Diseases & Drugs Flashcards
- Severe motor and cognitive retardation
- Corneal clouding
- skeletal abnormalities, hepatosplenomegaly
- TEM reveals many cytoplasmic vacuoles “inclusion bodies” positive stain with Sudan Black B (lipids) and PAS (glycogen)
- increased levels of lysosomal enzymes in plasma
- mutation in cis-Golgi located GlcNAc phosphotransferase -> absence of mannose 6-phosphate tag over enzymes targeted to lysosomes
I-Cell Disease
- Hemoglobinuria
- Defect in GPI anchors leading to improper anchoring of DAF and CD59
- Diagnosis by Ham’s test: defective RBCs lyse at pH6.2 but not normal RBCs
- mutation in PIG-A gene
Paroxysmal Nocturnal Hemoglobinuria
- x-linked recessive
- iduronate sulfatase (I2S) deficiency
- symptoms similar to hurler syndrome but no corneal clouding
- physical deformity and mental retardation can be mild to severe, Mongolian blue spots and popular rash
- degradation of Heparan Sulfate and dermatan sulfate,, so they accumulate
Hunter Syndrome
- autosomal recessive
- alpha-L-iduronidase deficiency
- Symptoms include: corneal clouding, coarse facies, skeletal abnormalities, otitis media, heptosplenomegaly, progressive and profound mental retardation, cardiomyopathy
- Accumulation of Heparan Sulfate and dermatan sulfate
Hurler Syndrome
- developmental delay, severe mental retardation, hyperactivity, challenging behavior, sleep disturbance, loss of skills and slow deterioration into vegetative state
- defect in catabolism of heparin sulfate
- accumulation of heparin sulfate
Sanfilippo
- Deficiency of dipamitoyl lecithin (dipalmitoyl
- Lack of surfactant in alveoli of lungs
- Begins shortly after birth
- tachypnea, tachycardia, chest wall retractions, expiratory grunting, flaring of nostrils, cyanosis
Infant Respiratory Distress Syndrome
antiobesity drug that inhibits gastric and pancreatic lipase, thereby decreasing fat absorption
Orlistat
drug that reduces the absorption of cholesterol
Ezetimibe
- Presence of excess fat in feces
- Stools having oily appearance,diffucult to flush, foul smelling
- lack of bile acids (due to liver damage, cholecystectomy), defects in or deficiency of pancreatic enzymes, defective mucosal cells
Steatorrhoea
- inability to maintain an adequate blood glucose level
- doll-like face with fatty cheeks
- relatively thin extremities and short stature
- protuberant abdomen
- hepatomegaly, renalmegaly
- hepatocytes are distended by glycogen and fat
- large, prominent lipid vacuoles
- lactic acidosis
- ketoacidosis
- metabolic acidosis
- neutropenia
- hyperuricemia
- hyperlipidemia
- severe fasting hypoglycemia
- In GSD Ib: bleeding and infection risk from neutropenia and neutrophil dysfunction
Von Gierke’s Disease
- deficiency in glucose-6-phosphatase
- mutation of G6PC gene [GSD Ia] or gene for Tranlocase1 protein [GSD Ib]
Von Gierke’s Disease (the deficient enzyme)
converts glucose 6-phosphate to glucose
glucose 6-phosphatase
- accumulation of glycogen in lysosomes of muscle and other cells
- floppy baby
- frog-like position of legs
- difficulty sucking/swallowing
- failure to meet developmental milestones (rolling over, sitting up, crawling, etc)
- severe cardiomegaly-> heart failure
- weak diaphragm -> difficulty breathing
- respiratory failure -> ventilator
- digestion problems
- PAS positive stain in muscle biopsy
Pompe’s Disease
- mutation in GAA gene (acid alpha glucosidase)
- deficiency of lysosomal acid alpha-1,4 glucosidase or acid alpha-1,6 glucosidase or both (acid maltase)
Pompe’s Disease (the deficient enzyme)
- Exercise intolerance: brief intense activity, less intense sustained activity
- Muscle cramps
- Myoglobinuria after exercise, can lead to acute renal failure
- Elevated serum creatine kinase 3 (CK-MM) at rest, increases after exercise
- Increased levels of blood ammonia, inosine, hypoxanthine, and uric acid
