Case Exam

Question 1

G6PD Def Age of Onset and Present

Answer 1

Neonatal with hemolytic anemia and neonatal jaundice

Question 2

G6PD Def info

Answer 2

Hereditary predisposition to hemolysis, X linked (malaria endemic areas)

Question 3

G6PD Def Enzyme

Answer 3

G6PD is first enzyme in HMP shunt (NADPH) essential for generation of reduced glutathione used in RBCs for detox. Deficiency leads to oxidation and aggregation of intracell proteins (Heinz bodies) and rigid RBCs readily hydrolyzed. Oldest RBCs hit first

Question 4

G6PD Def Genetics

Answer 4

X-linked. Med basin and africa. Manifests early as neonatal jaundice or acute hemolytic anemia

Question 5

G6PD Def Triggers

Answer 5

Viral/bacterial infections, drugs, toxins. Fava Beans (contains beta-glycoside = oxidative agent). Some immuno def due to loss of oxidative burst.

Question 6

G6PD Def Test

Answer 6

Test when old RBCs are present (not near attack or recent transfusion = false negative)

Question 7

Familial Hypercholesterolemia Age Onset and present

Answer 7

Hetero in adult and Homo in childhood. Presents with hypercholesterolemia, atherosclerosis, Xanthema, Arcus cornea

Question 8

Familial Hypercholesterolemia info

Answer 8

AD disorder of chol and lipid metabolism by mutations in LDLR. 1:500 white pops and accounts for 5% of cases.

Question 9

Familial Hypercholesterolemia Protein

Answer 9

LDL-R is a transmembrane glycoprotein predominantly expressed in liver and adrenal cortex. Binds ApoB 100 (sole protein of LDL) and ApoE (protein on VLDL, chylomicrons, HDL)

Question 10

Familial Hypercholesterolemia mutations

Answer 10

Decrease LDL endocyt efficiency leading to accumulation of plasma LDL leading to atherosclerosis by clearance of LDL by phagocytes (foam cell formation) leading to thrombus (MI and stroke)

Question 11

Familial Hypercholesterolemia Contributing factor

Answer 11

Diet

Question 12

Familial Hypercholesterolemia Findings

Answer 12

Hyperchol is first finding with Arcus cornea and tendon xanthomas at end of second decade

Question 13

Familial Hypercholesterolemia Tx

Answer 13

Low fat high carb diet. Drugs = bile acid sequesters, 3-OH-3 methylglutayl CoA reductase inhib, and nicotinic acid

Question 14

Hereditary Hemochromatosis Age of Onset and presentation

Answer 14

40-60yrs Male and after menopause for FM. Presents with fatigue, impotence, hyperpigmentation (bronzing), diabetes, cirrhosis, cardiomyopathy. Elevated serum transferrin iron sat and elevated serum Ferritin. AR.

Question 15

Hereditary Hemochromatosis Info

Answer 15

Disease of iron overload in pts with homo or compound hetero mutations in HFE gene. Homo = Cys282Tyr mutation; hetero = Cys282Tyr/His63Asp

Question 16

Hereditary Hemochromatosis Genetics

Answer 16

Carrier NA = 11% Cys and 27% His. Shows incomplete penetrance with Males>FM.

Question 17

Hereditary Hemochromatosis pathway

Answer 17

Iron release from enterocytes (digest SI) and macrophages (RBC) is regulated by circulating iron response protein = Hepcidin (synth in liver and blocks iron abs when stores are full). Mutant HFE inhibs herceptin signalling leading to iron overload

Question 18

Hereditary Hemochromatosis early s and s

Answer 18

fatigue, arthalgia, decreased libido, abd pain, increased transferrin or ferratin

Question 19

Hereditary Hemochromatosis late s and s

Answer 19

hepatomegaly, cirrhosis, heptocell carcinoma, DM, cardiomyopathy, bronzing

Question 20

Hereditary Hemochromatosis Tx

Answer 20

If ferratin is greater than 50 = phlembotomy

Question 21

Hemophilia Age of onset and presentation

Answer 21

Infancy to adulthood with hemarthomses and hematomas. X linked

Question 22

Hemophilia info

Answer 22

Hema A F8 and Hem B F9

Question 23

Hemophilia Prevelence

Answer 23

A 1:5000 B 1:100000

Question 24

Hemophilia Pathway

Answer 24

Coagulation system consists of proteases and protein cofactors in zymogen form and mus be activated to form a clot. 8 and 9 complex together to activate 10 (9=protease, 8=cofactor)

Question 25

Hemophilia mutations in 8

Answer 25

del, insertsm invertsm pt mutations. Most common = invert deletion of carboxyl terminus of F8 and results from intrachromo recombination btwn intron 22 F8 and homologous telomeric sequences.

