Diseases Flashcards
(121 cards)
Familial Hypercholesterolemia
High levels of LDL (transports cholesterol)
Mutations in LDL receptor result in:
- Inability to bind LDL
- Poor ability to bind LDL
- Failure of LDL receptor to associate w/ coated pits
Neiman-Pick Disease
Defect in sphingomyelinase
Causes sphingolipid accumulation
CNS defects, death <18 mos
Tay Sachs Disease
Defect in hexosaminidase A (breaks down phospholipids (GM2-ganglioside))
Causes accumulation in brain
Mental retardation, death <4 yrs
Hurler’s Syndrome
Defect in alpha-L iduronidase (breaks down mucopolysaccharides)
Mental retardation, death <10 yrs
Inclusion Cell Disease
Almost all hydrolases missing from lysosome, but found in blood
Lysosomes don’t function
Buildup of material (inclusions)
Death <7 yrs
Cystic Fibrosis (CAUSE)
CTFR gene defect (autosomal recessive) –> reduced quantity/function of CFTR protein –> defective ion transport (Cl- and bicarb) –> airway surface liquid depletion –> defective mucociliary clearance –> mucus obstruction, infection, inflammation –> scarring –> end stage lung disease
Cystic Fibrosis (SYMPTOMS/DIAGNOSIS)
salty sweat mucus obstruction in lungs, pancreas, vas deferens bacterial infections airway dilation diabetes chronic pancreatitis meconium ileus (in neonate) rectal prolapse NBS: immunoreactive trypsinogen, mutation analysis, sweat chloride testing hypochloremia hyponatremia hypoproteinemia vitamen E and K and zinc deficiency
Cystic Fibrosis (TREATMENT)
Gene therapy to replace defective CFTR protein
Pharmacotherapy to rescue CFTR function
Oral pancreatic enzyme supplements
Kalydeco for G551D mutations (unlocks chloride function)
Early treatment to avoid infection
Chest therapy
CFTR gene
Chromosome 7
CFTR protein (structure, function)
- Structure: 2 sets of 6 transmembrane domains, 2 ATP-binding cassettes, regulatory domain in middle, regulated by cAMP (PKA phosphorylation of R), gated by ATP
- Function: conducts Cl- across plasma membrane, regulates activity of some Na+ channels
CFTR mutations
Class I: stop codons introduced, splicing defects, CFTR not synthesized due to transcriptional errors (5-10%)
Class II: protein synthesized as immature form, degraded by ubiquitin-proteasomal pathway and never reaches cell surface, deltaF508 in NBD1 (>85%)
Class III: CFTR synthesized and transported to cell surface, but not functional (2-3%)
Class IV: CFTR protein is expressed at cell surface, but level of chloride conduction is reduced ( reduced amount expressed at cell surface (<1%)
CF and sweat ducts
Normal: good reabsorption, Cl- is taken back to blood circulation, Na+ is also reabsorbed to balance the charge, but there’s more Na+ coming into blood than Cl-, so the ductal lumen of sweat gland has negative charge, forms NaCl in lumen
CF: Cl- is not reabsorbed, less Na+ reabsorbed to try to balance more negative charge in lumen, produces lots more NaCl in sweat
CF and airway epithelium
Normal: Cl- and Na+ both reabsorbed at mucosal surface, some NaCl formed in airway lumen
High-salt model: Cl- isn’t reabsorbed, Na+ reabsorption is reduced, more NaCl is formed in lumen, water should follow NaCl into airway lumen (like sweat gland)
Low-volume model: Cl- isn’t reabsorbed, but Na+ is reabsorbed much more (for some reason), other Cl- reabsorption pathways work harder, more NaCl forms in blood, water follows NaCl to blood
Cholera
Cause: bacteria that produces toxin that crosses intestinal epithelium (A1 subunit gets into cytoplasm, activates adenylate cyclase all the time –> cAMP –> activates all ion transport systems –> causes electrolyte imbalance –> water follows ions
Signs/symptoms: diarrhea
Treatment: CF reduces water loss
Arsenic Poisoning (arsenate)
