Exam 2 Diseases/Drugs

Question 1

Lebers hereditary optic neuropathy

Answer 1

Caused by mutations in one of the genes in mitochondrial DNA; affects oxidative phosphorylation; leads to rapid occurrence of blindness

Question 2

Leigh syndrome

Answer 2

Sub-par utilization of oxygen due to some defect in pathways of oxidative phosphorylation; get lactic acidosis

Question 3

What results from mutation in isocitrate dehydrogenase?

Answer 3

Get formation of 2-hydroxyglutarate (2HG) instead of alpha-ketoglutarate. 2 HG competitively inhibits a-ketoglutarate-dependent dioxygenases (which have important role in demethylation reactions for histones and DNA); leads to hypermethylation in glioma and acute myelocytic leukemia

Question 4

How does low levels of fumarate in some kidney tumors contribute to the condition?

Answer 4

There are low levels of fumarase, so metabolic shift to aerobic glycolysis in cancer cells due to decreased TCA cycle.

Question 5

Chronic granulomatous disease (CGD)

Answer 5

Rare genetic disorder caused by defective gene for one of the subunits of NADPH oxidase. People w/ CGD have difficulty ridding themselves of bacterial infection, especially those caused by bacteria that produce catalase to protect themselves against the hydrogen peroxide generated by the macrophages and neutrophils that engulf them.
Often results in granuloma (a persisting nest of infected cells)
One of the genes for an NADPH oxidase subunit that is most frequently mutated in CGD is on the X chromosome

Question 6

Amyotrophic Lateral Sclerosis (ALS)

Answer 6

A fatal neurodegenerative disorder that affects the motor neurons. Can be familial (fALS) or sporadic (sALS). Is a protein misfolding disease in which there is protein aggregation. In 20% of fALS cases, there are mutations in the SOD1 gene, whose product is CuZnSOD. Can have problems with metal binding ligands or regions associated w/ metal binding. SOD1 mutations are autosomal dominant in fALS.

Question 7

Why is there tendency to develop hemolytic anemia when there is glucose-6-phosphate dehydrogenase deficiency?

Answer 7

Pentose phosphate pathway is the only source of NADPH for RBCs. NADPH is used to keep glutathione reduced. With low concentrations of reduced glutathione, RBC is more sensitive to oxidative stress. A lot of drugs present oxidative stress to cells. There is a tendency to develop hemolytic anemia. The gene for G6-P dehydrogenase is on X chromosome.

Question 8

Essential fructosuria

Answer 8

Caused by lack of fructokinase (which converts fructose to fructose 1-phosphate so it can be acted on by aldolase B to form DHAP and glyceraldehyde)
Relatively harmless; will have elevated blood fructose levels and fructose will be excreted in the urine

Question 9

Hereditary fructose intolerance (HFI)

Answer 9

Caused by deficiency of aldolase B. Fructose 1-P gets trapped intracellularly since it doesn’t get across cell membranes very well. There is a resulting drop in Pi and therefore ATP levels drop, which affects gluconeogenesis and results in hypoglycemia with vomiting. Also have hyperuricemia, liver damage, GI troubles, etc. Treatment is to omit fructose and sucrose (one of this disaccharide’s units is fructose) from diet

Question 10

Classic galactosemia

Answer 10

Uridyltransferase deficiency
Autosomal recessive
Treated by removal of galactose (and therefore lactose) from diet
Get accumulation of galactose 1-P which is shuttled into a side pathway; get more galactitol which causes cataracts
Also get more serious symptoms such as serious liver problems and mental retardation

Question 11

Galactokinase deficiency

Answer 11

Caused by deficiency in galactokinase

Causes galactosemia and galactosuria

Question 12

Aldose reductase deficiency

Answer 12

Caused by deficiency in aldose reductase, which produces galactitol from galactose; physiologically unimportant unless galactose levels are high (as in galactosemia)

Question 13

What are the names of the glycogen storage diseases?

Answer 13

Type I - Von Gierke
Type II - Pompe
Type III - Cori
Type IV - Andersen
Type V - McArdle
Type VI - Hers Disease
Type IX

Question 14

What are the enzymes affected by the glycogen storage diseases?

