Cystic fibrosis/Hereditary spherocytosis/Muscular dystrophy
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feiyingluu on November 22, 2010
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25 terms
Terms | Definitions |
|---|---|
 cystic fibrosis | most common lethal genetic disease affecting caucasians, approx 1:20, multi-organ disease, autosomal recessive, widespread disorder in epithelial transport affecting fluid secretion in exocrine glands and epithelial lining of respiratory, GI, reproductive tracts, abnormally viscid mucous secretions leading to clinical features of disease caused by mutations in CF transmembrane conductance regulator (CFTR) gene, also influenced by environmental and secondary genetic factor (CF modifiers) six mutations in CFTR gene found presents with persistent lung infections, chronic cough, bronchitis, sputum production, airway obstruction, pancreatic insufficiency, fat maldigestion, recurrent pancreatitis, meconium ileus (newborn stool stuck in intestine), azoospermia (congenital bilateral absence of vas deferens), elevated concentration of chloride in sweat |
| Class II mutation of CFTR | predominant mutation, detected in 66% of cystic fibrosis patients, results from three base pair deletion-->delete phenylanine at position 508 of amino acid chain |
| CFTR function | chloride transport channel, active in phosphorylated state, requires ATP, inhibit epithelial Na+ channels except sweat glands (potentiates channels), tissue specific function |
| normal CFTR function in respiratory epithelium | increases chloride secretion from cells, decreases sodium absorption into cells-->increase NaCl in respiratory lumen |
| normal CFTR function in intestinal epithelium | increases chloride secretion from cells, decreases sodium absorption into cells-->increase NaCl in GI lumen |
| normal CFTR function in sweat gland ducts | increases chloride absorption into cells, increases sodium absorption into cells-->decrease NaCl in sweat duct lumen |
| pathophysiology of CFTR mutation in pancreas | normal CFTR is cAMP activated Cl- channel on apical membrane of epithelial cells, act as HCO3-/Cl- exchanger, inhibits epithelial absorptive Na+ channels mutant CFTR result in decreased HCO3- secretion into lumen, have excessive absorption of Na+ and water due to loss of regulations of Na+ channels-->thicken protein rich acinar secretions-->ductal obstruction-->retention of pancreas enzymes-->destruction of pancreatic tissue, fibrotic tissue and fat replace pancreatic parenchym, maldigestion, steaorrhea |
| pathophysiology of CFTR mutation in lung | normal CFTR regulate absorption of Na+ through epithelial channels mutant CFTR result in excessive absorption of Na+ into cells-->increase water absorption into cells-->drier than normal airways-->thick mucus layer-->inhibit ciliary clearance, infections more common, can lead to destrction of lungs end stage lung disease=principal cause of death in cystic fibrosis |
| pathophysiology of CFTR mutation in sweat gland | normal CFTR regulates NaCl reabsoprtion into sweat ducts mutant CFTR result in high NaCl levels in sweat sweat is used for screening test for cystic fibrosis |
| mutant CFTR function in respiratory epithelium | decreased chloride secretion from cells, increased sodium absorption into cells-->decreased NaCl and water in respiratory lumen |
| mutant CFTR function in intestinal epithelium | decreased chloride secretion from cells, increased sodium absorption into cells-->decreased NaCl and water in GI lumen |
| mutant CFTR function in sweat gland ducts | decreased chloride absorption into cells, decreased absorption into cells-->increased NaCl in sweat duct lumen |
| sweat test | pilocarpine (muscarinic agonist) placed on forearm, two attached electrodes generate current-->force pilocarpine into skin-->stimulate sweat glands, gauze collect sweat from arm, measure chloride content on gauze chloride content >70mM (70mEq/L)-->suggest cystic fibrosis |
| dornase alfa | mucolytic agent, recombinant DNase, to break down DNA of dead neutrophiles trapped in mucus to increase viscosity of mucus, treatment for cystic fibrosis |
| gene therapy for cystic fibrosis | inhale spray to deliver normal CFTR DNA to lungs to replace defective cystic fibrosis gene |
| Hereditary spherocytosis | inherited disorder of red blood cells-->lose biconcavity-->become spherical in shape, 75% autosomal dominant (relatively mild), 25% autosomal recessive (more severe), incidence highest in Northern Europe caused by diverse mutations affecting ankyrin, band 3, spectrin, or protein 4.2-->reduced membrane stability-->loss of membrane fragments during shear stress in circulation-->spherical shape present hemolytic anemia, spenomegaly, hyperbilirubinemia, iron overload |
| spectrin | structural protein of red blood cell membrane skeleton, most abundant, consists of α and β chains forming heterodimers and then combining to form tetramer, linked to actin through actin binding domain (ABD) at its amino terminus, both α and β chains contain repeats of spacer domains which separate the two ABD of tetramer, α chain has two Ca2+ binding domains at carboxy terminus also bind protein 4.1, β chains attach to ankyrine |
| ankyrin | structural protein of red blood cell membrane skeleton, links spectrin to band 3 mutation in this protein is most common cause of hereditary spherocytosis |
| protein 4.1 | structural protein of red blood cell membrane skeleton, provides additional link between spectrin actin network and plasma membrane by binding glycophorin |
| protein 4.2 | structural protein of red blood cell membrane skeleton, interacts with band 3 and ankyrin |
| band 3 | structural protein of red blood cell membrane skeleton, transmembrane protein, acts as anion transporter allowing HCO3- to cross membrane |
| X-linked muscular dystrophies | heterogeneous group of inherited disorders, show progressive muscle weakness and wasting, characterized by replacement of muscle fibers by fibrofatty tissue, caused by abnormalities in gene coding for dystrophin two major types: Duchenne Muscular dystrophy (DMD), Becker Muscular dystrophy (BMD) |
| dystrophin | found in muscle cells and some neurons, provides strength to muscle cells by linking internal cytoskeleton to surface membrane, without structural support cell membrane becomes permeable-->sarcolemma breaks down-->influx of calcium-->phospholipase activation, oxidative cellular injury, death absence of protein complex proposed to be basis of myocyte degeneration |
| Duchenne Muscular dystrophy (DMD) | most severe and common type of muscular dystrophy, show almost absent dystrophin, X-linked, affects mostly males, 1:3500, characterized by muscle wasting, diagnosis usually occurs between 16 mo-8 years, death usually by age 30 96% have frameshift mutation in dystrophin gene, 30% are new mutations, 10-20% of new mutations occur in gametocyte (sex cell-->pass on to next generation) show delays in early childhood stages involving muscle, show learning difficulties, wheelchair bound by 12 years, cardiomyopathy at 14-18 years, respiratory problems and cardiomyopathy lead to congestive heart failure--usual cause of death |
| Becker Muscular dystrophy | milder form of muscular dystrophy, caused by point mutation in dystrophin gene, dystrophin present in sarcolemma but show mutation--some function preserved, affects 1:30000 births, most patients walk beyond age 15, survive to 4th or 5th decades of life |
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