cystic fibrosis ppt
TRANSCRIPT
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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