Download - Cystic fibrosis(genetic disease)
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Cystic fibrosis(genetic disease)
Presented by-Vl-aM.ScDepartment of biotechnologyCentral Mizoram university
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Outline
• What is cystic fibrosis (CF)?• What causes CF?• What are the manifestations?• How do you diagnose CF?• How do you treat CF?
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Cystic Fibrosis
• Inherited monogenic disorder presenting as a multisystem disease.
• Typically presents in childhood– 7% of CF patients diagnosed as adults
• Most common life limiting recessive trait among whites
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Cystic Fibrosis
• Prognosis improving–>38% of CF patients are older than 18– 13% of CF patients are older than 30
• Median survival–Males: 32 years– Females: 29 years
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Genetics of CF
• Autosomal recessive• Gene located on chromosome 7• Prevalence- varies with ethnic origin– 1 in 3000 live births in Caucasians in
North America and Northern Europe– 1 in 17,000 live births of African
Americans– 1 in 90,000 live births in Hawaiian
Asians
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Genetics of CF
• Most common mutation– Occurs in 70% of CF chromosomes– 3 base pair deletion leading to absence
of phenylalanine at position 508 (DF508) of the CF transmembrane conductance regulator (CFTR)
• Large number (>1000) of relatively uncommon mutations.
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Genetics of CF
• DF508 mutation leads to improper processing and intracellular degradation of the CFTR protein
• Other mutations in the CF gene produce fully processed CFTR proteins that are either non-functional or partially functional
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Mutation of CFTR
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• Normal airway epithelia
• CF altered airway epithelia
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Pathophysiology
• Lung–High rate of sodium absorption and low
rate of chloride secretion reduces salt and water content in mucus, depletes peri-ciliary liquid
–Mucus adheres to airway surface, leads to decreased mucus clearing
– Predisposition to Staph and Pseudomonas infections
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Pathophysiology
• Gastrointestinal– Biliary tree• Retention of biliary secretion• Focal biliary cirrhosis• Bile duct proliferation• Chronic cholecystitis, cholelithiasis
• Sweat–Normal volume of sweat– Inability to reabsorb NaCl from sweat
as it passes through sweat duct
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Pathophysiology
• Gastrointestinal– Biliary tree• Retention of biliary secretion• Focal biliary cirrhosis• Bile duct proliferation• Chronic cholecystitis, cholelithiasis
• Sweat–Normal volume of sweat– Inability to reabsorb NaCl from sweat
as it passes through sweat duct
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Manifestations
• Genitourinary– Late onset puberty• Due to chronic lung disease and inadequate
nutrition–>95% of male patients with CF have
azospermia due to obliteration of the vas deferens
– 20% of female patients with CF are infertile
–>90% of completed pregnancies produce viable infants
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Diagnosis
• DNA analysis not useful due to large variety of CF mutations
• Sweat chloride test >70 mEq/L• 1-2% of patients with clinical
manifestations of CF have a normal sweat chloride test–Nasal transepithelial potential
difference
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Diagnosis
• Criteria– One of the following
• Presence of typical clinical features• History of CF in a sibling• Positive newborn screening test
– Plus laboratory evidence for CFTR dysfunction• Two elevated sweat chloride concentrations on two
separate days• Identification of two CF mutations• Abnormal nasal potential difference measurement
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Treatment
• Major objectives– Promote clearance of secretions– Control lung infection– Provide adequate nutrition– Prevent intestinal obstruction
• Investigation into therapies to restore the processing of misfolded CFTR protein
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Treatment
• Lung–>95% of CF patients die from
complications of lung infection– Breathing exercises– Flutter valves– Chest percussion– ? Hypertonic saline aerosols
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Treatment
• Lung– Atelectasis• Chest PT + antibiotics
– Respiratory failure and cor pulmonale• Vigorous medical management• Oxygen supplementation• Only effective treatment for respiratory
failure is lung transplantation– 2 year survival >60% with lung transplatation
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Treatment
• Gastrointestinal– Pancreatic enzyme replacement– Replacement of fat-soluble vitamins-
especially vitamin E & K– Insulin for hyperglycemia– Intestinal obstruction• Pancreatic enzymes + osmotically active
agents• Distal- hypertonic radiocontrast material via
enema
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Treatment
• Gastrointestinal– End-stage liver disease- transplantation• 2 year survival rate >50%
–Hepatic and gallbladder complications treated as in patient without CF
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Summary
• CF is an inherited monogenic disorder presenting as a multisystem disease
• Pathophysiology is related to abnormal ion transportation across epithelia
• Respiratory, GI and GU manifestations
• Treatment is currently preventative and supportive
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REFERENCE:Collin F.S(2006) Cystic fibrosisNational Library of Medicine 2008,Cystic
FibrosisThe Nemours Foundation 2008,Cystic
fibrosis,accessed on 18 Aug ,2009Genetic Sciences Learning Center
2009,Cystic fibrosis,accessed on 18 Aug ,2009
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THANK YOU…….