week 5

Question 1

Defect in N-acetylglutamate synthase

Answer 1

unable to make N-acetylglutamate, lack activation of CPS-1, so urea cycle isn’t sped up; elevated ammonia in blood and urine, similar symptoms to CPS-1 deficiency

Question 2

Defect in CPS-1

Answer 2

unable to make carbamoyl phosphate needed for urea cycle; elevated ammonia in blood and urine, no accumulation of urea cycle intermediates; low protein diet, arg supplementation, treatment to reduce ammonia levels (agents that remove glycine or glutamine from the system)

Question 3

Defect in ornithine transcarbamoylase

Answer 3

most common urea cycle defect, X linked disease; hyperammonemia with orotic aciduria (high levels orotic acid)- precursor of pyrimidine synthesis, leads to buildup of carbomoyl-P in mito which diffuses into cytosol and stimulates pyrimidine synthesis

Question 4

Defect in argininosuccinate synthetase

Answer 4

hyperammonemia, orotic aciduria to smaller extent, too much hypercitrullinemia (citrulline has no where else to go); hypercitrullinemia type I

Question 5

Defect in argininosuccinate lyase

Answer 5

moderate hyperammonia with elevated levels of argininosuccinate

Question 6

Defect in arginase

Answer 6

elevated arginine in blood, ammonia slightly elevated

Question 7

treatments for urea cycle disorders

Answer 7

agents that conjugate with nitrogen containing compounds that will remove them from circulation; Benzoic acid- conjugates with glycine to form hippuric acid which is excreted; Phenylacetate- conjugates with glutamine to form phylacetylglutamine which is excreted; removing Gln means less chance of making ammonia

Question 8

Hypercitrullinemia type II

Answer 8

citrin deficiency, protein that takes Asp out of mito in exchange for Glu in the cytoplasm; need Asp as a substrate, so citrulline can accumulate and so can ammonia; avoid carbs (otherwise NADPH will build up) and eat high protein, high fat diet

Question 9

Cystinuria

Answer 9

defect in transport of Cystine, Lys, Arg, orthinine (dibasic amino acids), problems in kidney and intestines- poor absorption of these amino acids from gut and poor reabsorption from glomerular filtrate; Cystine (2 Cys connected via disulfide) accumulates in urine (cant be reabsorbed)- can precipitate and lead to kidney stones; drink lots of water for treatment; auto recessive

Question 10

Hartnut disease

Answer 10

defect in transport of neutral amino acids (Ile, leu, phe, thr, trp, val), affects intestines and kidney; can be overcome by dipeptide transport systems; Trp deficiency is main problem because leads to trouble making NAD (if niacin is low); get pellagra symptoms; treatment is Trp and niacin supplementation, auto recessive

Question 11

Cystinosis

Answer 11

lysosomal storage disease; can’t transport cystine out of lysosome; can lead to end stage kidney disease; treat with cysteamine which can break the cystines apart into products that can leave the lysosome

Question 12

Rapamycin

Answer 12

drug that acts on mTOR, which is activated by AKT as part of the Ras pathway; mTOR is a surveillance center that assesses the cell nutrient status and simulates protein synthesis

Question 13

ABL gene

Answer 13

non receptor tyrosine kinase, in leukemia (blood cancer), it becomes translocated and fuses to the BCR gene, which is constitutively active; Gleevac drug inhibits the action of the oncogene Abl-BCR product

Question 14

Polycythemia vera

Answer 14

too many RBCs are made, another blood cancer; mutation usually in the JAK-STAT pathway (erythropoitin released from kidney binds JAK-STAT receptor) stimulating increased RBCs: Jakafi drug inhibits action of JAK

Question 15

Protease inhibitors

Answer 15

inhibit degradation of proteins; useful for patients with multiple myeloma (Velcade-bortezimab); less degradation of excess antibody caused tumor cells to die from toxic buildup of proteins; also TF inhibitor doesn’t get broken down so growth factor genes aren’t transcribed- harmful for cancer cell growth