Question 26

Hemophilia mutations in 9

Answer 26

many different but no common. F9 Leyden = F9 variant by pt mutation in F9 promoter = svr childhood hemophilia with spont resolve at puberty

Question 27

Hemophilia presentation

Answer 27

Classically male disease (some FM with skewed X-inactivation). Clin A and B = bleeding into soft tissue, musc, joints within hours of trauma and continues for days. Severe = neonatal find with umbilical and circumcision bleeding. Moderate = once ambulatory. Mild = adult with trauma

Question 28

Hemophilia Classification

Answer 28

``` Severe = less than 1% Moderate = 1-5% Mild = 5-25% ```

Question 29

Hemophilia Genetics

Answer 29

New mutations for F8 invert and pt mutations due to male meiosis in pt maternal GF. Del mutations in female meiosis.

Question 30

NIDDM Age of Onset and presentation

Answer 30

Multifactorial disease with hyperglycemia, insulin resistance, obesity, acanthiosis nigricans

Question 31

NIDDM Race

Answer 31

Native Americans of Prima Arizona

Question 32

NIDDM Disease

Answer 32

Results from derangement of insulin secretion and resistance to insulin action. Response to glucose loads is inadequate with basal insulin high but not high enough to account for the hyperglycemia. Hyperglycemia desensitizes beta cells so that less insulin is released for given glucose levels, also the high insulin levels down regulate insulin receptors. Finally, glucagon is unopposed.

Question 33

NIDDM Genetics

Answer 33

Confusing. Icelandic with repeat polymorphism intron in TF TCF7L2 assoc with glucagon expression. Pro12AlA mut in PPARG in fins and mexicans = nuclear receptor that regs adipose fx. Strongly enviromental

Question 34

NIDDM Presentation

Answer 34

Usually affects middle aged with insidious onset without ketoacidosis. Hyperglycemia monitered by HBA1C lvls (7% and less = normal)

Question 35

Ornithine Transcarbamylase Def Onset and present

Answer 35

X-linked. hemizygous male with null at neonatal; hetero FM with severe illness, post partum, or never. With hyperammonia and Coma

Question 36

Ornithine Transcarbamylase Def Pathway

Answer 36

X linked disroder of urea cycle metabolism. Leads to hyperammonia and arginine becomes an essential AA. Defect causes increased glutamine and alanine (pool of N) leading to ammonia buildup (lvls >200 = brain dmg).

Question 37

Ornithine Transcarbamylase Def Present

Answer 37

Upon birth, males with with null mutation are lethargic and vomit. OTC and CPS def not detected by screenings.

Question 38

Ornithine Transcarbamylase Def Diff

Answer 38

Btwn OTC and CPS (both low citrulline) measure urine orotic acid (increased in OTC)

Question 39

Ornithine Transcarbamylase Def Tx

Answer 39

D10W, IV ammonul, Arginine HCL IV, hemodialysis. Chronic treatment is high carb diet and phenylbutyrate

Question 40

Ornithine Transcarbamylase Def Genetics

Answer 40

Male germ line mutations frequent. Males with partial OTC def have carrier daughters and no affected sons

Question 41

Tay Sachs Disease Onset and present

Answer 41

AR. Infantile to adult with neurodegeneration, retinal cherry red spots, psychosis.

Question 42

Tay Sachs Disease Enzyme

Answer 42

Infantile GM2 gangliosidosis disorder caused by def Hexosaminidase A.

Question 43

Tay Sachs Disease Ethnic

Answer 43

Ash Jews, french canadians, cajuns, amish (genetic drift)

Question 44

Tay Sachs Disease Gangliosidosis

Answer 44

ceramide oligosacc abundant in brain (cell surface) and function as receptor for glycoprotein hormones, bacterial toxins, and involved in cell diff and cell-cell interactions

Question 45

Tay Sachs Disease Hexosamidase A

Answer 45

Lysosomal enzyme with 2 subunits: Hex A (15) and B (5). Tay sachs is due to HexA mutation by removal of terminal N-acetyl galactosamine leading to accumulation. Infantile is due to 2 null mutations; adult and juvenile due to null and low residual hetero

Question 46

Breast and Ovarian Cancer mutation

Answer 46

AD. BRCA1/2 is majority of familial breast cancer. Is a TF for DNA repair and are tumor suppressors. Mutations lead to chromosome instability and frequent mutations in other TSGs.

Question 47

Breast and Ovarian Cancer two hit

Answer 47

2nd mutation cia intragene mutation or promoter hypermethylation

Question 48

Breast and Ovarian Cancer Genetics

Answer 48

Pop prevelence varies wildly (founder effect indicated). Iceland = BRCA2 999del15, Ash Jews = BRCA1 185delAG and BRCA2 617delT.

Question 49

Breast and Ovarian Cancer BRCA1

Answer 49

FM breast and ovary. 50-80% penetrance

Question 50

Breast and Ovarian Cancer BRCA2

Answer 50

FM breast and ovary; male breast and prostate. Penetrance 40% breast, 10% ovarian.

Question 51

HNPCC mutation

Answer 51

AD. Mutation in DNA mismatch repair genes. Microsatellite instability in 85%. Muts in MSH 2,6; MLH 1,3; PMS 1,2. Needs 2 hits but second hit penetrance in 80%. Perdom effect of microstellite instability is loss of TGFBR2 which allows escape of growth control.

Question 52

HNPCC Clinical

Answer 52

Develop polyps at younger ager (50) at splenic junction and ileocecal junction. Less aggressive and less chromo instab than others. Additional cancers = stomach, SI, pancreas, kidney, endometrium and ovaries.

Question 53

HNPCC confirm

Answer 53

minimal criteria of 3 members with HNPCC related tumors with at least 2 primary

Question 54

Retinoblastoma Mutation

Answer 54

AD, mut Rb1 loss of fx. 13q14. New germline = paternal; new somatic = maternal. Muts 50% at CpG. Full penetration of second hit.

Question 55

Retinoblastoma present

Answer 55

Bilaterial at 1st yr; unilateral 24-30 mnths

Question 56

Retinoblastoma secondary

Answer 56

Secondary neoplasms are osteosarcomas, sarcoma, melanomas.