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Genetics > Hemoglobinopathies > Flashcards

Hemoglobinopathies Flashcards

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Biology 101 flashcards
1
Q

where are the alpha like and beta like globin clustered

A

chromosome 16 and 11 respectively

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2
Q

how many alpha and beta globins are there

A

4 alphas and 2 betas

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3
Q

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

A

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

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4
Q

what is the embryonic hemoglobin and when do they diminish

A

zeta 2 and epsilon 2

diminish at about 8 weeks post conception

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5
Q

what is fetal hemoglobin

A

HbF - alpha 2 and gamma 2

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6
Q

what is adult hemoglobin

A

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

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

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7
Q

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

A

hemoglobinopathies

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8
Q

mutation in nucleotide sequence of globin chain

decreased or absent globin chain synthesis

A

qualitative - hemoglobinopathies

quantitative - thalassemia

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9
Q

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

A

hemoglobin S

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10
Q

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

A

HbA

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11
Q

homozygous inheritance of sickle cell hemoglobin means what

A

no production of HbA

and persons has HbSS

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12
Q

what is the nucleotide change in HbS

A

GAG –> GTG

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13
Q

what causes crises in sickle cell anemia

A

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

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14
Q

what suppresses transcription of fetal globin (gamma) after birth

A

methylation of CpG islands in DNA of promoters

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15
Q

what mechanism is used to treat sickle cell anemia and why

A

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

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16
Q

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

A

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

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17
Q

why is forming fetal globins useful to treat sickle cell

A

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

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18
Q

those with sickle cell trait have what genotype

A

HbAS (or normal hemoglobin and one abnormal)

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19
Q

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

A

low oxygen saturation such as extreme exercise or deep sea diving

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20
Q

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

A

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

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21
Q

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

A

heterozygote advantage towards deadly form of malaria (falciparum advantage)

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22
Q

what is hemoglobin C

A

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

23
Q

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

A

HbA travels the fastest, then HbS, the HbC

24
Q

persons with HbC and HbSC have what manifestations

A

HbC - mild hemolysis

HbSC - sickling similar to sickle cell but not as severe

25
Q

is there allelic heterogenity for HbS or HbC

A

nah

26
Q

difference between alpha and beta thalassemia

A

alpha - reduced production of alpha globin synthesis

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

27
Q

where is alpha thalassemia common

A

south east asia, africa, and mediterranean

28
Q

cause of alpha thalassemia

A

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

29
Q

what happens with increase loss of alpha globin genes

A

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

30
Q

difference between cis and trans alpha thalassemia and which is worse

A

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

31
Q

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

A

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

32
Q

characteristics of Hb Bart syndrome

A

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

33
Q

what occurs in hemoglobin H disease

A

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

34
Q

symptom of HbH disease

A

hepatosplenomegaly, mild to moderate microcytic hypochromic hemolytic anemia

35
Q

how many alpha genes absent in alpha thalassemia carriers/trait

A

two

have normal or low hemoglobin levels

36
Q

where is beta thalassemia common

A

north africa, middle east, mediterranean

37
Q

is there allelic heterogenity in beta thalassemia

A

yeah (~250 mutations)

38
Q

difference between beta plus and beta zero thalassemia

A

beta plus - reduce expression of beta genes

beta zero - complete suppression of beta genes

39
Q

what happens with the bone marrow in beta thalassemia

A

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

40
Q

what happens with the alpha globins in beta thalassemia

A

they precipitate and bind to RBC resulting in severe hemolytic anemia

or at high conc from alpha 4 tetramers which is toxic

41
Q

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

A

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

42
Q

what is beta thalassemia intermedia

A

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

43
Q

what is beta thalassemia minor (“B-thalassemia carrier”, “

A 
mostly heterozygotes (one normal and one mutant beta globin gene)
almost normal HbA levels
44
Q

when does beta thalassemia major present

A

at six months when gamma globins are switched off

45
Q

treatment for beta thalassemia major

A

transfusion to correct anemia and suppress erythropoiesis (iron deposition - manage with diet or iron chelation)

bone marrow transplant from HLA identical sibling

46
Q

which is more common - hemophilia A or B

A

hemophilia A

47
Q

where are genes for both factor 8 and 9 located

A

on long arm X-chromosome

48
Q

common cause of hemophilia A

A

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

49
Q

common cause of hemophilia B

A

point mutations and deletions in FIX gene

50
Q

explain hemophilia A inversion

A

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

51
Q

recombinant protein make clotting factors that can replace what

A

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

52
Q

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

A

allelic heterogenity

53
Q

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

A

gene deletion

54
Q

mutation that is most commonly observed in persons with hemophilia A

A

intron inversion

Genetics (19 decks)

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