haemoglobinopathies and thalassaemia Flashcards
(119 cards)
1
Q
what are the 3 types of haemoglobin?
A
HbA (α2 β2)
HbA2 (α2 δ2)
HbF (α2 γ2 ) - foetal Hb
2
Q
where is the α globin gene found?
A
The α globin gene is carried on chromosome 16
3
Q
how many copies of the α globin gene found on each chromosome?
A
each chromosome has 2 copies of the alpha globin gene
4
Q
what is found on chromosome 11?
A
β, δ and γ globin genes
5
Q
how many copies of the β, δ and γ globin genes are there?
A
2 copies
6
Q
when does foetal Hb (HbF α2 γ2 )
change to HbA?
A
3-6 months after birth
7
Q
how does the switch from foetal haemoglobin occur?
A
γ chain production is replaced by β chain production
8
Q
what are haemoglobinopathies?
A
A mutation in the globin genes that give rise to different types and amounts of haemoglobin
9
Q
what are the 2 types of haemoglobinopathies?
A
structural variants
thalassaemia
10
Q
what causes the structural variants in haemoglobinopathies?
A
Mutation of globin gene which produces functionally abnormal haemoglobin
11
Q
what causes thalassaemia?
A
Mutation of globin gene which results in reduced or no globin chain synthesis
12
Q
which of the haemoglobinopathies is a qualitative defect?
A
structural variants
13
Q
which of the haemoglobinopathies is a quantitative defect?
A
thalassaemia
14
Q
what are the structural variants characterised by?
A
the synthesis of structurally abnormal globin chains
15
Q
how many structural variants have been described?
A
> 1000 different structural variants have been described
16
Q
what are the 4 most common examples of structural variants?
A
Hb S
Hb C
Hb D
Hb E
17
Q
what are some of the genetic reasoning of structural variants?
A
Usually a point mutation within the globin genes
Usually single amino acid substitutions on a globin gene
Alter the function of the haemoglobin
18
Q
what is the most frequent structural variant?
A
sickle cell
19
Q
what gave sickle cell its name?
A
its characteristic sickle shaped red cells
20
Q
what is Haemoglobin S made up of?
A
2 α chains
2 β chains
21
Q
what happens to the structure of Hb S during sickle cell?
A
An amino acid substitution one or both of the β genes
Glutamic acid in position 6 is replaced by valine
22
Q
what does the structural variant in sickle cell lead to?
A
Leads to the production of functionally abnormal Haemoglobin S
23
Q
what is the difference in solubility of deoxygenated HbS and deoxygenated HbA?
A
Deoxygenated HbS is 50 times less soluble than deoxygenated HbA
24
Q
what is the role of deoxygenated HbS in the formation sickle cell?
A
Deoxygenated HbS lose solubility and polymerise into long rigid chains which deform the red cell into sickle shapes
25
when if HbS soluble?
when it is fully oxygenated
26
what are the conditions that predispose cells to sickling?
Hypoxia-insufficient levels of oxygen in the blood
Acidosis-Increased levels of acid in blood
Increased body temperature
27
how can sickling be reversed?
after re-oxygenation
28
what are the 2 types of inheritance which lead to sickle cell?
- Homozygous (Hb S+S) both β globin genes affected
| - Heterozygous (HB A+S) only one β globin gene affected
29
what are the features of sickle cell trait (5)?
```
Normal haemoglobin level
Normal red cells in blood film
Usually asymptomatic
HbA and HbS present
Care must be taken when an individual is exposed to reduced oxygen concentration (<40%)
```
30
what are some symptoms of sickle cell trait?
Haematuria
| Renal papillary necrosis
31
what are the features of Sickle cell Disease/Sickle Cell Anaemia?
Only HbS produced (HbS+S)
Severe haemolytic anaemia
Punctuated by crises
Jaundice
32
what are the clinical expressions of Sickle cell disease/Sickle cell anaemia?
Normal life
Severe crises
Shortened lifespan
33
what are the clinical features of Sickle cell anaemia (11)?
```
Ulcers of lower leg
Dactylitis
Susceptibility to infection
Enlarged spleen
Pulmonary hypertension
Retinopathy
Priapism
Liver damage
Gallstones
Kidney infections
Severe crises
```
34
what are the types of crises?
Vaso-occlusive crises
Visceral sequestration crises
Aplastic crises
Haemolytic crises
35
which is the most frequent type of crisis?
Vaso-occlusive crises
36
in vaso-occlusive crises where do infarctions occur?
Bones
Lungs
Spleen
Brain
37
what causes sequestration crises?
Caused by sickling within organs and pooling of blood
| Exacerbation of anaemia
38
when is splenic sequestration seen?
typically in infants
39
what are examples of sequestration crises?
sickle chest syndrome
splenic sequestration
hepatic sequestration
girdle sequestration
40
when do aplastic crises occur?
as a result of infection - Parvo virus
| Folic acid deficiency
41
what are aplastic crises characterised by?
Sudden drop in Hb
Fall in reticulocytes
Transfusion support
42
what are haemolytic crises characterised by?
