Familial

Hypercholesterolemia

Gourav Kumar
M.Sc. Biotech second sem 2
207
 WAT IS CHOLESTEROL
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.
 DESIRABLE
CHOLESTEROL LEVEL

Desirable — Less than 200

mg/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
 LOW DENSITY LIPOPROTEINS

It is also called “ bad “ cholesterol

The cholesterol from LDL is the main

source of damaging and blockage in the
arteries.

Thus, the more LDL-cholesterol you

have in your blood greater the chances
for heart diseases.
 HIGH DENSITY 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.
 Symptoms of Hyper Cholesterolemia
 High cholesterol rarely causes symptoms. It is
usually detected during a regular blood test that
measures cholesterol level. So diagnosis of below
character gives clue for HYPERCHOLESTEROLEMIA:-
The first symptom of coronary artery disease
(CAD) is often chest pain (angina).

Chest pain may occur during activities that

increase the heart rate.

However, many people have CAD for several

years without symptoms.

Transient ischemic attack (TIA) is warning

signs of an oncoming stroke.
 What is Hypercholestermia
Hypercholesterolemia is a high level of
cholesterol in the blood that can cause plaque
to form and build up leading to blockages in
the arteries (arteriosclerosis), increasing the
risk for heart attack, stroke, circulation
problems, and death.
 Familial Hypercholesterolemia
It is autosomal dominant disorder.

It causes high levels of LDL cholesterol and

finally coronary heart disease.

50% risk of coronary heart disease by the age

of 50 yrs in men.

And at least 30% in women by the age of 60

years.
 TYPES OF FH

I. HOMOZYGOUS FH

II. HETEROZYGOUS FH

III. Apo-B-100 associated

 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. 
 ADULTS
Most patients do not survive beyond age 30
years 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.
 HETEROZYGOUS FH
It is an autosomal dominant disease
characterized by elevated plasma
concentration of LDL cholesterol (LDL-
C) ,depends 95 percent on age and
sex.
WHO has estimated that HtFH is properly
diagnosed in only about 15% of affected
patients.

As many as 30% of patients do not survive in

their first myocardial infarction :-

so early detection of HtFH therefore has the

potential to save many lives and prevent early
morbidities related to CAD.
 Apolipoprotein B

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.
 CAUSES
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 is considered "heterozygous."
In rare cases, a child may inherit the
gene from both parents. Individuals who
inherit both genes are considered
"homozygous." Homozygous familial
hypercholesterolemia is much more
severe.
 CLINICAL FEATURE
OF FH
The clinical characteristics of FH include:-

Elevated concentrations of plasma LDL.

Deposition of LDL-cholesterol in the arteries

called ATHEROMAS.

Deposition of LDL-cholesterol in tendons and

skin called XANTHOMAS.
XANTHOMAS, ARCUS CORNEA and
ATHEROSCLEROSIS will develop during
childhood in HOMOZYGOTES.

Shown in the Table below are representative

values of various plasma lipids in normal,
heterozygote FH and homozygote FH
individuals.
 Total
Triglycer
Genotyp Choleste LDL HDL
Age, yrs ides
e rol (mg/dl) (mg/dl)
(mg/dl)
(mg/dl)

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

Heterozy
1-19 300 ± 60 240 ± 60 45 ± 10 80 ± 50
gotes

Homozy 680 ± 625 ±

1-19 35 ± 10 100 ± 50
gotes 170 160

Normal >20 200 ± 40 125 ± 30 55 ± 15 80 ± 30

Heterozy
>20 380 ± 80 300 ± 80 45 ± 15 150 ± 75
gotes
 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.
 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.
 Class 2 Mutations:

Class 2A mutations result in an LDLR protein

that fails to be transported out of the ER.

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

of the newly synthesized LDLR protein is
transported to the Golgi but at a reduced rate
compared to wild-type.
 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 to
isolate fibroblasts from the patient and do in
vitro ligand-binding assays.
Class 4 Mutations:
 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).
Mutations in the APOB, LDLR, LDLRAP1, and PCSK9
genes 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.
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 vitamins
such as vitamin E and vitamin A.
Cytogenetic Location: 2p24-p23
Molecular Location on chromosome 2: base pairs 21,077,805 to
21,120,449

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

between positions 24 and 23.
More precisely, the APOB gene is located from base pair
21,077,805 to base pair 21,120,449 on chromosome 2.
 LDLR
“low density lipoprotein receptor.”
The LDLR gene provides instructions for
making a protein called a low-density lipoprotein
receptor. This receptor binds to low-density
lipoproteins (LDLs), which are the primary
carriers of cholesterol in the blood.

LDLR sit on the outer surface of many types of

cells, where they pick up LDL circulating in the
bloodstream and transport them into the cell.
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 drop
off their cargo, they are recycled back to the
cell surface to pick up more low-density
lipoproteins.
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 of chromosome

19 at position 13.3.
More precisely, the LDLR gene is located from base pair
11,061,131 to base pair 11,105,489 on chromosome 19.
 LDLRAP1

“low density lipoprotein receptor adaptor protein 1.”

The LDLRAP1 gene (also known as autosomal recessive
hypercholesterolemia 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.
Cytogenetic Location: 1p36-p35
Molecular Location on chromosome 1: base pairs
25,742,752 to 25,767,963

The LDLRAP1 gene is located on the short (p) arm of

chromosome 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.
 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.
Cytogenetic Location: 1p32.3
Molecular Location on chromosome 1: base pairs
55,277,807 to 55,303,110

The PCSK9 gene is located on the short (p) arm of chromosome

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.
 Tests
 A history or physical exam and other tests to check
certain medical conditions (such as diabetes, thyroid
or kidney problems) that may raise cholesterol levels
are usually the first steps in evaluating 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.
 Treatment for Hyper Cholesterolemia
 There 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 can

double the reduction in LDL levels achieved through a
diet. Weight loss can be achieved by decreasing your
calorie intake and increasing exercise.
THANK you