L7 Genetic disorders of hemoglobin

Question 1

In the synthesis of hemoglobin, what happens at 3-6 months?

Answer 1

Gamma-beta switch from HbF > HbA

Question 2

What genes make up HbA? (Adult)

HbA2 is also a type of hemoglobin that exists in small amount (with 2 alpha genes and 2 delta genes)

Answer 2

2 alpha-globin genes

2 beta-globin genes

Question 3

What is the main pathology of Thalassaemia syndromes that can be summarized in a sentence?

Answer 3

Reduced rate of synthesis of alpha/beta chains > imbalanced globin chain

Question 4

What can be seen in CBC of patients with thalassemia?

Answer 4

1. Increased RBC (due to to BM compensatory response to ineffective hematopoiesis)
2. Microcytic hypochromic anemia

Question 5

Alpha thalassemia is more common in Far East, and is mostly caused by gene deletions/ point mutations?

Answer 5

gene deletion

1-4 alpha genes are deleted

Question 6

How many alpha gene(s) deleted can cause a cinically asymptomatic alpha thalassemia trait?

Answer 6

1-2

1 alpha-globin gene affected: alpha+ (a-/aa) > asymptomatic
2 alpha-globin gene affected: alpha heterozygote (–/aa or -a/-a)

Question 7

Which type of deletion is MC in HK which is an implication antenatal screening?

Answer 7

SEA deletion (alpha heterozygote)

Question 8

In alpha thalassemia parents with 2 genes deleted, although it may be completely asymptomatic in parents, but 1/4 offspring can develop ___________.

Answer 8

Hydrops fetalis

Question 9

In patients with 3 alpha genes deleted, HbH Hemoglobin H disease) disease arise.
Breifly explain.

Answer 9

beta 4 (–/-a)
- Excess beta globin chain form tetramer beta-4 (HbH)
> Instability causes chronic hemolytic anemia
- 2 Hb are affected in this case

Question 10

Number and types of genes in a normal hemoglobin?

Answer 10

2 alpha and 2 beta genes in HbA

Question 11

Is transfusion needed when 3 alpha genes are deleted in alpha-thalassemia patients?

Answer 11

Not required unless in acute illness, remaining functional alpha globin gene can provide enough alpha globin chains for production of HbA.

Yet, during acute illness when life span of red cells is decreased, patient might require transfusion.

Question 12

Some golf ball like material can be seen in peripheral blood in a patient with alpha thalassemia. What are they?

Answer 12

HbH inclusion body

Question 13

If mother is diagnosed with alpha-thalassemia with 3 alpha globin genes delted, what to do?

Answer 13

Folate replacement to compensate for hemolytic anemia

1/4 offspring develop hydrops fetalis

Question 14

What happen when 4 alpha genes are deleted?

Answer 14

• Hydrops fetalis: gamma4 (Hb Barts) (–/–)
• Excess gamma globin chain form tetramer gamma4 (all 4 are gamma chains)
• incompatible with life

Question 15

What is hydrops?

Answer 15

Edema in 2 or more fetal compartments:

• severe anemia > compensation by raising CO > HF > edema
• Doppler USG: increased in blood flow MCA
• Proceed to genetic testing by invasive molecular testing

Question 16

Alpha thalassemia mode of inheritance?

Answer 16

Autosomal recessive

Question 17

Beta thalassemia is more common in the Mediterranean region, and is mostly caused by gene deletion/point mutation?

Answer 17

Point mutations

Question 18

What is beta thalassemia?

Answer 18

Ineffective erhtropoiesis and hemolysis due to precipitation of excess alpha chains in BM

Question 19

List all the types of beta thalassemia and their possible forms.

B = normal beta chain 
B+ = reduced inactivation of beta globin gene 
B0 = complete inactivation of beta globin gene

Answer 19

1. Minor:
   B/B0 or B/B+
2. Intermedia
   B+/B+ or B+/B0
3. Major
   B0/B0 or B+/B0

B = normal beta chain 
B+ = reduced inactivation of beta globin gene 
B0 = complete inactivation of beta globin gene

Question 20

Which of the following are clinical features of beta thalassemia major?

