Chapter : 7 - Genetic Disorders of Haemoglobin - Thalassaemia

Question 1

What are the three types of Haemoglobin?

Answer 1

• Hb A - α2β2
• Hb A2 - α2δ2
• Hb F - α2γ2

Question 2

What percentage of Hb A2 is found in normal adult haemoglobin?

Answer 2

1.5-3.5%

Question 3

True or False? There is NO Hb F found in normal adult haemoglobin.

Answer 3

FALSE!! There is about 0.5% of Hb F in adult haemoglobin.

Question 4

What is the primary Embryonic haemoglobin despite its relative instability ?

Answer 4

Hb Gower 1

Question 5

On which chromosome is the β-globin cluster ( e, γ, δ and β) located on?

Answer 5

Chromosome 11q

Question 6

On which chromosome is the ‘α-globin cluster’ ( ζ and α ) located on?

Answer 6

Chromosome 16p

Question 7

True or False? In healthy individuals there are our α-globin genes and two β-globin genes .

Answer 7

TRUE!!

Question 8

Fill in the blanks. “ All the globin genes have __________ (coding regions) and__________ (non-coding regions whose DNA is not represented in the finished protein).”

Answer 8

Three exons ( coding regions)
Two introns ( Non- coding regions)

Question 9

Fill in the blanks. “ _________ regulates α-globin synthesis.”

Answer 9

HS-40

Question 10

When does the main switch to adult haemoglobin from foetal haemoglobin occur?

Answer 10

3-6 months AFTER birth.

Question 11

What is the major transcriptional factor gene regulator of the switch from foetal to adult haemoglobin?

Answer 11

BCL11A

Question 12

Which Haemoglobin defect is found most commonly in persons of sub- Saharan African origin?

Answer 12

Hb C

Question 13

True or False? Hb D is detected frequently in Western China and South Asia, and Hb E in South-East Asia.

Answer 13

TRUE!!

Question 14

At which position is the Gamma ( γ)gene located?

Answer 14

The γ gene may have two sequences, which code for either a glutamic acid or alanine residue at position 136 .

Question 15

What are examples of unstable haemoglobins?

Answer 15

Hb Köln & Hb Zurich - may result in ‘Heinz body’ congenital haemolytic anaemias.

Question 16

True or False? Beta (β) -Thalassaemia is more common in the Mediterranean region, while Alpha( α) -thalassaemia is more common in South and South-East Asia.

Answer 16

TRUE!!

Question 17

Which Thalassemia is Transfusion dependent?

Answer 17

Thalassemia Major

Question 18

Which thalassemia is non- transfusion dependent with a moderate degree of anaemia due to a variety of genetic defect?

Answer 18

Thalassemia Intermedia

Question 19

What are the characteristics of Thalassemia minor?

Answer 19

Usually due to a carrier state for α- or β-thalassaemia and characterized by erythrocyte microcytosis and mild or no anaemia.

Question 20

What are the clinical features of Three alpha deletion?

Answer 20

*Moderately severe (haemoglobin 70–110 g/L) microcytic, hypochromic anaemia

• Splenomegaly

Question 21

What is the name given to Three alpha chain deletion?

Answer 21

Hb H diseases ( a tetramer of self-associating β-globin chains, β4)

Question 22

Fill in the blanks. “A four alpha chain deletion results in __________.”

Answer 22

Hydrops fetalis

Question 23

How can one be diagnosed with Hb H disease ( Three alpha deletion )?

Answer 23

This can be detected in red cells of these patients by electrophoresis or in reticulocyte preparations

Question 24

What are the clinical features of one or two alpha chain deletion?

Answer 24

• These are usually not associated with anaemia
• The mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) are LOW and the red cell count is OVER 5.5 × 1012/L.

Question 25

How is one or two alpha deletion normally diagnosed?

Answer 25

Haemoglobin electrophoresis is usually normal and DNA analysis is needed to be certain of the diagnosis.

Question 26

True or False? In Beta Thalassemia major , there is ineffective erythropoiesis and chronic haemolysisi.

Answer 26

TRUE!!

Question 27

What are the clinical features of Beta Thalassemia major?

