Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

M2MWeek4 > Hemoglobinopathies and Thalassemias > Flashcards

Hemoglobinopathies and Thalassemias Flashcards

1
Q

What is the major for of adult hemoglobin?

A

HbA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is HbA made of?

A

It is a tetramer of 2 alpha and 2 beta globin chains

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

On which chromosome are all of the alpha and alpha-like genes located?

A

Chr 16

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

On which chromosome are all of the beta and beta-like genes located?

A

Chr 11

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

How many copies of alpha are in the alpha cluster? How many copies of beta are in the beta cluster?

A

2 copies of alpha but only 1 copy of beta

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the transcriptional orientation of the alpha-cluster?

A

zeta-alpha2-alpha1 (note this is the spatial order and the temporal order)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the transcriptional orientation of the beta-cluster?

A

epsilon-gammaG-gammaA-delta-beta (note this is the spatial order and the temporal order)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Where is the Locus Control Region (LCR) located?

A

At the most upstram region of each cluster

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How does the LCR influence gene expression?

A

It presumably makes physical contact with the promoter and/or negative regulatory regions via specific transcriptional factors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What happens if you delete the entire LCR of the beta cluster?

A

This would cause beta-thalassemias (zero Beta-globin synthesis leads to precipitation of the Alpha-globin chains)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the minor form of adult hemoglobin?

A

HbA2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is HbA2 made of?

A

It is a tetramer of 2 alpha and 2 delta globin chains

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

About what percentage of adult blood is normally HbA2?

A

About 2%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the delta hemoglobin level so much lower than the beta level?

A

Delta has a weaker promoter

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the 3 embryonic hemoglobins that are made in the yolk sac?

A

Hb Gower I (Zeta2Epsilon2); Hb Gower II (Alpha2Epsilon2); Hb Portland (Zeta2Gamma2)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Which fetal hemoglobin made of and where is it made?

A

HbF = alpha2gamma2. Made in liver

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What happens with globin switching during early embryogenesis?

A

Zeta and Epsilon are turned off; Alpha and Gamma are turned on

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What happens with globin switching around the time of birth?

A

Gamma is turned off; Beta and delta are turned on

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Why must globin switching occur?

A

HbF has a ^ affinity for O2 at low pO2 than HbA. Thus; HbF is better suited to bind O2 at the placenta (lower pO2) and HbA is better to bind O2 at the lung (higher pO2)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What are the 3 main types of hemogloinopathies?

A

Structural Variants (qualitative hemoglobinopathies); Thalassemias (quantitative hemoglobinopathies); Hereditary Persistence of Fetal Hemoglobin (HPFH)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

How does HbKemsey alter hemoglobin binding?

A

Binding is too tight (structural variant)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

How does HbKansas alter hemoglobin binding?

A

Binding is too weak (structural variant)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What type of hemoglobin is seen in Sickle Cell Anemia?

A

HbSS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What is the carrier frequency of HbSS in people of African origin?

A

10%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What is the genetic mutation in sickle cell anemia?

A

Single base mutation at codon#6 in the Beta-globin gene. Changes glutamate to valine.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What is physically occurs due to the mutation in sickle cell anemia?

A

HbSS is 80% less soluble when not bound to O2; polymerizes into long fibers that distort the RBC into a characteristic sickle shape; Sickled cells become
lodged in the micro-capillaries and further exacerbate the sickling crisis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What type of hemoglobin is seen in Hemoglobin C disease?

A

HbCC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What is the genetic mutation in Hemoglobin C disease?

A

Single base mutation at codon#6 of the Beta-globin gene. Changes glutamate to lysine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What physically ocurs due to the mutation in Hemoglobin C disease?

A

HbCC is less soluble than HbA and tends to form cyrstals; reduces deformability of RBC. Milder form than sickle cell

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What is sickle cell trait (HbS trait)?

A

Heterozygousity of HbS/HbA

31
Q

What is hemoglobin C trait (HbC trait)?

A

Heterozygousity of HbC/HbA

32
Q

Are individuals with HbS trait or HbC trait affected?

A

They are clinically normal except when under severe low pO2 stress

33
Q

What is Hemoglobin SC disease?

A

When an individual is compound heterozygote for the Beta S and C traits. (BetaS/BetaC). Have a milder anemia than sickle cell

34
Q

What technology can be used to diagnosis sickle cell anemia?

A

Restriction Fragment Length Polymorphism (RFLP)

35
Q

Which restriction enzyme is used in RFLP in diagnosing sickle cell?

A

MstII

36
Q

How does the RFLP work in diagnosing sickle cell?

A

MstII is destroyed in exon 1 by the A-to-T change in the BetaS mutant allele. The normal allele BetaA gives 1.15 kb + 0.20 kb fragments. The BetaS mutant allele give one 1.35 kb fragment.

37
Q

Can MstII distringuish between Beta-A and Beta-C hemoglobin?

A

No; the MstII site is still present on the beta-C globin. It is a different base pair that is mutated

38
Q

What does thalassemia mean?

A

It is a disease of imbalanced globin levels

39
Q

Why is it bad to have imbalanced globin levels?

A

Instead of forming tetramers (Alpha2Beta2) they will start to form homotetramers (alpha4; Beta4; Gamma4). These tetramers are poor O2 carriers and precipitate inside the RBC. This decreases the lifespan of the RBC

40
Q

What usually causes alpha-thalassemia?

A

Deletions of one or both copies of the alpha-globin gene in the alpha cluster.

41
Q

Which genes are in excess in alpha-Thalassemia? Which hemoglobins are affected?

