Inherited blood disorders

Question 1

What is defective in alpha thalassaemia

Answer 1

Deletion in one/both alpha genes(90%) -> defect alpha chain production-> excess beta like globin formation. Point mutation in 10%

Question 2

What are the 4 possible alpha thalassaemia syndromes

Answer 2

1. I deletion: silent carrier.
2. 2 deletions: alpha-thalassaemia minor. Assymptomatic.
3. 3 del: HbH disease. Unstable Hb -> microcytic anaemia. Survive to adult.
4. 4 del: Hb Barts hydrops fetalis.

Question 3

Which gene encodes beta globin subunit and mutations result in beta thalassaemia

Answer 3

HBB Chr 11p15.4

Question 4

Example of genetic modifier in thalassaemia

Answer 4

Co-inheritance of alpha and beta thalassaemia mutations-> decrease imbalance

Question 5

Phenotype beta thalassaemia major

Answer 5

Anaemia, diaroeah, fever, hepatosplenomegaly. Transfusion dependent from 6month

Question 6

Example of disorder showing heterozygous advantage

Answer 6

Sickle cell disease

Question 7

How test for haemoglobinopathies?

Answer 7

1. FBC and microscope analysis
2. Hb pattern analysis eg by HPLC
3. DNA only in complicated cases

Question 8

How can gene therapy be used

Answer 8

Lentivirus vectors used as infect quiescent cells and carry large cassettes. Intro exogenous beta globin and anti sickling globin. Current phase 1 trials

Question 9

What are Hb alpha genes

Answer 9

HBA1, HBA2 on Chr 16. 2:1 genes exp in 3:1 ratio

Question 10

Name 2 inherited bleeding disorders

Answer 10

Von willebrand disease (VWD) and haemophilia

Question 11

Gene involved in vin willebrand disease

Answer 11

VWF 12p13.2

Question 12

Mode of inheritance of haemophilia

Answer 12

X link recessive

Question 13

Incidence of haemophilia

Answer 13

Male live births type A 1/5,000. Type B 1/30,000

Question 14

Genetic abnormalities in haemophilia A

Answer 14

45% large gene inversion in intron 22. 2-3% inversion intron 1. Rest are point mutations mostly

Question 15

Coagulation factors affected in haemophilia A and B

Answer 15

A: factor 8, B: factor 9

Question 16

Other inherited bleeding disorders

Answer 16

Congenital afibrinogenemia (factor 1 deficiency), factor 7 deficiency,

Question 17

What is factor 7 deficiency

Answer 17

Diagnosed about 6 months, when bleed into gastro tract, AR, 13q34, familial private mutations >130 decsribed, factor 7 binds tissue factor to initiate clot cascade.

Question 18

Examples inherited thrombophilias

Answer 18

Factor V Leiden thrombophilia, factor II prothrombin thrombophilia, hereditary antithrombin deficiency