Hemoglobinopathies

Question 1

where are the alpha like and beta like globin clustered

Answer 1

chromosome 16 and 11 respectively

Question 2

how many alpha and beta globins are there

Answer 2

4 alphas and 2 betas

Question 3

when do the alpha, beta, and gamma globins dominate?

Answer 3

alpha - dominates from 8 weeks post conception till end of life

beta - stay low up until birth then starts increasing at 12 weeks then stays high

gamma - high post conception then starts to diminish 8 weeks after birth then stays low

Question 4

what is the embryonic hemoglobin and when do they diminish

Answer 4

zeta 2 and epsilon 2

diminish at about 8 weeks post conception

Question 5

what is fetal hemoglobin

Answer 5

HbF - alpha 2 and gamma 2

Question 6

what is adult hemoglobin

Answer 6

HbA (major component - 98%) - alpha 2 and beta 2

HbA2 (minor component - 2%) - alpha 2 and delta 2

Question 7

caused by production of structurally abnormal hemoglobin or insufficient production of normal hemoglobin

Answer 7

hemoglobinopathies

Question 8

mutation in nucleotide sequence of globin chain

decreased or absent globin chain synthesis

Answer 8

qualitative - hemoglobinopathies

quantitative - thalassemia

Question 9

single point mutation in beta globin chain that changes glutamic acid to valine at position 6

Answer 9

hemoglobin S

Question 10

which hemoglobin travels faster to the anode(positively charged) - HbS or HbA

Answer 10

HbA

Question 11

homozygous inheritance of sickle cell hemoglobin means what

Answer 11

no production of HbA

and persons has HbSS

Question 12

what is the nucleotide change in HbS

Answer 12

GAG –> GTG

Question 13

what causes crises in sickle cell anemia

Answer 13

anemia, hemolysis, vaso-occlusive ischemia around abdomen and long bone

Question 14

what suppresses transcription of fetal globin (gamma) after birth

Answer 14

methylation of CpG islands in DNA of promoters

Question 15

what mechanism is used to treat sickle cell anemia and why

Answer 15

induction of expression of fetal gamma globins because it alters epigenetic gene regulatory mechanism and can change acetylation of chromatin proteins

Question 16

drugs used to treat sickle cell/activate expression of fetal gamma globins

Answer 16

5-azacytidine (Decitabine; demethylating agent)
Hydroxyurea
Butyrate compounds (inhibit histone deacetylation)

Question 17

why is forming fetal globins useful to treat sickle cell

Answer 17

decreased formation of HbS (now 25% formation of HbF)
decreases degree of sickling
HbF has altered oxygen affinity

Question 18

those with sickle cell trait have what genotype

Answer 18

HbAS (or normal hemoglobin and one abnormal)

Question 19

what causes persons with sickle cell trait to have a sickle cell crisis

Answer 19

low oxygen saturation such as extreme exercise or deep sea diving

Question 20

how does a person with sickle cell mating with person with sickle cell trait show pseudo dominance

Answer 20

they have 50% probability of having child with sickle cell hence an autosomal recessive disease looks like autosomal dominant

Question 21

what explains the high incidence of heterozygotes of sickle cell in places like Africa, mediterranean, middle east, and india

Answer 21

heterozygote advantage towards deadly form of malaria (falciparum advantage)

Question 22

what is hemoglobin C

Answer 22

missense mutation changing glutamate to lysine at 6th position of beta globin chain

Question 23

how fast do HbA, HbS, and HbC travel in anode?

Answer 23

HbA travels the fastest, then HbS, the HbC

Question 24

persons with HbC and HbSC have what manifestations

Answer 24

HbC - mild hemolysis

HbSC - sickling similar to sickle cell but not as severe

Question 25

is there allelic heterogenity for HbS or HbC

Answer 25

nah

Question 26

difference between alpha and beta thalassemia

Answer 26

alpha - reduced production of alpha globin synthesis beta - reduced production of beta globin synthesis (more common because only 2 beta globin genes)

Question 27

where is alpha thalassemia common

Answer 27

south east asia, africa, and mediterranean

Question 28

cause of alpha thalassemia

Answer 28

deletion of alpha globin gene due to unequal crossing over during homologous recombination

