week 2

Question 1

Thalassemia

Answer 1

autosomal recessive; caused by many types of genetic mutations that lead to common outcome- reduced or elimination of globin proteins, leading to loss of oxygen carrying capacity and aggregation of remaining globin chains, causing RBC destruction; major type called Cooley’s Anemia is complete absence of beta globin- serious side effects; minor form is reduced amounts of beta globin, no symptoms unless high altitude or exertions; disease can be caused by mutation in splice junctions; mutation in invariant sequence results in NO splicing- major form, may result in use of cryptic splice junction in middle of intron- non-functional protein; mutation in consensus sequence leads to reduced splicing, milder outcome

Question 2

Shiga toxin

Answer 2

found in certain E coli strains; contains RNA glycosidase activity and eliminates a critical A residue from the catalytic 28S rRNA in the large ribosomal unit, meaning that peptide bond formation can no longer occur-inhibits translation, causing human cell death

Question 3

Cholera and diptheria

Answer 3

target the eEF2 elongation factor, important for translocation of the ribosome, resulting in dead human cells

Question 4

sonic hedgehog disease

Answer 4

autosomal dominant preaxial polydactyly; single base change in an enhancer region drastically affects Tc of sonic hedgehog gene

Question 5

Sulfonylurea-based drugs (glipizide)

Answer 5

given to type II diabetics; they bind to and close the potassium channels on the beta cells in order to increase calcium influx and thus insulin release from the beta cells

Question 6

MODY: Maturity onset diabetes of the young

Answer 6

usually age 15-25; genetic mutation, may be in glucokinase which decreases its affinity for glucose (higher Km), leading to a higher threshold of glucose needed in order to enter the beta cell, produce ATP, and stimulate insulin release

Question 7

Lack of liver glycogen synthase

Answer 7

Type 0 Glycogen storage disease; unable to store glucose as glycogen, meaning don’t have stores to raise glucose when fasting; fasting hypoglycemia; hyperketonemia (high ketone bodies); hyperglycemia after eating due to inability to store excess glucose and lactic acidemia because the excess glucose will go through glycolysis; treatment: feed uncooked corn starch, which slowly releases glucose from digestive system

Question 8

Lack of glucose 6 phosphatase

Answer 8

GSD type 1, von Gierke disease; unable to release degraded glycogen or gluconeogenesis products into the blood, fasting hypoglycemia; hepatomegaly due to increased glycogen in liver (G6P activates glycogen synthase and inhibits phosphorylase, lactic acidosis- high G6P goes through glycolysis, small amount of glucose gets out through debranching enzyme; no ketone bodies formed because fatty acid synthesis is favored, leading to gout and hyperlipidemia

Question 9

Lack of lysosomal alpha-glucosidase activity

Answer 9

type 2 GSD, Pompe disease; used to cause death within 2 years; lysosomal storage disease- leads to inability to degrade glycogen and so glycogen builds up in the cell, impairing its ability to function; Lumizyme enzyme replacement therapy (has mannose-6-P tag)- effective for heart but not skeletal muscle

Question 10

lack of debranching enzyme

Answer 10

type 3 GSD, Cori disease; fasting hypoglycemia, hepatomegaly (can’t break down all glycogen), elevated glycogen levels with abnormal structure (limit dextrins), inflamed liver

Question 11

Lack of branching enzyme

Answer 11

type IV GSD, Anderson disease; fatal disease, low levels of non-branched, insoluble glycogen, cirrhosis (scarring of the liver), needs liver transplant

Question 12

lack of muscle phosphorylase

Answer 12

type V GSD, McArdle disease; inability to use muscle glycogen as an energy source, weakness and cramping after exercise

Question 13

lack of liver glycogen phosphorylase

Answer 13

type VI, Her disease; hepatomegaly (can’t break down glycogen), fasting hypoglycemia; could also be due to mutation in PKA, phosphorylase kinase or phosphorylase which affects its functioning

Question 14

lack of muscle PFK-1

Answer 14

type VII GSD, Tarui syndrome; muscle can’t do glycolysis to make ATP; exercise intolerance, not able to use glycogen as an energy source

Question 15

Fanconi-Bickel syndrome

Answer 15

GLUT2 mutations- affects liver, pancreas, kidney, intestines; glycogen accumulation in liver and kidney; fasting hypoglycemia, glucose in the urine, short stature, glucose can’t leave tissues

Question 16

Beriberi

Answer 16

thiamin deficiency caused by alcoholism (alcohol blocks B1 uptake from the gut); Dry Beriberi: affects nervous system, since not enough energy for fuel, nystagmus (fast uncontrollable eye movements), confusion, tingling, speech difficulties; wet Beriberi: after cardiovascular system, increased heart rate, shortness of breath, CHF

Question 17

Wernicke-Korsakoff syndrome

Answer 17

brain disorder due to lack of thiamin; Wernicke encephalopathy: confusion, loss of mental activity, loss of muscle coordination, nystagmus; Korsakoff syndrome (not reversible damage), inability to form new memories, loss of memory, confabulation, hallucinations

Question 18

PDH deficiency

Answer 18

lactic acidemia (have to do more glycolysis), neurological problems because brain isn’t getting enough energy; usually X linked dominant because E1 subunit located on X chromosome

Question 19

Kearns-Sayre Syndrome

Answer 19

deletion in mitochondrial DNA, affects nerves and muscle

Question 20

Pearson Syndrome

Answer 20

deletion of mito DNA, affects the bone marrow

Question 21

MERRF

Answer 21

Myoclonic Epilepsy and ragged red fiber disease; point mutation in tRNA lys

Question 22

MELAS

Answer 22

mitochondrial encephalopathy, lactic acidosis, and strokelike episodes; point mutation in tRNA leu

Question 23

Leigh disease

Answer 23

missense mutation in mito DNA; affects nerve and muscle, sometimes mutation occurs in ATP synthase

Question 24

LHON

Answer 24

leber hereditary optic neuropathy; missense mutation in mito DNA; usually mutation in complex I; note: partial loss of activity in complex I, III, or IV leads to exercise intolerance

Question 25

TCA cycle and cancer

Answer 25

associated with mutation in succinate dehydrogenase, fumarase, or isocitrate dehydrogenase- produces 2-hydroxyglutarate (oncometabolite) instead of 2 alpha KG when there is a mutation in IDH1 or IDH2; this blocks the histone demethylases (hydroxylases)- same effect seem when mutation in fumarase or SDH; leads to alterations in gene expression and differentiation, hypermethylation of the genome

Question 26

Hypoxia inducible factor

Answer 26

HIF; normally HIF binds DNA regulatory elements under low O2 conditions to induce genes to increase glycolysis and RBCs to adapt; proline hydroxylation of HIF, which requires alpha KG, leads to degradation of HIF; accumulation of 2 HG, succinate, or fumarate will block this hydroxylase, leading to HIF remaining active even when O2 is high, and more glycolysis/lactic acid formation, tumor phenotype