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M2MWeek4 > Hemoglobinopathies and Thalassemias > Flashcards

Hemoglobinopathies and Thalassemias Flashcards

1
Q

What is the major for of adult hemoglobin?

A

HbA

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2
Q

What is HbA made of?

A

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

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3
Q

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

A

Chr 16

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4
Q

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

A

Chr 11

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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

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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)

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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)

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8
Q

Where is the Locus Control Region (LCR) located?

A

At the most upstram region of each cluster

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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

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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)

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11
Q

What is the minor form of adult hemoglobin?

A

HbA2

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12
Q

What is HbA2 made of?

A

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

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13
Q

About what percentage of adult blood is normally HbA2?

A

About 2%

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14
Q

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

A

Delta has a weaker promoter

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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)

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16
Q

Which fetal hemoglobin made of and where is it made?

A

HbF = alpha2gamma2. Made in liver

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17
Q

What happens with globin switching during early embryogenesis?

A

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

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18
Q

What happens with globin switching around the time of birth?

A

Gamma is turned off; Beta and delta are turned on

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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)

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20
Q

What are the 3 main types of hemogloinopathies?

A

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

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21
Q

How does HbKemsey alter hemoglobin binding?

A

Binding is too tight (structural variant)

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22
Q

How does HbKansas alter hemoglobin binding?

A

Binding is too weak (structural variant)

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23
Q

What type of hemoglobin is seen in Sickle Cell Anemia?

A

HbSS

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24
Q

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

A

10%

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25
What is the genetic mutation in sickle cell anemia?
Single base mutation at codon#6 in the Beta-globin gene. Changes glutamate to valine.
26
What is physically occurs due to the mutation in sickle cell anemia?
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
27
What type of hemoglobin is seen in Hemoglobin C disease?
HbCC
28
What is the genetic mutation in Hemoglobin C disease?
Single base mutation at codon#6 of the Beta-globin gene. Changes glutamate to lysine
29
What physically ocurs due to the mutation in Hemoglobin C disease?
HbCC is less soluble than HbA and tends to form cyrstals; reduces deformability of RBC. Milder form than sickle cell
30
What is sickle cell trait (HbS trait)?
Heterozygousity of HbS/HbA
31
What is hemoglobin C trait (HbC trait)?
Heterozygousity of HbC/HbA
32
Are individuals with HbS trait or HbC trait affected?
They are clinically normal except when under severe low pO2 stress
33
What is Hemoglobin SC disease?
When an individual is compound heterozygote for the Beta S and C traits. (BetaS/BetaC). Have a milder anemia than sickle cell
34
What technology can be used to diagnosis sickle cell anemia?
Restriction Fragment Length Polymorphism (RFLP)
35
Which restriction enzyme is used in RFLP in diagnosing sickle cell?
MstII
36
How does the RFLP work in diagnosing sickle cell?
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
Can MstII distringuish between Beta-A and Beta-C hemoglobin?
No; the MstII site is still present on the beta-C globin. It is a different base pair that is mutated
38
What does thalassemia mean?
It is a disease of imbalanced globin levels
39
Why is it bad to have imbalanced globin levels?
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
What usually causes alpha-thalassemia?
Deletions of one or both copies of the alpha-globin gene in the alpha cluster.
41
Which genes are in excess in alpha-Thalassemia? Which hemoglobins are affected?
Gamma and beta globin are in excess. Affects the formation of both fetal and adult hemoglobins
42
What are the two alpha-thal alleles?
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
Where is alpha-thal-1 allele common?
In Southeast Asia
44
What is the result of the homozygous state of alpha-thal-1 allele (--/--)?
Hydrops fetalis (stillborn)
45
How is fetal development sustatined with (--/--)?
Most fetal hemoglobin is gamma4 (Hb Bart�s) although there is enough zeta2gamma2 (Hb Portland) to sustain fetal development
46
What is alpha-thalassemia-1 trait?
Heterozygous (AA/--). Have mild anemia
47
If you are homozygous for alpha-thal-2 allele (A-/A-) what is it called?
Alpha-thalassemia-2 trait
48
What is the disease phenotype in alpha-thalassemia-2 trait?
Mild anemia
49
What is the disease phenotype in heterozygous A-thal-2?
No disease phenotype in (AA/A-). Silent carrier
50
What is HbH disease?
When an individual is compound heterozygote for alpha-thal-1/alpha-thal-2 (A-/--)
51
What is the disease phenotype for HbH disease?
Severe anemia. Pts have only 25% of normal alpha-globin level. 5-30% of their hemoglobin is Beta4 (HbH); which precipitates
52
Why is Beta-thalassemia so complex and varied?
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
What are the two different classification of B-thalassemia based on clinical conditions?
Thalassemia major and thalassemia minor
54
How is thalassemia major classified?
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
How is thalassemia major treated?
Treat temporarily with blood transfusions. Iron accumulation from repeated transfusion leads to organ failure.
56
What is used to try to combat organ failure from repeated transfusions?
Iron chelation therapy (desferrioxamine) is used to reduce the complications of iron overload
57
What is the clinical phenotype of thalessemia minor?
Clinically normal. Carriers of 1 B-thalassemia allele
58
What are the 2 different classifications of thalassemia based on molecular nature of mutation?
Simple B-thalassemia and complex thalassemia
59
What causes simple B-thalassemia?
Mutations or deletions that impair the production of the B-globin chain alone. Other genes in the B-globin cluster unaffected
60
What causes complex thalassemia?
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
What are the two classifications of thalassemia based on the biochemical nature of the disease?
B+-thalassemia and Bo-thalassemia (beta-naught). (dBo-thalassemia (delta beta naught) seems to be in its own category?)
62
What occurs with HbA in B+-thalassemia?
Some B-gloin is made so that some HbA is present. *Note this is the most common form (90% of cases)
63
What causes the decrease in B-globin synthesis seen in B+-thalassemia?
Mutations affecting transcription; RNA processing; or protein stability
64
How much HbA is present with Bo-thalassemia?
There is no B-globin synthesized so NO HbA is present.
65
What causes Bo-thalassemia?
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
What is the [Hb] in Bo-thalassemia?
[Hb] is ~5% of normal level (of which 95% is alpha2gamma2 with 5% alpha2delta2). Not enough for good survival
67
What occurs in dBo-thalassemia?
No delta or Beta synthesis due to deletion of the coding sequences for both delta- and beta-globin
68
What is the phenotype of dBo-thalassemia?
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
What compensates for the lack of HbA in dB0-thalassemia?
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
What causes HPFH?
No delta or Beta synthesis due to deletion of the coding sequences for both delta- and beta-globin
71
Describe the 2 mechanisms that lead to increased gamma-globin expression in HPFH?
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
Describe the diseases seen in HPFH individuals?
HPFH individuals are disease free. Adequate levels of ? chains are still made due to the disruption of the perinatal globin switch from ? to ?.
73
What percentage of hemoglobin is HbF in HPFH?
100% of hemoglobin is HbF. This is about 17-35% of normal level of total hemoglobin

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