Cystic fibrosis(genetic disease)

Cystic fibrosis(genetic disease)

Presented by-Vl-aM.ScDepartment of biotechnologyCentral Mizoram university

Outline

• What is cystic fibrosis (CF)?• What causes CF?• What are the manifestations?• How do you diagnose CF?• How do you treat CF?

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

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

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

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.

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

Mutation of CFTR

• Normal airway epithelia

• CF altered airway epithelia

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

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

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

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

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

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

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

Treatment

• Lung–>95% of CF patients die from

complications of lung infection– Breathing exercises– Flutter valves– Chest percussion– ? Hypertonic saline aerosols

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

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

Treatment

• Gastrointestinal– End-stage liver disease- transplantation• 2 year survival rate >50%

–Hepatic and gallbladder complications treated as in patient without CF

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

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

THANK YOU…….