Answer 14

Type I - Von Gierke (glucose 6-phosphatase)
Type II - Pompe (lysosomal alpha glucosidase)
Type III - Cori (glycogen debranching enzyme)
Type IV - Andersen (glycogen branching enzyme)
Type V - McArdle (muscle glycogen phosphorylase)
Type VI - Hers (liver glycogen phosphorylase)
Type IX - liver glycogen phosphorylase kinase

Question 15

Von Gierke Disease

Answer 15

Glycogen storage disease that affects glucose-6-phosphatase
Organs involved: liver, kidney
Characteristics: hypoglycemia, enlarged liver, lactic acidosis, ketosis
High levels of G6-P activate glycogen synthase b, the normally inactive form
Get accumulation of glycogen
Type IB is G6P translocase deficiency

Question 16

Pompe Disease

Answer 16

Glycogen disease that affects lysosomal alpha glucosidase
Glycogen structure: normal
Organs involved: generalized
Characteristics: enlarged heart, cardiorespiratory failure
Causes accumulation of glycogen in lysosomes
Organ affected that leads to death is heart

Question 17

Cori Disease

Answer 17

Glycogen storage disease that affects glycogen debranching enzyme
Glycogen structure: short outer chains on fasting (b/c only glycogen phosphorylase can function and it will only get so far)
So, get limited glycogen breakdown
Organs involved: generalized
Characteristics: enlarged liver, moderate hypoglycemia, acidosis
Symptoms are like a milder Type I

Question 18

Andersen Disease

Answer 18

Glycogen storage disease that affect glycogen branching enzyme.
Glycogen structure: few branch points
Organs involved: generalized
Characteristics: cirrhosis, progressive liver failure

Question 19

McArdle Disease

Answer 19

Glycogen storage disease that affects muscle glycogen phosphorylase
Glycogen structure: normal
Organs involved: skeletal muscle
Characteristics: muscle cramps on exercise

Question 20

Hers Disease

Answer 20

Glycogen storage disease that affects liver glycogen phosphorylase
Glycogen structure: normal
Organs involved: liver
Characteristics: enlarged liver, moderate hypoglycemia, mild acidosis (like milder Type I)

Question 21

Type IX

Answer 21

Enzyme defect: liver glycogen phosphorylase kinase
Glycogen structure: normal
Organs involved: liver
Deficiency said to be X-linked recessive
Enzyme has multiple subunits, each coded by a different gene
Some of these genes are X-linked, but at least one isn’t

Question 22

I-Cell Disease

Answer 22

Results from an enzyme deficiency such that lysosomal enzymes do not acquire the targeting signal, mannose-6-phosphate
Fibroblasts in this disease have dense inclusion bodies (I-cells) that are deficient in many lysosomal enzymes
Lysosomes become engorged w/ indigestible structures, leading to death in infancy
Have abnormalities in joints, mental retardation, enlarged liver, heart problems, etc.

Question 23

Mucopolysaccharidoses (MPS)

Answer 23

A series of hereditary diseases resulting from mutations in genes coding for degradative enzymes acting on glycosaminoglycan (mucopolysaccharides)
Enzymes are almost all hydrolases and deficiency leads to mental retardation and/or structural deformities
Have an autosomal recessive inheritance (w/ exception of X-linked Hunter Syndrome). In general, heparan sulfate accumulation seems to lead to mental retardation.

Question 24

Hurler’s Disease

Answer 24

Type I MPS due to deficiency in α-L-irudonidase
Degradation of dermatan sulfate and heparan sulfate are affected
Accumulation of dermatan sulfate and heparan sulfate
There is corneal clouding, mental retardation, dwarfing, dysmorphic facial features, upper airway obstruction and hearing loss

Question 25

Hunter Syndrome

Answer 25

Type II MPS due to deficiency of iduronate sulfatase No corneal clouding, but mild to severe mental retardation and physical deformity There is defect in removal of sulfate group (last to be added, first to be removed) Degradation of dermatan sulfate and heparan sulfate are affected

Question 26

Sanfilippo Syndrome

Answer 26

Type III MPS that has locus heterogeneity (multiple gene changes can give rise to same set of symptoms) Deficiency in one of the 4 degradative enzymes 4 enzymatic steps are necessary for removal of N-sulfated or N-acetylated glucosamine residues from heparan sulfate Severe mental retardation but little structural change

Question 27

Morquio Syndrome

Answer 27

Type IV MPS due to deficiency of a galactose-6-sulfatase or β-galactosidase Leads to accumulation of keratan sulfate Normal intelligence but severe deformation

Question 28

What drugs inhibit pancreatic lipase?