Question 29

what happens with increase loss of alpha globin genes

Answer 29

if 1 - silent carrier, no clinical problems if 2 - mild anemia if 3 - beta 4 tetramer (HbH) -> moderate hemolytic anemia if all 4 - lethal; hydrops fetails

Question 30

difference between cis and trans alpha thalassemia and which is worse

Answer 30

both have only 2 alpha globin genes in cis, both on one chromosome but on trans one on each chromosome cis is worse because offspring has a chance of getting the chromosome without any alpha globin genes on it

Question 31

what occurs in hemoglobin bart hydrops fetalis syndrome (Hb Bart)

Answer 31

all 4 alpha globins deleted in fetus gammas increase but no alpha to bind to so they aggregate and form gamma 4 tetramers leading to death in neonatal period

Question 32

characteristics of Hb Bart syndrome

Answer 32

fetal onset of generalized edema, ascites, pleural and pericardial effusions, and severe hypochromic anemia

Question 33

what occurs in hemoglobin H disease

Answer 33

only one alpha globin present some HbA can be made and fetus can survival until birth after birth there will be beta 4 tetramers forming because of deficiency in alpha globins

Question 34

symptom of HbH disease

Answer 34

hepatosplenomegaly, mild to moderate microcytic hypochromic hemolytic anemia

Question 35

how many alpha genes absent in alpha thalassemia carriers/trait

Answer 35

two have normal or low hemoglobin levels

Question 36

where is beta thalassemia common

Answer 36

north africa, middle east, mediterranean

Question 37

is there allelic heterogenity in beta thalassemia

Answer 37

yeah (~250 mutations)

Question 38

difference between beta plus and beta zero thalassemia

Answer 38

beta plus - reduce expression of beta genes | beta zero - complete suppression of beta genes

Question 39

what happens with the bone marrow in beta thalassemia

Answer 39

they try to compensate and expands to perform erythropoiesis and this leads to bone deformity and fractures

Question 40

what happens with the alpha globins in beta thalassemia

Answer 40

they precipitate and bind to RBC resulting in severe hemolytic anemia or at high conc from alpha 4 tetramers which is toxic

Question 41

what is beta thalassemia major (AKA cooley's anemia or mediterranean anemia)

Answer 41

mutation in both beta globin genes low or absent HbA levels (high HbA2 and HbF) homozygotes or compound heterozygotes for beta 0 or beta plus genes

Question 42

what is beta thalassemia intermedia

Answer 42

one severe mutation and second mutation is less severe low HbA levels (some beta synthesis still going on) mostly homozygotes or compound heterozygoes

Question 43

what is beta thalassemia minor ("B-thalassemia carrier", "

Answer 43

``` mostly heterozygotes (one normal and one mutant beta globin gene) almost normal HbA levels ```

Question 44

when does beta thalassemia major present

Answer 44

at six months when gamma globins are switched off

Question 45

treatment for beta thalassemia major

Answer 45

transfusion to correct anemia and suppress erythropoiesis (iron deposition - manage with diet or iron chelation) bone marrow transplant from HLA identical sibling

Question 46

which is more common - hemophilia A or B

Answer 46

hemophilia A

Question 47

where are genes for both factor 8 and 9 located

Answer 47

on long arm X-chromosome

Question 48

common cause of hemophilia A

Answer 48

large inversions that disrupt FVIII gene (most common), deletions, insertions, point mutations (allelic heterogenity)

Question 49

common cause of hemophilia B

Answer 49

point mutations and deletions in FIX gene

Question 50

explain hemophilia A inversion

Answer 50

repeat sequences on the same chromosome misalign aberrantly and then recombination occurs hence exon 1 - 22 are displaced towards the telomere and are oriented in a direction opposite of their normal orientation

Question 51

recombinant protein make clotting factors that can replace what

Answer 51

pooled serum (can lead to antibodies against recombinant protein in some patients)

Question 52

In two families with history of β-thalassemia, one family had a splice site mutation and the other family had a promoter mutation of the β- globin gene. This illustrates the principle of

Answer 52

allelic heterogenity

Question 53

mutations that is most commonly observed in a child with a-thalassemia

Answer 53

gene deletion

Question 54

mutation that is most commonly observed in persons with hemophilia A

Answer 54

intron inversion