Increased rate of haemolysis
Fall in Hb
Rise in reticulocytes
Pain
43
what are the screening tests for sickle syndromes?
positive sickle solubility test
| haemoglobin electrophoresis
44
what is a disadvantage of the positive sickle solubility test?
Does not differentiate between homozygous and heterozygous inheritance
45
what are the results of haemoglobin electrophoresis in homozygous inheritance?
shows the presence of a single major moving band in the position of HbS
46
what are the results of haemoglobin electrophoresis in heterozygous inheritance?
HbA and HbS bands-heterozygous inheritance
47
what are the prophylactic treatments for crises?
Folic acid
Good nutrition and hygiene
Vaccination
Antibiotics to reduce infection risk
48
how are crises treated?
Rest
Rehydration
Warmth
Pain relief
49
what are other treatment options (sickle cell)?
```
Pregnancy support and monitoring
Monitor HbS levels
Transfusion support
Hydroxyurea
Transplantation
```
50
what is the prognosis for Sickle cell disease (HbS+S)?
- High mortality rate
| - Median survival rate 50 years
51
why has the survival rate for sickle cell disease increased?
Increased with introduction of vaccination programme
| Awareness of acute splenic sequestration syndrome
52
why are neonatal screening programmes beneficial?
Identifies all those potentially affected
Ensures early treatment
Reduces mortality and morbidity rates.
53
what are some of the screening services for Sickle cell disease (7)?
```
Testing partners of affected mother
Genetic counselling for high risk parents
Antenatal diagnosis
Testing of newborn
Identification of “at risk” infant
Begin vaccination programme
Begin antibiotic treatment
```
54
what are other clinically significant haemoglobinopathies?
HbC-West Africa
HbD-Indian sub-continent
HbE- South East Asia
55
what happen in HbC haemoglobinopathy (4)?
Glutamic acid is replaced by lysine at position 6
Enlarged spleen
Mild haemolytic anemia
Target cells
56
what happens in HbD haemoglobinopathy (3)?
Glutamic acid is replaced by glutamine at position 121
Homozygotes have mild haemolytic anaemia
Target cells
57
what happens in HbE haemoglobinopathy?
Glutamic acid is replaced with Lysine at position 26
| Mild microcytic hypochromic anaemia
58
what are the combinations of HbS with other genetic defects of haemoglobin?
HbS/HbC
| HbS/β-thalassaemia
59
how are the combinations of HbS diagnosed?
Diagnosis by Hb electrophoresis and family studies
60
what are thalassaemias?
Genetic disorders that result from a reduced or absent synthesis of α or β haemoglobin chains
61
what are the 3 criteria for thalassaemia classification?
- the affected globin gene
- reduction rate of synthesis of globin
- genotype
62
what are the options for the affected globin gene in thalassaemia?
α globin chains
| β globin chains
63
what are the options for reduction in rate of synthesis of globin in thalassaemia?
Total reduction
| Partial reduction
64
what are the genotype options for thalassaemia?
Heterozygous
| Homozygous
65
how common is thalassaemia?
Among the most common single gene disorders in the world
66
where is β thalassaemia common?
Mediterranean
Africa
India
Greece
67
where is α thalassaemia common?
Indonesia
South-east Asia
Southern China
68
how many α globin genes?
4 - 2 pairs
69
where are α globin genes found?
chromosome 16
70
what do 95% of thalassaemias result from?
95% thalassaemias result from a deletion on one or both pairs of globin genes
71
what are the 6 possible genotypes for α thalassaemia?
```
normal
α+ heterozygote
α+ homozygote
αo heterozygote
αo homozygote - Barts hydrops foetalis
αo homozygote - Barts hydrops foetalis
αo α+ double heterozygote - Hb H disease
```
72
what genotype is known as α+ heterozygote?
α-/αα
73
what is the genotype known as α+ homozygote?
α-/α-
74
what is the genotype that is known as αo heterozygote?
αα/--
75
what is the αo homozygote - Barts hydrops foetalis
| genotype?
--/--
76
what is the αo α+ double heterozygote - Hb H disease genotype?
--/α-
77
what is the normal alpha genotype?
αα/αα
78
what does the clinical severity of α Thalassaemia syndromes depend on?
Varies according to how many missing or inactive genes
79
which are the silent carriers of α Thalassaemia syndromes?
α+ heterozygote α-/αα
80
what are the characteristics of α+ heterozygote α-/αα?
- Deletion in one single globin gene
- No haematological abnormality
- Can only be defined with complete and reliable DNA analysis
81
which genotype is the α thalassaemia trait?
α+ homozygote α-/α- or αo heterozygote αα/--
82
what are the characteristics of thalassaemia trait?
- Clinically indistinguishable
- Identical laboratory profiles
- Normal haemoglobin electrophoresis
- Only DNA analysis will differentiate
83
what are the clinical features of α thalassaemia trait?
Mild microcytic, hypochromic anaemia
No significant symptoms of disease
MCH lower in αo than α+
84
what are the characteristics of Haemoglobin H disease --/α-?