- Diagnosis by Ischemic exercise test: squeeze rubber ball with BP cuff tied to the arm (lack of increase in blood lactate and exaggerated blood ammonia elevations suggest defect in conversion of glycogen or glucose to lactate
McArdle’s Disease
- Ashkenazi Jews and Japanese population
- similar symptoms of McArdle’s disease
- hemolysis
- increased bilirubin levels
- jaundice
Tarui’s Disease
- accumulation of glycogen with long outer branches with very few branch points
- Failure to thrive
- hypotonia
- hepatomegaly
- splenomegaly
- progressive liver cirrhosis and failure
Anderson Disease
- deficiency or defect in branching enzyme
- 4,4-transferase
Anderson Disease (the deficient enzyme)
- accumulation of glycogen with short outer branches
- hepatomegaly
- growth retardation
- muscle weakness
- hypoglycemia
Cori/Forbes Disease
- deficiency or defect in debranching enzyme
- 4,6-transferase
Cori/Forbes Disease (the deficient enzyme)
- high glycogen content in liver
- tendency toward hypoglycemia
Hers’ Disease
- liver glycogen phosphorylase deficiency
Hers’ Disease (deficient enzyme)
inhibits HMG CoA reductase decreasing FPP thereby decreasing CoQ biosynthesis
Statin Drugs
Binds to F0 subunit and inhibits flow of protons into matrix
Oligomycin
- Poison that inhibits all enzymes requiring lipoic acid as coenzyme (E2 of PDC) leading to inefficient conversion of pyruvate to acetyl CoA causing accumulation of pyruvate and lactic acid
- Competes with Pi for ATP synthase
Arsenic
- Congenital lactic acidosis
- Neurodegeneration, muscle spasticity, early death
- X-linked
Pyruvate Dehydrogenase Deficiency
- Defect in mitochondrial ATP production
- Mutations in PDC, ETC, or ATP synthase
Leigh Syndrome
Condenses with oxaloacetate to form fluorocitrate and inhibit aconitase
Rat Poison (Fluoroacetate)
Inhibits ETC by inhibiting adenine nucleotide translocase (transport of ADP into and ATP out of mitochondria)
Atractyloside
Uncoupling agent
Dinitrophenol
Odorless chemical used in broad-spectrum insectide that inhibits transfer of electrons from clomplex I to Q
Rotenone
Inhibits Complex III
Antimycin A
- binds irreversibly to complex IV
- sources are from burning polyurethane and nitroprusside
- treated by nitrites if given rapidly
Cyanide
- binds to complex IV less tightly that cyanide
- Headache, nausea, tachycardia, tachypnea, cherry red lips and cheeks (carboxyhemoglobin)
- Sources are propane, vehicle exhaust, tobacco smoke, house fires, paint strippers
Carbon Monoxide
Binds to Coenzyme Q
Doxorubicin
- X-linked recessive
- Generally asymptomatic unless triggered by drugs increasing ROS (anti-malarial drugs)
- NADPH not synthesized
- Heinz bodies, hemolytic anemia
G6PDH (Glucose 6-Phosphate Dehydrogenase) Deficiency
- Fructose in urine
- asymptomatic
- fructokinase deficiency
Essential Fructosuria
- Symptoms appear when fruit juices are first introduced
- hypoglycemia, hyperuricemia, lactic acidosis
- deficiency of aldolase B
Hereditary Fructose Intolerance (HFI)
- Galactosemia, galactosuria, cataracts
- Deficiency of galactokinase
Non Classical Galactosemia
- Galactosemia, galactosuria, cataracts, hyperbilirubinemia, jaundice, mental retardation
- deficiency of galactose 1-phosphate uridyl transferase (GALT)
Classical Galactosemia
inhibits aldehyde dehydrogenase enzyme in alcohol metabolism
Disulfiram
- defect or deficiency of phosphofructokinase in the muscle and erythrocytes
Tarui’s Disease (Deficient enzyme)
- deficiency of muscle phosphorylase (glycogen phosphorylase)
McArdle’s Syndrome (Deficient enzyme)
- defect in sialidase enzyme responsible for removal of sialic acid in glycoproteins
- sialic acid accumulates in neurons, bone marrow, and various cells
- coarse facial features: flat nasal bridge, puffy eyelids, enlarged gums and tongue
- hypotonia,
Mucolipidosis Type 1 (sialidosis)