A. Severe anemia, transfusion dependent
B. Extramedullary hematopoiesis, thus splenomegaly
C. Bone expansion
D. Osteoporosis
E. Iron overload
F. Infections due to splectomy and transfusion

Answer 20

All of the above

C: intesnse BM hyperplasia > bossed skull, hair-on-end appearnce on Xray

E: due to transfusion

Question 21

In a peripheral blood film, there is microcytic hypochromic anemia, with nucleated RBCs, target cells and basophilic stippling. Which type of thalassemia?

Answer 21

Beta thalassemia major

Question 22

What can be seen in HPLC (High performance liquid chromatography) in patients with beta thalassemia major ?

Answer 22

Absence of HbA peak, majority is HbF (compensation)

Question 23

What is the treatment for beta thalassemia major patients?(3)

Answer 23

1. Regular transfusion, consider allogenic stem cell transfusion
   - splenectomy can be considered to reduce blood requirement
2. Folic acid
3. Vitamin D, biphosphonates for osteoporesis

Question 24

List 3 things to do to prevent adverse effects from regular transfusion.

Answer 24

1. Iron chelation (to prevent iron overload)
2. Endocrine therapy (secondary to Fe overload): Treatment is according to DM/ hypopituitarism and hypoparathyroidism accordingly
3. Immunisation for HBV

Question 25

Compared to major, beta thalassemia intermedia is: A. Less severe, without the need for regular transfusion B. diagnosed by increase HbF and HbA2 C. HbA is present

Answer 25

All except C | HbA is absent!

Question 26

Beta thalassemia minor: A. Asymptomatic patients B. Only 1 beta globin gene is affected C. There is an increase in HbA2 in HPLC

Answer 26

All of the above

Question 27

What are the 2 types of NTDT? (non-transfusion-dependent thalassemia)

Answer 27

1. HbH disease | 2. Beta thalassemia intermedia

Question 28

Which of the following is correct about antenatal screening? A. It is not useful in detecting alpha-thalassemia B. There is and increase in HbA2 +/- HbF in beta thalassemia patients C. Can be done as usual in IDA patients

Answer 28

B only A: inHbH and HbB is useful C: IDA patients: false negative can be present, correct IDA before the test

Question 29

Which of the following should be done for high risk couples? A. Invasive (chorionic villus samping)/ non-invasive (fetal cell-free DNA) B. Molecular study: GAP-PCR for SEA deletion C. Molecular study: PCR-DNA D. Ultrasound E. Counselling

Answer 29

All of the above B: in alpha thalassemia C: in beta thalassemia D: hydrops fetalis/ fetal anemia in possible alpha-thalassemis fetus

Question 30

Varient hemoglobins are caused by ___________mutations in coding region of globin genes, causing production of Hb with different physical properties.

Answer 30

missense

Question 31

What is the MC variant Hb in our locality?

Answer 31

HbE- beta chain variant alpha2, betaE2

Question 32

In patient with HbE (beta chain variant), what is happen and how is it diagnosed?

Answer 32

- reduced rate of synthesis of beta chain > blood picture shows mild thalassemia or normal - Dx: HPLC - increased HbE

Question 33

Is HbE variant totally harmless? Why?

Answer 33

No. Harmful if co-ingherited with beta-thalassemia (1 beta produces beta E globin while other is B0/ B+ ) > causing beta thalassemia major/ intermedia like disease

Question 34

HbS is also a beta chain variant, which causes?

Answer 34

Sickling of red cells at low O2 tension

Question 35

What can be shown in the HPLC of patients with HbS?

Answer 35

HbS peak, reducing or absent HbA

Question 36

Which of the following about HbS beta chain variant is incorrect? A. It does not require regular transfusion B. Stem cell transplantation is a treatment option C. Vaso-occlusive crisis is one of the systemic complications D. Aplastic crisis is one of the systemic complications E. Hemolysis is one of the systemic complications

Answer 36

A

Question 37

Mode of transmission of beta thalassemia?

Answer 37

Autosomal recessive