L7 Genetic disorders of hemoglobin Flashcards
In the synthesis of hemoglobin, what happens at 3-6 months?
Gamma-beta switch from HbF > HbA
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)
2 alpha-globin genes
2 beta-globin genes
What is the main pathology of Thalassaemia syndromes that can be summarized in a sentence?
Reduced rate of synthesis of alpha/beta chains > imbalanced globin chain
What can be seen in CBC of patients with thalassemia?
- Increased RBC (due to to BM compensatory response to ineffective hematopoiesis)
- Microcytic hypochromic anemia
Alpha thalassemia is more common in Far East, and is mostly caused by gene deletions/ point mutations?
gene deletion
1-4 alpha genes are deleted
How many alpha gene(s) deleted can cause a cinically asymptomatic alpha thalassemia trait?
1-2
1 alpha-globin gene affected: alpha+ (a-/aa) > asymptomatic
2 alpha-globin gene affected: alpha heterozygote (–/aa or -a/-a)
Which type of deletion is MC in HK which is an implication antenatal screening?
SEA deletion (alpha heterozygote)
In alpha thalassemia parents with 2 genes deleted, although it may be completely asymptomatic in parents, but 1/4 offspring can develop ___________.
Hydrops fetalis
In patients with 3 alpha genes deleted, HbH Hemoglobin H disease) disease arise.
Breifly explain.
beta 4 (–/-a)
- Excess beta globin chain form tetramer beta-4 (HbH)
> Instability causes chronic hemolytic anemia
- 2 Hb are affected in this case
Number and types of genes in a normal hemoglobin?
2 alpha and 2 beta genes in HbA
Is transfusion needed when 3 alpha genes are deleted in alpha-thalassemia patients?
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.
Some golf ball like material can be seen in peripheral blood in a patient with alpha thalassemia. What are they?
HbH inclusion body
If mother is diagnosed with alpha-thalassemia with 3 alpha globin genes delted, what to do?
Folate replacement to compensate for hemolytic anemia
1/4 offspring develop hydrops fetalis
What happen when 4 alpha genes are deleted?
- Hydrops fetalis: gamma4 (Hb Barts) (–/–)
- Excess gamma globin chain form tetramer gamma4 (all 4 are gamma chains)
- incompatible with life
What is hydrops?
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
Alpha thalassemia mode of inheritance?
Autosomal recessive
Beta thalassemia is more common in the Mediterranean region, and is mostly caused by gene deletion/point mutation?
Point mutations
What is beta thalassemia?
Ineffective erhtropoiesis and hemolysis due to precipitation of excess alpha chains in BM
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
- Minor:
B/B0 or B/B+ - Intermedia
B+/B+ or B+/B0 - Major
B0/B0 or B+/B0
B = normal beta chain B+ = reduced inactivation of beta globin gene B0 = complete inactivation of beta globin gene
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
All of the above
C: intesnse BM hyperplasia > bossed skull, hair-on-end appearnce on Xray
E: due to transfusion
In a peripheral blood film, there is microcytic hypochromic anemia, with nucleated RBCs, target cells and basophilic stippling. Which type of thalassemia?
Beta thalassemia major
What can be seen in HPLC (High performance liquid chromatography) in patients with beta thalassemia major ?
Absence of HbA peak, majority is HbF (compensation)
What is the treatment for beta thalassemia major patients?(3)
- Regular transfusion, consider allogenic stem cell transfusion
- splenectomy can be considered to reduce blood requirement - Folic acid
- Vitamin D, biphosphonates for osteoporesis
List 3 things to do to prevent adverse effects from regular transfusion.
- Iron chelation (to prevent iron overload)
- Endocrine therapy (secondary to Fe overload): Treatment is according to DM/ hypopituitarism and hypoparathyroidism accordingly
- Immunisation for HBV
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
All except C
HbA is absent!
Beta thalassemia minor:
A. Asymptomatic patients
B. Only 1 beta globin gene is affected
C. There is an increase in HbA2 in HPLC
All of the above
What are the 2 types of NTDT? (non-transfusion-dependent thalassemia)
- HbH disease
2. Beta thalassemia intermedia
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
B only
A: inHbH and HbB is useful
C: IDA patients: false negative can be present, correct IDA before the test
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
All of the above
B: in alpha thalassemia
C: in beta thalassemia
D: hydrops fetalis/ fetal anemia in possible alpha-thalassemis fetus
Varient hemoglobins are caused by ___________mutations in coding region of globin genes, causing production of Hb with different physical properties.
missense
What is the MC variant Hb in our locality?
HbE- beta chain variant
alpha2, betaE2
In patient with HbE (beta chain variant), what is happen and how is it diagnosed?
- reduced rate of synthesis of beta chain > blood picture shows mild thalassemia or normal
- Dx: HPLC - increased HbE
Is HbE variant totally harmless? Why?
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
HbS is also a beta chain variant, which causes?
Sickling of red cells at low O2 tension
What can be shown in the HPLC of patients with HbS?
HbS peak, reducing or absent HbA
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
A
Mode of transmission of beta thalassemia?
Autosomal recessive