Answer 28

Orlistat and Alii inhibit pancreatic lipase, preventing triglyceride absorption and digestion

Question 29

What drug reduces triglycerides by inhibiting DGAT (AcylCoA: 1,2-diacylglycerol acyltransferase)?

Answer 29

Lovaza. DGAT typically re-converts fatty acids and diacylglycerols into triacylglycerides once they pass through the gut lumen are in the enterocytes

Question 30

What does metformin do?

Answer 30

It is used to treat diabetes. It is an activator of AMPK (AMP-activated protein kinase). This is kind of odd since AMPK inhibits insulin secretion in the pancreas. However, might work not by increasing insulin secretion but by making pt more sensitive to whatever insulin is already present

Question 31

Medium chain acyl CoA dehydrogenase deficiency (MCADD)

Answer 31

Deficiency in enzyme in first oxidative step in breakdown of medium chain fatty acids Autosomal recessive disorder Get accumulation of medium chain fatty acids in the liver Symptoms in early childhood: lethargy, vomiting, hypoketosis, hypoglycemia, liver dysfunction

Question 32

Lipodystrophy

Answer 32

Rare disorder Don't gain weight but have conditions associated w/ obesity (Type II diabetes, high triglycerides, fatty liver, etc.) Have severely reduced leptin production Found that adipose tissue is like an organ Normal people want to store fat in adipose tissues (fat cells get large but # of cells stays the same) If there is no fat tissue to go to, fat is stored in other organs (liver, heart, muscles, pancreas) Visceral fat is that which blocks up organs, leading to organ failure or dysfunction

Question 33

Metabolic syndrome

Answer 33

If there is nowhere to store fat, it goes to other organs Clinical profile of someone w/ metabolic syndrome: large waistline since fat is probably surrounding organs Syndrome has many symptoms: stressing out of vasculature

Question 34

Statins

Answer 34

Competitively inhibit HMGR (HMG CoA reductase) from cholesterol synthesis by mimicking the transient intermediate mevaldyl CoA

Question 35

Ezetimibe

Answer 35

(Zeta) Inhibits cholesterol uptake in the gut; work at small intestine brush border; doesn't enter bloodstream

Question 36

Vytorin

Answer 36

Ezetimibe + simvastatin

Question 37

Clinical manifestations of hyperlipidemia linked to elevated plasma chylomicrons and/or LDL

Answer 37

Cutaneous xanthomas, lipemic plasma, lipemia retinalis (veins and arteries of the eye have milky appearance due to amount of fat in blood), tuberous xanthomas, palmar crease xanthomas

Question 38

Familial hypercholesterolemia (FH)

Answer 38

Autosomal dominant disorder Caused by mutations in the gene encoding the LDL receptor (also known as apoB100/apoE receptor) When LDL receptor functions normally, LDL particles are taken up by the cells, leading to increased intracellular cholesterol levels and inhibition of cholesterol synthesis When intracellular cholesterol is high, expression of cholesterol synthesis genes is blocked HMGR can be down-regulated transcriptionally or by phosphorylation by AMPK or by degradation

Question 39

What are the classes of LDL receptor mutations?

Answer 39

Class 1: no receptors synthesized; mutations in LDLR promoter, frameshift or splicing mutations Class 2: receptors are synthesized, but retained intracellularly in the ER or golgi complex; such as if not folded properly and doesn't make it out of the cell because of this Class 3: receptors reach the cell surface but lack normal LDL binding Class 4: receptors reach the cells surface and bind LDL but are not clustered in coated pits and endocytosed; they are bound and frozen at cell surface

Question 40

Anti-PCSK9 antibody

Answer 40

PCSK9 is a normal human proteins that binds LDL receptor and stimulates receptor endocytosis; endosomes containing the receptor fuse w/ lysosomes, resulting in degradation of receptor in lysosomes; thus, get less LDL receptor Anti-PCSK9 antibodies bind PCSK9 and prevent its interaction w/ LDLR Increases the surface presence of LDLR, so it can bind LDL particles and bring them into the cell