A

Gamma and beta globin are in excess. Affects the formation of both fetal and adult hemoglobins

42
Q

What are the two alpha-thal alleles?

A

Alpha-thal-1 (–; or deletion of both copies of alpha globin genes in the alpha cluster) and Alpha-thal-2 (alpha-; or deletion of one of two alpha-globin genes in the alpha cluster)

43
Q

Where is alpha-thal-1 allele common?

A

In Southeast Asia

44
Q

What is the result of the homozygous state of alpha-thal-1 allele (–/–)?

A

Hydrops fetalis (stillborn)

45
Q

How is fetal development sustatined with (–/–)?

A

Most fetal hemoglobin is gamma4 (Hb Bart�s) although there is enough zeta2gamma2 (Hb Portland) to sustain fetal development

46
Q

What is alpha-thalassemia-1 trait?

A

Heterozygous (AA/–). Have mild anemia

47
Q

If you are homozygous for alpha-thal-2 allele (A-/A-) what is it called?

A

Alpha-thalassemia-2 trait

48
Q

What is the disease phenotype in alpha-thalassemia-2 trait?

A

Mild anemia

49
Q

What is the disease phenotype in heterozygous A-thal-2?

A

No disease phenotype in (AA/A-). Silent carrier

50
Q

What is HbH disease?

A

When an individual is compound heterozygote for alpha-thal-1/alpha-thal-2 (A-/–)

51
Q

What is the disease phenotype for HbH disease?

A

Severe anemia. Pts have only 25% of normal alpha-globin level. 5-30% of their hemoglobin is Beta4 (HbH); which precipitates

52
Q

Why is Beta-thalassemia so complex and varied?

A

Disease is caused by every possible type of mutation in the B-globin gene. ^ allelic heterogeneity means most Pts with B-thalassemia are compound heteroxygotes (carry 2 diff. mutant alleles of B-globin gene)

53
Q

What are the two different classification of B-thalassemia based on clinical conditions?

A

Thalassemia major and thalassemia minor

54
Q

How is thalassemia major classified?

A

Clinical conditions. Characterized by sever anemia; most RBCs are destroyed b4 being released into circulation. Thinning bone cortex; enlarged liver/spleen from massive effort of blood production.

55
Q

How is thalassemia major treated?

A

Treat temporarily with blood transfusions. Iron accumulation from repeated transfusion leads to organ failure.

56
Q

What is used to try to combat organ failure from repeated transfusions?

A

Iron chelation therapy (desferrioxamine) is used to reduce the complications of iron overload

57
Q

What is the clinical phenotype of thalessemia minor?

A

Clinically normal. Carriers of 1 B-thalassemia allele

58
Q

What are the 2 different classifications of thalassemia based on molecular nature of mutation?

A

Simple B-thalassemia and complex thalassemia

59
Q

What causes simple B-thalassemia?

A

Mutations or deletions that impair the production of the B-globin chain alone. Other genes in the B-globin cluster unaffected

60
Q

What causes complex thalassemia?

A

Large deletions that remove the B-globin gene plus other genes in the B-cluster; or the LCR. (Note that some deletions within B-cluster cause HPFH instead of thalassemia)

61
Q

What are the two classifications of thalassemia based on the biochemical nature of the disease?

A

B+-thalassemia and Bo-thalassemia (beta-naught). (dBo-thalassemia (delta beta naught) seems to be in its own category?)

62
Q

What occurs with HbA in B+-thalassemia?

A

Some B-gloin is made so that some HbA is present. *Note this is the most common form (90% of cases)

63
Q

What causes the decrease in B-globin synthesis seen in B+-thalassemia?

A

Mutations affecting transcription; RNA processing; or protein stability

64
Q

How much HbA is present with Bo-thalassemia?

A

There is no B-globin synthesized so NO HbA is present.

65
Q

What causes Bo-thalassemia?

A

Deletion of the B-globin gene; nonsense or frameshift mutations at the 5� of the coding region that lead to an early stop codon; or mutations that result in no RNA synthesis.

66
Q

What is the [Hb] in Bo-thalassemia?

A

[Hb] is ~5% of normal level (of which 95% is alpha2gamma2 with 5% alpha2delta2). Not enough for good survival

67
Q

What occurs in dBo-thalassemia?

A

No delta or Beta synthesis due to deletion of the coding sequences for both delta- and beta-globin

68
Q

What is the phenotype of dBo-thalassemia?

A

Milder clinical phenotype than B0-thalassemia because the remaining gamma gene(s) is still active after birth instead of switching off as would normally occur.

69
Q

What compensates for the lack of HbA in dB0-thalassemia?

A

HbF (A2gamma2) compensates. About 5-18% of normal level of hemoglobin is produced. (*Note: depending on the range of the deletion; this may be classified as either dB0-thalassemia or HPFH)

70
Q

What causes HPFH?

A

No delta or Beta synthesis due to deletion of the coding sequences for both delta- and beta-globin

71
Q

Describe the 2 mechanisms that lead to increased gamma-globin expression in HPFH?

A

1: extended deletion of additional downstream sequences;l ikely brings a cis-acting enhancer element closer to the ?-globin gene. 2: mutations in the promoter region of one of the two gamma-globin genes that destroy the binding site of a repressor

72
Q

Describe the diseases seen in HPFH individuals?

A

HPFH individuals are disease free. Adequate levels of ? chains are still made due to the disruption of the perinatal globin switch from ? to ?.

73
Q

What percentage of hemoglobin is HbF in HPFH?

A

100% of hemoglobin is HbF. This is about 17-35% of normal level of total hemoglobin

M2MWeek4 (4 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions