Cystic Fibrosis Ppt

8/3/2019 Cystic Fibrosis Ppt

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MANISHA PADMAKUMAR

11408025


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INTRODUCTION

Cystic fibrosis is a genetic disorder that mainly

affects the digestive systems and lungs.

The exocrine glands like those secreting sweat,

mucus, digestive fluids, etc are mainly affected.

Abnormally thick mucus and salty sweat isproduced which are the main cause of other

symptoms in cystic fibrosis.

It might cause early death due to multiple organ

failure.

It is most common in caucasian populations.


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HISTORYIt was misdiagnosed as whooping cough,pneumonia,bronchitis,etc.

But awareness traced back to 1700s.

Discovered and studied 1930 onwards.

The term cystic fibrosis was coined by Dr. Dorothy Andersen who

published an article, "Cystic Fibrosis of the Pancreas and Its Relation to

Celiac Disease: a Clinical and Pathological Study," in 1938

and hypothesized that CF was a recessive disease .

1952 Paul di Sant Agnese discovered abnormalities in sweat-thus sweat

test.1988 the first mutation for CF, F508 was discovered by Francis

Collins, Lap-Chee Tsui and John R. Riordan.


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PREVALENCE

In the world

In the United States, approximately 30,000 individuals, 3000 Canadians,

and 20,000 Europeans have CF.

Occurs mostly in whites of caucasian decent.

Less common in African Americans, Native Americans, and Asian

Americans.

2500 babies are born with CF each year in the United States

1 in every 20 Americans is an unaffected carrier of an abnormal CF gene.

In India

No statistics are found as it might be misdiagnosed.

But according to the statistics of indians settled in US and UK, the

incidence should be possibly 100,000 patients in India.


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CELEBRITIES WITH CYSTIC

FIBROSIS

Lisa Bentley (Canadian

Ironman triathlete)

Bob Flannagan(American

performance artist, comic, writer,poet, and musician.)


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SYMPTOMS

GENERAL SYMPTOMSsalty tasting skin

poor growth and poor weight gain despite a normal food

intake

accumulation of thick, sticky mucusfrequent chest infections

coughing or shortness of breath

Males can be infertile sometimes

Digestive problems frequent affected newborn infant fails to pass faeces (meconium)

protrusion of internal rectal membranes (rectal prolapse)

Clubbed fingers and toes


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HOW CYSTIC FIBROSIS

AFFECTS THE BODYSWEAT GLANDS-

Sweat produced too salty(2-5 times more

than normal)

Thus more exhaustion or more sweating

leads to salt loss and dehydration


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RESPIRATORY SYSTEM-Normally epithelial cells lining the respiratory tracts and

the exocrine glands in the airways produce a thin slipperysecretion called MUCUS.

It provides a protective lubricant coating which captures

microbes and dust from getting into the lungs and causinginfections. This can be coughed out by the body with the

help of cilia.

In CF mucus produced is thick and sticky. This inhibits

movement of cilia and thus plugs the airways and ducts

and accumulates microbes. Causes infections.


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Infections lead to inflammation which causes

airways to get blocked and thus breathing problems

result.This cycle continues,spreading the infection and

thus damaging the the lungs(pulmonary

exacerbation.

Thus coughing, wheezing, pneumonia, bronchitis.


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Malnutrition and weak. Rectal prolapse.

Can also lead to pancreatic or intestinal inflammation.

If pancreas impaired,islet cells affected. Thus diabetes

can also occur.

Vitamin absortion decreases causing severe weakness.


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REPRODUCTORY SYSTEMIn men with CF sometimes vas deference in blocked or

absent. Sperm production and transport affected.

Thus almost 97% of men with CF are infertile(not

sterile).

In women also conceiving might become a problem

due to blockage of reproductory tracts by mucus but

mostly they are not infertile.


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GENETIC AND MOLECULAR BASIS OF

CYSTIC FIBROSIS

Locus: 7q31.2

Gene Structure: The normal allelic variant

for this gene is about 250,000 bp long and

contains 27 exons.

Coding Sequence (CDS): 4443 bp within

the mRNA code for the amino acid sequence

of the gene's protein product.

Protein Size: The CFTR protein is 1480

amino acids long and has a molecular weight

of 168,173 Da.


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THE CFTR PROTEIN-It is the cystic fibrosis transmembrane conductance regulator protein.

The normal CFTR protein product is a chloride channel protein found in

membranes of cells that line passageways of the lungs, liver, pancreas, intestines,reproductive tract, and skin. CFTR is also involved in the regulation of other

transport pathways.

It generally has five domains: two membrane-spanning domains (MSD1 and

MSD2) that form the chloride ion channel, two nucleotide-binding domains (NBD1

and NBD2) that bind and hydrolyze ATP (adenosine triphosphate), and a

regulatory (R) domain.


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NORMAL FUNCTION OF CFTR-Regulates movement of chloride ions out of mucus

producing cells.Thus water follows by osmosis principle.

So mucus thinned and slippery.

CFTR functions principally as a cAMP-induced

IN CASE OF CF-Mutated CFTR cannot allow chloride ions to move out of

the cells.

Water cannot escape and thin the mucus.Thus mucus is thick and forms clogs.


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MUTATIONDelta F508, the most common CF-causing mutation, occurs in

the DNA sequence that codes for the first nucleotide-binding

domain (NBD1).

508 is a deletion() of 3 nucleotides that result in the loss of

the amino acid at the phenylalanine position at the 508th position

of the protein.

3-D STRUCTURE OF NBD1 DOMAIN


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CONTINUED.

When a CFTR protein with the delta F508 mutation reaches the

ER, the quality-control mechanism of this cellular componentrecognizes that the protein is folded incorrectly and marks the

defective protein for degradation. As a result, delta F508 never

reaches the cell membrane.

People who are homozygous for delta F508 mutation tend to have

the most severe symptoms of cystic fibrosis due to critical loss of

chloride ion transport.

This mutation accounts for two-thirds (66-70%) worldwide and90% of cases in United States,however there are 1400 other

mutations that can produce CF.


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INHERITANCE PATTERNCystic fibrosis has anautosomal recessive inheritance

Thus if both the parents are carriers, the child has 25% chances of

becoming affected and 50% chances of being a carrier.Since autosomal, can occur in male and female populations alike.


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DIAGNOSIS

SWEAT TESTSweat glands are activated by a chemical called pilocarpine

and mild electricity.

Gauze pad or filter paper used to collect the accumulated

sweat.Normal sweat chloride content 60 is diagnostic for CF(for

infants over 6 months.


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GENETIC TESTINGBlood or buccal smear tested for F508 mutation

70% are homozygous for F508 mutation. Others have one

F508 mutation and another form of CFTRmutation(heterozygous)

NEW BORN SCREENINGIMMUNOREACTIVE TRYPSINOGEN test is done in 2-3 days

of the birth of the baby from blood sample.

If levels high, CF positive.

CARRIER SCREENING

Before pregnancy,blood test performed on healthy adultswith family history of CF to determine whether they carry a

recessive gene mutation that could cause disease in their

children.


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PRENATAL TESTINGAMNIOCENTESIS-

Done in the second trimester ,typically between the 15th and 18th

weeks of pregnancy.thin needle is inserted into the uterus through the abdomen and a

small amount of amniotic fluid is drawn out which is then analyzed

for genetic and chromosomal abnormalities.

CHORIONIC VILLI SAMPLING-

Done in the first trimester, between the 10th and 12th week of

pregnancy.

thin needle inserted into the uterus through either the abdomen or

the cervix

Small sample of placenta is removed and analyzed for any genetic

and chromosomal abnormalities.


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MOLECULAR DIAGNOSIS

Multiplex ligation dependent probe amplification(MLPA)

Quantitative fluorescent multiplex PCR


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TREATMENT

LUNG DISORDERSChest Physical Therapy

CPT also is called chest clapping or percussion. It involves pounding

the chest and back over and over with hands or electrical percussor

to loosen the mucus from lungs so that it can be coughed up.

Exercise

Not too much as salt content is lost due to sweating.

Medicines

Antibiotics are the main treatment to prevent or treat lung

infections. They can be oral, inhaled, or intravenous (IV) antibiotics.Inhaled medicines generally given by aerosols or metered dose

inhalers.(MDI)

Nebulizers can also be used.


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Medicines ctnd.BRONCHODIALATORS-open airways,clear mucus. Eg-Albuterol

MUCOLYTICS-Thins mucus. Eg-Pulmozyme

ANTI-INFLAMMATORY- Reduces inflammations. Eg-steroids and non-steroidal Ibuprofen

ANTIBIOTICS-Fights infection. Eg-Tobramycin

Oxygen therapyLung transplants


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DIGESTIVE DISORDERSNutritional therapy-

a well-balanced diet that's rich in calories, fat, and proteinOral pancreatic enzymes to help digest fats,proteins and

absorb more vitamins.

Supplements of vitamins A, D, E, and K

High-calorie shakes

A high-salt diet or salt supplements

Oral pancreatic enzymes

Antacids

Surgery- of blocked intestines or pancreas.


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GENE THERAPYUse of normal DNA to correct for the damaged genes

that cause diseaseIn the case of CF, gene therapy involves inhaling a spray

that delivers normal DNA to the lungs

The goal is to replace the defective CF gene in the lungs

to cure or slow the progression of the diseaseMore research is going on in this area to improve

methods for transfer of therapeutic DNA into the affected

patient with minimum or no risks


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PREVENTION

Through carrier screening if both parents arefound to be carriers, the couple should go for

genetic counseling before having a baby.

IVF techniques can be used to select healthy

embryo for carrier parents.

Awareness about the disease in general


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REFERENCES

Wikipedia

www.cff.org

www.medecinenet.com

Ghr.nlm.nih.gov

www.ornl.gov

www.news-medical.net

www.genome.gov
http://www.cff.org/http://www.medecinenet.com/http://www.ornl.gov/http://www.news-medical.net/http://www.genome.gov/http://www.genome.gov/http://www.news-medical.net/http://www.news-medical.net/http://www.news-medical.net/http://www.ornl.gov/http://www.medecinenet.com/http://www.cff.org/


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THANKYOU

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Cystic Fibrosis Ppt