Question 41

Bile acid sequestrants

Answer 41

Block reabsorption of bile acids in the gut, thus leading to bile acid excretion in the feces and cholesterol is eliminated

Question 42

Lopitamide

Answer 42

Inhibits microsomal triglyceride transfer protein (MTP or MTTP), which is necessary for the assembly and secretion of chylomicrons and VLDL assembly and secretion in the liver

Question 43

Tay-Sachs Disease

Answer 43

``` A sphingolipidoses Accumulation of gangliosides Deficiency of β-hexosaminidase A Rapid and progressive neurodegeneration Cherry-red macula, muscular weakness, seizures ```

Question 44

Gaucher Disease

Answer 44

Autosomal inheritance of gene for glucoceribrosidase that is encoded on chromosome 1 Treated by injection of glucocererbrosidase There is accumulation of glucocerebrosides that causes multiple problems, but no neurological degeneration

Question 45

Farber Disease

Answer 45

Accumulation of cerramide Painful and progressive joint deformity Hoarse cry Tissues show granulomas

Question 46

Nemann-Pick Disease

Answer 46

Accumulation of sphingomyelin Hepatosplenomegaly Neurodegenerative course

Question 47

NSAIDs

Answer 47

Non-steroidal anti-inflammatory drugs Inhibit COX enzymes Reduce production of prostaglandins and thromboxanes Reduce pain, fever, and inflammation Side effects: GI irritation, ulcers, bleeding, etc. (since COX-1 helps create GI lining)

Question 48

Aspirin

Answer 48

Works on both COX-1 and COX-2 to inhibit arachidonic acid's entry into the active site of the enzyme Acetyl group of aspirin binds to serine in COX By blocking activity of the COX enzymes, relieves some of the effects of pain and fever Non-selective Many side effects

Question 49

Reyes Syndrome

Answer 49

Swelling of brain and possible death when kids are given baby aspirin

Question 50

Tylenol

Answer 50

Thought to work by inhibiting activity of COX-3, an alternatively spliced form of COX-1

Question 51

Low dose aspirin therapy

Answer 51

Aspirin irreversibly inhibits COX 1 and 2 Has a short half-life New platelets are constantly being made Will therefore reduce but not abolish the ability for blood to clot, thereby reducing heart attacks and strokes

Question 52

Coxibs

Answer 52

COX 2 inhibitors There is a valine at position of 523 in COX-2 instead of isoleucine in COX-1 This leads to a side pocket in COX 2; they developed molecules that could bind to side pocket in COX-2 and prevent entry of arachnoid acid into the active site Found that these COX-2 inhibitors are good for treating osteoarthritis and rheumatoid arthritis, but show an increase in risk for heart attack and stroke

Question 53

Cystinuria

Answer 53

There are 7 aa transporters that exist and are used in aa uptake in the gut and re-uptake in the proximal convoluted tubule In cystinuria, transporter for cysteine, ornithine, arginine and lyseine is defective and all 4 aa's appear in the urine since they are aren't reabsorbed in the proximal convoluted tubule Cysteine precipitates in the acidic urine, forming stone (calculi) since it's not soluble in acidic pH of urine This is a recessive genetic condition

Question 54

Kwarshiarkor

Answer 54

Prevalent in western Africa more than U.S. Caused by protein malnutrition due to very protein-deficient diet Failure to gain weight and swollen abdomen are characteristic Can treat it w/ re-introduction of proteins

Question 55

Parkinson Disease

Answer 55

Caused by degeneration of dopamine neurons in the substantia nigra pars compacta Symptoms: Paucity of spontaneous movement, tremor at rest, muscle rigidity, shuffling gait, etc. Oral administration of L-DOPA found to be beneficial, but effects diminish after 5 years

Question 56

MAO Inhibitors

Answer 56

The first anti-depressants | MAO inhibitors block degradation of catecholamines (epinephrine, norepinephrine, dopamine)

Question 57

Fluoxetine

Answer 57

(Prozac) Blocks reuptake of serotonin Serotonin is typically degraded by MAO

Question 58

Phenylketonuria (PKU)

Answer 58

