Week 6

Question 1

HAE (Hereditary Angioedema)

Answer 1

C1 inhibitor deficiency, autosomal dominant; C1 esterase remains active and cleaves C2 and C4; also regulates kinin pathway, increased bradykinin leads to swelling symptoms of the skin, airway, intestines; airway obstruction is more serious complication

Question 2

Paroxysmal nocturnal hemoglobinuria (PNH)

Answer 2

DAF deficiency- C3 convertase remains active longer and make a lot of C3b and opsonizes RBC which then lyse; dark urine from RBC lysis

Question 3

C3 deficiency

Answer 3

most serious consequences, prone to bacterial infections

Question 4

Deficiencies in components of MAC complex

Answer 4

associated with Neisserial infections

Question 5

Sensitivity

Answer 5

proportion of true positives accurately detected, ability to correctly identify positive cases; a/(a+c) where a is true positives and c is false negatives

Question 6

Specificity

Answer 6

proportion of true negatives accurately detected; d/(b+d) where b is false positives and d is true negatives

Question 7

Positive predictive value

Answer 7

a/(a+b); proportion of positive results that are true positives; increases with prevalence of disorder in a population

Question 8

Negative predictive value

Answer 8

d/(c+d); proportion of negative results that are true negatives

Question 9

Knudson hypothesis

Answer 9

hereditary mechanism for cancer; you inherit the first “hit” or mutation which knocks out the allele on one chromosome; if you get a second hit, knocking out the allele on the other chromosome it leads to cancer

Question 10

Li Fraumeni syndrome

Answer 10

associated with brain tumors, sarcomas, leukemia and many cancers; germline mutation of P53 gene- p53 important for regulation of cell cycle, genome stability, apoptosis if too much DNA damage; p53 regulated by Mdm2 which adds ubiquitin for degradation

Question 11

Hereditary retinoblastoma

Answer 11

germline mutation of RB1, which pauses cell cycle at G1/S checkpoint to check for growth factors and DNA damage by binding E2F transcription factor, only released if phosphorylated by CDK4; see white reflex on exam; mutation takes away brake on cell cycle- E2F can remain active

Question 12

Hereditary Breast and Ovarian Cancer

Answer 12

germline mutation of BRCA1 or BRCA2 tumor suppressor genes, which form complex in response to DNA damage that repairs double stranded breaks; PARP-1 inhibitors (Poly ADP-ribose polymerase) work by producing double stranded breaks in cancer patients on purpose, which can’t be repaired in BRCA mutated patients, leading to cell death, primarily in tumor cells which are dividing more

Question 13

Familial Adenomatous Polyposis

Answer 13

germline mutation of the APC gene, important for protein degradation of Beta catenin, which is a Tc coactivator leading to upregulated MYC and cyclins and cell growth; degradation of beta-catenin can be stopped by WNT signaling or APC mutation; loss of APC leads to lack of beta catenin degradation and continued proliferation; observe lots of polyps in colon; APC mutation is first step in multistep process leading to colon cancer

Question 14

Wilms Tumor

Answer 14

kidney tumor resulting from germline mutation of WT1 gene, a transcription factor

Question 15

Neurofibromatosis

Answer 15

characterized by multiple benign tumors involving peripheral nerves; germline mutation of NF1, encoding neurofibromin, which is a GAP (GTPase activating protein) that acts as brake on Ras signaling; mutation leads to consitutive Ras- cell division/proliferation

Question 16

Gorlin syndrome- Nevoid basal cell carcinoma syndrome

Answer 16

mutation of PTCH tumor suppressor gene; in growing cells, SMO activates GLI, which is a transcription activator leading to Tc of proliferation genes (cyclins); PTCH inhibits SMO, so GLI can’t be activated; to overcome PTCH block growing cells need SHH to bind to PTCH turning it off and allowing SMO to be activated; mutations in PTCH prevent it from putting a brake on GLI signaling; targeted therapy: vismodegib inhibits SMO (acts like PTCH)

Question 17

Familial Melanoma

Answer 17

mutation of CDKN2A gene, which encodes p16- which inhibits CDK4 (normally phosphorylates Rb); loss of p16- excess CDK4 activity–> Rb phosphorylation–> E2F active; CDKN2A gene also encodes p14 which inhibits Mdm2 (adds ubiquitin to p53); loss of p14 leads to excess degradation of p53

Question 18

Purine nucleoside phosphorylase deficiency

Answer 18

inosine or guanosine + phosphate leads to ribose-1-phosphate + free base (hypoxanthine or guanine); deficiency leads to T cell deficiency (dGTP accumulates, reduced production or dCTP, reduced DNA synthesis); hypouricemia (low uric acid levels because lack of bases to degrade)

Question 19

HGPRT deficiency (hypoxanthine-guanine phosphoribosyl transferase)

Answer 19

unable to produce IMP or GMP; Lesch-Nyhan syndrome if less than 2% activity (neuro effects, self-mutilation, gout); only gout results if 2-10% of activity

Question 20

Adenosine Deaminase Deficiency

Answer 20

buildup of adenosine, which is toxic- buildup of dATP which inhibits ribonucleotide reductase- blocks formation of deoxynucleotides; SCID results

Question 21

Lesch-Nyhan syndrome

Answer 21

less than 2% HGPRT activity; mental status change, self-mutilation, gout (buildup of PRPP)

Question 22

Hereditary Orotic Aciduria

Answer 22

retarded growth and development, hypochromic anemia, excessive excretion of orotic acid; reduced activity of orotate phosphoribosyl transferase and orotidine phosphate decarboxylase (UMP synthase)- can’t synthesize pyrimidines de novo; need uridine therapy