Chapter : 7 - Genetic Disorders of Haemoglobin - Thalassaemia Flashcards
What are the three types of Haemoglobin?
- Hb A - α2β2
- Hb A2 - α2δ2
- Hb F - α2γ2
What percentage of Hb A2 is found in normal adult haemoglobin?
1.5-3.5%
True or False? There is NO Hb F found in normal adult haemoglobin.
FALSE!! There is about 0.5% of Hb F in adult haemoglobin.
What is the primary Embryonic haemoglobin despite its relative instability ?
Hb Gower 1
On which chromosome is the β-globin cluster ( e, γ, δ and β) located on?
Chromosome 11q
On which chromosome is the ‘α-globin cluster’ ( ζ and α ) located on?
Chromosome 16p
True or False? In healthy individuals there are our α-globin genes and two β-globin genes .
TRUE!!
Fill in the blanks. “ All the globin genes have __________ (coding regions) and__________ (non-coding regions whose DNA is not represented in the finished protein).”
Three exons ( coding regions)
Two introns ( Non- coding regions)
Fill in the blanks. “ _________ regulates α-globin synthesis.”
HS-40
When does the main switch to adult haemoglobin from foetal haemoglobin occur?
3-6 months AFTER birth.
What is the major transcriptional factor gene regulator of the switch from foetal to adult haemoglobin?
BCL11A
Which Haemoglobin defect is found most commonly in persons of sub- Saharan African origin?
Hb C
True or False? Hb D is detected frequently in Western China and South Asia, and Hb E in South-East Asia.
TRUE!!
At which position is the Gamma ( γ)gene located?
The γ gene may have two sequences, which code for either a glutamic acid or alanine residue at position 136 .
What are examples of unstable haemoglobins?
Hb Köln & Hb Zurich - may result in ‘Heinz body’ congenital haemolytic anaemias.
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.
TRUE!!
Which Thalassemia is Transfusion dependent?
Thalassemia Major
Which thalassemia is non- transfusion dependent with a moderate degree of anaemia due to a variety of genetic defect?
Thalassemia Intermedia
What are the characteristics of Thalassemia minor?
Usually due to a carrier state for α- or β-thalassaemia and characterized by erythrocyte microcytosis and mild or no anaemia.
What are the clinical features of Three alpha deletion?
*Moderately severe (haemoglobin 70–110 g/L) microcytic, hypochromic anaemia
- Splenomegaly
What is the name given to Three alpha chain deletion?
Hb H diseases ( a tetramer of self-associating β-globin chains, β4)
Fill in the blanks. “A four alpha chain deletion results in __________.”
Hydrops fetalis
How can one be diagnosed with Hb H disease ( Three alpha deletion )?
This can be detected in red cells of these patients by electrophoresis or in reticulocyte preparations
What are the clinical features of one or two alpha chain deletion?
- 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.
How is one or two alpha deletion normally diagnosed?
Haemoglobin electrophoresis is usually normal and DNA analysis is needed to be certain of the diagnosis.
True or False? In Beta Thalassemia major , there is ineffective erythropoiesis and chronic haemolysisi.
TRUE!!
What are the clinical features of Beta Thalassemia major?
- Severe Anaemia - 3-6 months after birth ( patient may present within the first year with failure to thrive, pallor , swollen abdomen)
- Enlargement of liver an spleen - ( occurs due to excessive red cell destruction, extramedullary haemopoiesis and later because of iron overload)
- 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
- Transfusional iron overload.
5.Infections
- 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 .
- Hepatocellular carcinoma
- Osteoporosis
In Thalassemia major, which infections are likely to occur post- splenectomy?
Haemophilus and meningococcal infections
Which causative agent associated with Thalassemia major due to iron over load being treated with deferoxamine can cause severe Gastroenteritis?
Yersinia enterocolitica
-
” The skull is bossed with prominent frontal and parietal bones; the maxilla is also enlarged.” can be associated with which pathology?
Beta Thalassemia major
What are the types of cells found in Beta Thalassemia major?
- Normoblasts
- Target cells
- Basophilic stippling in the blood film
- Howell - Jowell bodies
What type of cells are found in Hb H disease?
- Marked hypochromic, microcytic cells
- Target cells
- Poikilocytosis
Deeply stained deposits (‘golf ball’ cells) are associated with which disease?
Hb H disease
What is the stain used to identify Hb H disease?
Supravital staining with brilliant cresyl blue or methylene blue
How is the diagnosis made for Beta Thalassemia major?
- 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
What is the treatment for Beta Thalassemia major?
- Regular Blood Transfusions - 2–3 units every 3–4 weeks.
- Iron chelation
- Regular folic acid
- Splenectomy
- Endocrine Therapy
- Immunization
- Allogenic Stem cell transplantation
8 . Gene Therapy
- Luspatercept - (synthetic IgG1 antibody–activin II receptor fusion protein).
Fill in the blanks. “ A beta Thalassemia TRAIT can be diagnosed by_________.”
A raised level of Hb A2 (>3.5%).
What are the clinical features of Beta Thalassemia Trait?
- Hypochromic, micro- cytic blood picture (MCV and MCH low)
- High Red Cell count (>5.5×1012/L)
- Mild anaemia (haemoglobin 100–120 g/L)
What are the genetic causes of Beta Thalassemia Intermedia?
- 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.
- β-thalassaemia trait alone of unusual severity (‘dom- inant’ β-thalassaemia trait)
- β-thalassaemia trait in associ- ation with another mild globin abnormality such as Hb Lepore.
What are the clinical features of Beta Thalassemia Intermedia?
- Liver fibrosis & cirrhosis
- Bone deformities and extramedullary erythropoiesis
- Leg ulcers
- Gallstones
- Osteoporosis
- Pulmonary hypertension
- Venous thrombosis
Fill in the blanks. “ _______________ is a type of Thalassemia Intermedia WITHOUT iron overload or extramed- ullary haemopoiesis.”
Hb H disease
What is Haemoglobin Leopre?
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.