Answer 27

1. Severe Anaemia - 3-6 months after birth ( patient may present within the first year with failure to thrive, pallor , swollen abdomen) 2. Enlargement of liver an spleen - ( occurs due to excessive red cell destruction, extramedullary haemopoiesis and later because of iron overload) 3. Expansion of bones- caused by intense marrow hyperplasia leads to a thalassaemic facies and to thinning of the cortex of many bones, with a tendency to fractures and bossing of the skull with a ' HAIR ON END ' appearance on X-ray 4. Transfusional iron overload. 5.Infections 6. Liver disease - in thalassaemia major is most frequently a result of hepatitis C, but hepatitis B is also common where the virus is endemic. Liver disease can also be as a result of iron overload . 7. Hepatocellular carcinoma 8. Osteoporosis

Question 28

In Thalassemia major, which infections are likely to occur post- splenectomy?

Answer 28

Haemophilus and meningococcal infections

Question 29

Which causative agent associated with Thalassemia major due to iron over load being treated with deferoxamine can cause severe Gastroenteritis?

Answer 29

Yersinia enterocolitica -

Question 30

" The skull is bossed with prominent frontal and parietal bones; the maxilla is also enlarged." can be associated with which pathology?

Answer 30

Beta Thalassemia major

Question 31

What are the types of cells found in Beta Thalassemia major?

Answer 31

* Normoblasts * Target cells * Basophilic stippling in the blood film * Howell - Jowell bodies

Question 32

What type of cells are found in Hb H disease?

Answer 32

* Marked hypochromic, microcytic cells * Target cells * Poikilocytosis

Question 33

Deeply stained deposits (‘golf ball’ cells) are associated with which disease?

Answer 33

Hb H disease

Question 34

What is the stain used to identify Hb H disease?

Answer 34

Supravital staining with brilliant cresyl blue or methylene blue

Question 35

How is the diagnosis made for Beta Thalassemia major?

Answer 35

* High-performance liquid chromatography (HPLC) is now usually used as the first-line method to diagnose haemoglobin disorders. *HPLC or haemoglobin electrophoresis (Fig. 7.12b) reveals the absence or almost complete absence of Hb A, with almost all the circulating haemoglobin being Hb F. * HbA2 percentage is raised , normal or reduced . * Iron overload testing

Question 36

What is the treatment for Beta Thalassemia major?

Answer 36

1. Regular Blood Transfusions - 2–3 units every 3–4 weeks. 2. Iron chelation 3. Regular folic acid 4. Splenectomy 5. Endocrine Therapy 6. Immunization 7. Allogenic Stem cell transplantation 8 . Gene Therapy 9. Luspatercept - (synthetic IgG1 antibody–activin II receptor fusion protein).

Question 37

Fill in the blanks. " A beta Thalassemia TRAIT can be diagnosed by_________."

Answer 37

A raised level of Hb A2 (>3.5%).

Question 38

What are the clinical features of Beta Thalassemia Trait?

Answer 38

1. Hypochromic, micro- cytic blood picture (MCV and MCH low) 2. High Red Cell count (>5.5×1012/L) 3. Mild anaemia (haemoglobin 100–120 g/L)

Question 39

What are the genetic causes of Beta Thalassemia Intermedia?

Answer 39

1. Homozygous β-thalassaemia with production of more Hb F than usual, e.g. due to mutations of the BCL11A gene, or with milder defects in β chain synthesis. 2. β-thalassaemia trait alone of unusual severity (‘dom- inant’ β-thalassaemia trait) 3. β-thalassaemia trait in associ- ation with another mild globin abnormality such as Hb Lepore.

Question 40

What are the clinical features of Beta Thalassemia Intermedia?

Answer 40

* Liver fibrosis & cirrhosis * Bone deformities and extramedullary erythropoiesis * Leg ulcers * Gallstones * Osteoporosis * Pulmonary hypertension * Venous thrombosis

Question 41

Fill in the blanks. " _______________ is a type of Thalassemia Intermedia WITHOUT iron overload or extramed- ullary haemopoiesis."

Answer 41

Hb H disease

Question 42

What is Haemoglobin Leopre?

Answer 42

This is an abnormal haemoglobin caused by unequal crossing- over of the β and δ genes to produce a polypeptide chain con- sisting of the δ chain at its amino end and the β chain at its carboxyl end.