Question 16

Leukocyte Adhesion Deficiency (LAD-1)

Answer 16

failure of leukocytes to migrate to infection site, due to CD18 deficiency (Type I), CD18 is beta subunit of LAF1 integrin, which is an adhesion molecule in blood vessels that directs leukocyte migration out of vessel (diapedesis) to the infection site; mutation leads to impaired wound healing because immune cells are not directed to the infection site

Question 17

Chronic Granulamatous Disease

Answer 17

X linked condition where you have a mutation in phagocyte oxidase, which is necessary to kill bacteria through production of ROS; phagocytes still engulf microbes but are unable to kill, leading to granuloma formation because immune system tries to contain infection by surrounding with layer of cells

Question 18

Drugs that inhibit microtubules

Answer 18

Colchicine- binds tubulin and prevents polymerization, used to treat gout; Toxol- binds microtubules and prevents depolymerization, chemo drug; Vinblastine- binds microtubules and prevents formation of mitotic spindle, chemo drug

Question 19

Primary Ciliary Dyskinesia

Answer 19

loss of inner or outer dynein arms of cilia leads to impaired ciliary motility; leads to male and female infertility

Question 20

Drugs that inhibit microfilaments

Answer 20

Cytochalosins: binds actin filaments and prevents polymerization; phalloidin: prevents depolymerization

Question 21

Epidermolytic bullosa simplex (EBS)

Answer 21

deficiency of keratins (intermediate filaments) leads to blistering disease of the skin

Question 22

Alcaptonuria

Answer 22

buildup of homogentisic acid, which oxidizes in air and turns black (black urine), may lead to arthritis

Question 23

Phenylketonuria (PKU)

Answer 23

Classical: missing Phe hydroxylase; non-classical: missing tetrahydrobiopterin; leads to buildup of phenylpyruvate, phenyllactactate, phenylalanine; treatable with restricted Phe diet; if non-classical also need to supplement with THB, DOPA, 5-hydroxytryptophan

Question 24

Tyrosinemia Type 1

Answer 24

lack of fumarlyacetoacetate hydrolase, leads to accumulation of succinylacetone and succinylacetate, leads to oxidative damage of liver and kidney; treat with low Phe and Tyr diet, nitisinone drug which blocks formation of homogentisic acid

Question 25

Tryosemia Type 2

Answer 25

defect in tyrosine aminotransferase; leads to skin and eye lesions, neuro problems; low Phe and Tyr diet

Question 26

Homocysteinemia/uria

Answer 26

high levels of homocysteine and methionine in blood and urine; most commonly due to mutation in cystathione synthase- B6 supplement may help if reduced binding of enzyme to B6; also could be caused by B12 deficiency or mutation of methionine synthase, mutation to N5N10 methylene THF reductase (makes N5 methyl THF); homocysteine inhibits endothelial cell growth and promotes smooth muscle proliferation, leading to atherosclerosis; also blocks coagulation cascade inhibitor leading to clots; treatment: B12, folate, B6

Question 27

Maple Syrup Urine Disease

Answer 27

lack the branched chain alpha keto acid dehydrogenase; leads to ketoacidosis and mental retardation; B1 may help (needed for oxidative decarboxylations), dietary restriction of branched chain amino acids

Question 28

Nonketotic hyperglycinemia

Answer 28

defect in glycine cleavage enzyme leads to buildup of glycine which is transaminated to make oxalate, insoluble- crystalizes as kidney stones; neonatal encephalopathy is most severe form- gly is NT and accumulates in brain

Question 29

primary oxaluria type I

Answer 29

lack of glycine transaminase in the peroxisome

Question 30

Porphyrias

Answer 30

defect in heme biosynthesis leading to accumulations in the pathway; if precursor has conjugated double bonds, exposure to UV light forms radical intermediates and skin damage