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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