```
Deletion within 3 α globin genes
Moderate to severe anaemia and hepatosplenomegaly
Hb 80g/l
Transfusion support often unnecessary
Adult blood contains 5-35% Hb H ( β4)
```
85
what is visible on a blood film of a patient with Haemoglobin H disease?
Microcytosis and hypochromasia
Poikilocytosis
Target cells
Polychromasia
Hb H inclusion bodies
86
what is the main cause of haemolytic anaemia in Haemoglobin H disease?
Hb H inclusion bodies
87
which is the most severe form α thalassaemia?
Haemoglobin Barts Hydrops Foetalis --/--
88
what happens to the α globin genes in Haemoglobin Barts Hydrops Foetalis --/--
all 4 α globin genes are deleted
89
what form of haemoglobin is formed in Haemoglobin Barts Hydrops Foetalis?
No functionally normal haemoglobin formed
| Functionally useless Hb Barts (γ4) and HBH ( β4) formed
90
what is the concentration of haemoglobin in patients of Haemoglobin Barts Hydrops Foetalis ?
at delivery 60 g/l
91
what usually happens in the pregnancy of a foetus with Haemoglobin Barts Hydrops Foetalis?
pregnancy usually terminates in the third trimester
92
what do β Thalassaemia syndromes result from?
Usually results from point mutations within the β globin gene
93
how are β Thalassaemia syndromes classified?
Individuals grouped according to severity of their symptoms
94
what are the 3 groups of β Thalassaemia syndromes?
- β thalassaemia trait
- β thalasaemia major
- β thalassaemia intermedia
95
what is the mildest form of β Thalassaemia syndromes?
β thalassaemia trait -heterozygous
96
what causes β thalassaemia trait -heterozygous?
One abnormal β globin gene
97
what is found in the lab investigations of β thalassaemia trait?
```
Mild microcytic hypochromic anaemia
Target cells
Raised red cell count
Nucleated red cells
Tear drop cells
Microspherocytes
```
98
what would be seen in a HPLC showing β thalassaemia trait?
- Raised Hb F
- Raised Hb A2
- Important to differentiate thalassaemia from Iron deficiency
99
what causes β thalassaemia major-Homozygous?
Inherit two abnormal β globin genes
100
what are the skeletal deformities in β thalassaemia major caused by?
Erythroid hyperplasia
| Expansion of bone marrow volume
101
what are signs of β thalassaemia major?
Severe anaemia
Gross hepatosplenamegaly
Failure to thrive
skeletal deformities
102
what would be seen in a bone marrow investigation for β thalassaemia major?
- extreme erythroid hyperplasia
- masked ineffective erythropoiesis
- aggregates of excess α globin chains promotes intramedullary death of developing erythroblasts
- Reduced lifespan of circulating red cells
103
what causes the Extreme erythroid hyperplasia?
excessive growth of immature red blood cells
104
why is marked ineffective erythropoiesis important?
does not result in the functional release of new erythrocytes
105
what does Hb electrophoresis show in β thalassaemia major?
Marked increase in HbF (up to 98%)
| No HbA
106
what are other tests to diagnose thalassaemia?
```
Hb Electrophoresis
Quantification of HbF
Column chromatography
Immunoassay
HPLC
Isoelectric focusing
DNA analysis
```
107
what is the treatment for thalassaemia?
Regular blood transfusions
Maintain Hb at 100-120 g/l
Chelation therapy
108
why is it important to maintain Hb at 100-120 g/l in the treatment of thalassaemia?
Suppresses erythropoiesis
| Prevents skeletal changes
109
what is a side effect of lifelong transfusion?
leads to accumulation of large amounts of iron within the body
Iron is toxic
Damages heart and liver
110
what are some more treatments for thalassaemia?
```
Vitamin C
Splenectomy
Immunisation
Antibiotic therapy
Folic acid
Bone marrow transplant
```
111
what is the prognosis for thalassaemia without treatment?
5 years
112
what is the prognosis for thalassaemia with treatment?
Without chelation 20-30 years
| With chelation 50 years+
113
when is a bone marrow transplant successful?
Without chelation 20-30 years
| With chelation 50 years+
114
true or false Not all cases of homozygous β thalassaemia have severe disease?
true
115
true or false there are only a few varieties of β thalassaemic mutations?
false - Wide diversity of β thalassaemic mutations
116
what is β thalassaemia intermedia?
Encompasses all cases of β thalassaemia with significant symptoms of disease which do not need regular blood transfusion to maintain Hb above 70g/l
117
what does thalassaemia intermedia arises from?
Inheritance of “mild” β thal mutations
Co-inheritance with a gene that increase the rate of γ globin synthesis
Co-inheritance with α thalassaemia
118
what are the laboratory and clinical findings of thalassaemia intermedia?
Bone changes
Bones break more easily
Hypersplenism
119
is there iron overload in thalassaemia intermedia?
yes - due to morbidity-excessive absorption of dietary iron