Caused by partial or substantial defect in phenylalanine hydroxylase, resulting in elevated levels of phenylalanine in blood and urine Symptoms: hypopigmentation (due to inhibition of tyrosinase essential for melanin formation), CNS symptoms (intellectual disability, developmental delay, seizures) Treatment is diet deficient in phenylalanine Can also be caused by deficiencies in any of the several enzymes required to synthesize BH4 or in dihydropteridine reductase, which regenerates BH4 from BH2

Question 59

Maple syrup urine disease (MSUD)

Answer 59

Autosomal recessive Partial or complete deficiency in mitochondrial branched chain alpha-keto acid dehydrogenase, that oxidatively decarboxylates Leu, Ile, and Val (branched chain amino acids, BCAAs) These BCAAs and their corresponding alpha-keto acids accumulate in blood, causing interference w/ brain functions Characteristic maple syrup odor in urine due to rise in Ile Treatment: synthetic formula free of BCAA's supplemented w/ limited amounts of Leu, Ile, and Val to allow normal growth and development w/o producing toxic levels

Question 60

Albinism

Answer 60

Autosomal recessive Results from defective copper-requiring tyrosinase activity White skin, pink eyes, hypopigmented pale skin, sensitive to sunlight Treatment is protection from UV exposure Arises from deficiency in enzyme tyrosinase, which metabolizes tyrosine to form melanin

Question 61

Malignant melanoma

Answer 61

Most serious form of skin cancer Due to abnormal growth of melanocytes in the skin, caused by mutations in protein kinase called BRAF, which is involved in the proliferative pathway Most pts w/ malignant melanoma have glutamic acid instead of valine at 600 position of BRAF This causes the pathway to be super-activated; get tumor cell growth

Question 62

Sabfrafenib

Answer 62

Prevents activation of MEK by BRAF

Question 63

Trametinib

Answer 63

Prevents activation of ERK by MEK

Question 64

Homocystinuria

Answer 64

Group of rare disorders involving defects in metabolism of homocysteine Characterized by high plasma and urinary levels of homocysteine and methionine Patients exhibit lens dislocation, skeletal abnormalities (long limbs and fingers), intellectual disability, increased risk for developing blood clots; there is association b/w cardiovascular disease mortality and total plasma Hcy Treatment includes restriction of methionine and supplementation w/ vitamins B6, B12, and folate

Question 65

Alkaptonuria

Answer 65

Rare, non-fatal metabolic condition involving deficiency in homogentisic acid oxidase, resulting in accumulation of homogentistic acid 3 characteristic symptoms: homogentistic aciduria (urine becomes dark upon standing), large joint arthritis that can be severely crippling, deposition of black pigment in cartilage and collagenous tissue Diets low in Phe and Tyr reduce the levels of HA and decrease the amount of pigment deposited in body tissues

Question 66

Erectile dysfunction treatment

Answer 66

NO acts by stimulating guanylate cyclase in vascular smooth muscle. Erectile dysfunction is treated by Viagra and related drugs that inhibit phosphodiesterase-5, a cGMP-specific phosphodiesterase that is responsible for the degradation of cGMP in the vascular smooth muscle of the penis

Question 67

What does gout occur due to?

Answer 67

Hyperuricemia due to decreased uric acid excretion or increased uric acid production Due to lost regulation of PRPP synthase and PRPP amidotransferase or defects in salvage pathway leading to increased PRPP and guanine

Question 68

Allopurinol

Answer 68

Drug used to treat gout; is an xanthine oxidase suicide inhibitor; decreases urate, increases xanthine and hypoxanthine, decreases PRPP

Question 69

Lesch-Nyhan Syndrome

Answer 69

X-linked recessive Severe HGPRT deficiency: decreased IMP and GMP, increased PRPP and de novo purine pathway Hyperuremia, gouty arthritis, kidney stones, tophi Neurological disability: spasticity, hyperflexxia, Behavioral problems: cognitive dysfunction, agression, self-injury

Question 70

SCID

Answer 70

Severe combined immunodeficiency syndrome Autosomal recessive disorder Mutations in ADA (adenosine deaminase) Infants subject to bacterial, candidiasis, viral, protazoal infections Both T and B cells reduced (dATP is toxic) Cloned ADA into an adenovirus vector: successful gene therapy