor adaptor protein 1.

The LDLRAP1 gene (also known as autosomal recessivehypercholesterolemia or ARH) provides instructions for

making a protein that helps remove cholesterol from the

bloodstream.

The function of the LDLRAP1 protein is particularly

important in the liver, which is responsible for clearing most

excess cholesterol from the body.

The LDLRAP1 protein interacts LDL. 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.

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Cytogenetic Location: 1p36-p35

Molecular Location on chromosome 1: base pairs25,742,752 to 25,767,963

The

LDLR

AP

1 gene is located on the short (p) arm ofchromosome 1 between positions 36 and 35.

More precisely, the LDLRAP1 gene is located from base pair

25,742,752 to base pair 25,767,963 on chromosome 1.

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PCSK9

proprotein convertase subtilisin/kexin type 9.The PCSK9 gene provides instructions for making a protein

that helps regulate the amount of cholesterol in the

bloodstream.

The PCSK9 protein appears to control the number of low-

density lipoprotein receptors, which are proteins on the

surface of cells. The receptors bind to LDLs, which are the

primary carriers of cholesterol in the blood. Low-density

lipoprotein receptors are particularly abundant in the liver.

The PCSK9 protein helps control blood cholesterol levels by

breaking down low-density lipoprotein receptors before they

reach the cell surface.

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Cytogenetic Location: 1p32.3

Molecular Location on chromosome 1: base pairs55,277,807 to 55,303,110

The PCSK9 gene is located on the short (p) arm ofchromosome 1 at position 32.3.

More precisely, the PCSK9 gene is located from base pair

55,277,807 to base pair 55,303,110 on chromosome 1.

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Tests

A history or physical exam and other tests to checkcertain medical conditions (such as diabetes,

thyroid or kidney problems) that may raise

cholesterol levels are usually the first steps inevaluating whether a person has risk factors for

heart disease.

To measure cholesterol, HDL, and triglyceride levels,

a fasting blood test is used. This means you do not

eat or drink anything except water for 12 hours

before the test.

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Treatment for Hyper CholesterolemiaThere are many different ways to treat high cholesterol

like Nonpharmacological Therapy, Diet,Weight loss,Exercise, Statins &Pharmacological(Drug) therapy

Standard nonpharmacological therapy mostly consists

of adjusting to eating and exercise habits.

Diet minimizes extra cholesterol and fat intake,especially saturated fat.

Weight Loss, even if losing 5-10lbs. of weight candouble the reduction in LDL levels achieved through adiet.Weight loss can be achieved by decreasing your

calorie intake and increasing exercise.

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THANK you