Symptoms: headaches, confusion, diarrhea, drowsiness, lactic acidosis eventually leading to convulsions, hair loss, blood in urine, cramping muscles
Cause: Arsenate (structural analog of phosphate) binds glyceraldehyde-3-phos, prevents formation of 1,3-bisphosphate by glyceraldehyde-3-phosphate dehydrogenase, forms 3-phosphoglycerate by hydrolysis w/o producing ATP; occurs in glycolysis; occurs in tissues that rely on glycolysis (RBCs, brain)
Treatment: chelation to remove As, K+ supplement to decrease risk of heart problems
Pyruvate Kinase Deficiency
Symptoms: Chronic anemia (b/c of affected RBCs), splenic hemolysis (lack of ATP causes cellular swelling)
Cause: Mutations in enzyme lead to loss of activity, expression, or stability of pyruvate kinase, which prevents formation of pyruvate from phosphoenol-pyruvate; occurs in last step of glycolysis; occurs in RBCs (explode)
Treatment: splenectomy, blood transfusions, iron chelation, gene therapy
Lactic acidosis
Symptoms: nausea, vomiting, hyperventilation, abdominal pain, lethargy, anxiety, anemia, hypotension, tachycardia
Cause: Under anaerobic conditions pyruvate accumulates, cant enter TCA cycle –> forms excess lactate –> acidosis; occurs in glycolysis; occurs in tissues
Arsenic poisoning (arsenite)
Symptoms: Headaches, confusion, diarrhea, drowsiness, lactic acidosis eventually leading to convulsions, hair loss, blood in urine, cramping muscles
Cause: Arsenite binds to lipoate cofactor and inhibits pyruvate dehydrogenase –> prevents conversion of pyruvate to acetyl CoA before TCA cycle; occurs in glycolysis; occurs in tissues that rely on glycolysis (brain, RBCs)
Treatment: chelation to remove As, K+ supplement to decrease risk of heart problems
Pyruvate Dehydrogenase deficiency
Symptoms: lactic acidosis at birth (neonatal death with metabolic form, psychomotor retardation with chronic neurological form)
Cause: X-linked, mutations in PDH limits conversion of pyruvate to acetyl CoA, accumulation of lactate, reduction of ATP, neuro symptoms b/c brain depends on glucose ox; occurs entering TCA cycle; occurs in tissues
Treatment: high fat/low carb diet (ketogenic), thiamin supplement
Pyruvate Carboxylase Deficiency
Symptoms: buildup of pyruvate, lactic acidosis, hypoglycemia (lack of gluconeogenesis b/c of less oxaloacetate), neurological dysfunction (affects myelin sheath and NTs), developmental delay (different types w/ different severities)
Causes: mutations in enzyme lead to loss of activity, expression, or stability of PC. which prevents formation of oxaloacetate from pyruvate and acetyl CoA for gluconeogenesis; occurs exiting TCA cycle; occurs in tissues
Treatment: none, avoid fasting, implement high carb/high protein diet (prevent activation of gluconeogenesis), add biotin cofactor to increase enzyme activity, hydration, citrate
Cyanide poisoning
Symptoms: hyperventilation from massive lactic acidosis
Causes: CN blocks ETC by binding Fe3+ in cytochrome oxidase (transporter) –> backs up e- flow and reduces ATP production
Treatment: nitrite oxidizes Hb to met-Hb (w/ Fe3+), which binds CN and removes it from cytochrome oxidase, rhodonase (liver) detoxifies CN from dietary sources or medicine
MELAS (mitochondrial encephalopathy)
Symptoms: progressive neurodegeneration
Causes: mutation in tRNA leucine; occurs in OxPhos (mitochondria)
Kearns-Sayre Syndrome
Symptoms: Late-onset ptosis (droopiness of body part), opthalmoplegia (weakness/paralysis of extraoccular muscles)
Causes: deletions of tRNA and OxPhos genes; occurs in OxPhos (mitochondria)
NARP (neurogenic weakness ataxia w/ retinitis pigmentosa)
Symptoms: sensory neuropathy, ataxia, blindness, dementia
Causes: mutated ATP6; occurs in OxPhos (mitochondria)
