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Haemoglobinopathies Flashcards

1
Q

What is the inheritance of haemoglobinopathies?

A

vast majority are autosomal recessive

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2
Q

On which chromosome are the alpha like globin genes?

A

chromosome 16

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3
Q

How many genes are there for the alpha globin?

A

2

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4
Q

What alpha like globin genes are there?

A

zeta (and a pseudo zeta and pseudo alpha which are non functional)

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5
Q

On which chromosome are the beta like globin genes?

A

chromosome 11

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6
Q

How many genes are there for the beta globin?

A

1

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7
Q

What beta like globin genes are there?

A

epsilon, gamma (2 slightly different versions that are functionally identical) and delta (also a pseudo beta which is non functional)

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8
Q

How is transcription of globin genes controlled?

A

via the locus control region (LCR) which is very important for developmental regulation, tissue specific regulation and environmental regulation - particular for the beta like globins

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9
Q

Where are the globin genes expressed in the embryonic stage of development?

A

in the yolk sac

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10
Q

What are the 3 embryonic globins?

A

zeta, alpha 2, gamma and epsilon

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11
Q

What are the 3 embryonic haemoglobins?

A

zeta-epsilon, zeta-gamma and alpha2-epsilon

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12
Q

Where is expression of globin in the fetal stage of development?

A

in the liver and spleen and then in the bone marrow

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13
Q

What is the major fetal form of haemoglobin?

A

HbF- alpha and gamma

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14
Q

When does adult haemoglobin start being produced?

A

in the late stages of pregnancy so that by 6 months there is enough adult haemoglobin

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15
Q

What are the two types of adult haemoglobin and which is more common?

A

alpha2beta2 which makes up 97.5% and alpha2delta2 which makes up 2% - the remaining 0.5% is fetal haemoglobin

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16
Q

What are the different haemoglobinopathies?

A

alpha and beta thalassemias (decreased synthesis of one or more globin chain), structural variants (altered globin polypeptide without altering rate of synthesis), hereditary persistence of fetal haemoglobin (clinically benign)

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17
Q

What is HbE?

A

a haemoglobinopathy with altered structure and altered synthesis - gives a mild thalassemia phenotype

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18
Q

How many structural variants of haemoglobin are there?

A

over 500

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19
Q

Where is alpha thalassemia most common?

A

south east asia

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20
Q

Where is beta thalassemia most common?

A

southern europe, middle east, north africa, south east asia, indian subcontinent

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21
Q

Where is sickle cell disease most common?

A

Africa, Middle East and Indian subcontinent

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22
Q

What is alpha thalassemia?

A

a deficiency of alpha globin chains

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23
Q

What is beta thalassemia?

A

a deficiency of beta globin chains

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24
Q

What happens if both alpha and beta synthesis are reduced?

A

it is a milder phenotype than if just one is reduced because the clinical symptoms are a result of the imbalance between the alpha and beta

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25
What is the pathology of thalassemia due to?
the homotetramers (beta homotetramers in alpha thalassemia and alpha homotetramers in beta thalassemia)
26
What mutations causes the majority of alpha thalassemias?
deletions
27
What mutations cause the majority of beta thalassemias?
point mutations
28
What is the difference between beta + and beta 0 beta thalassemia?
beta + means some protein is being made where as beta 0 means no protein is being made - beta + would have a milder phenotype
29
Describe the pathophysiology of untreated beta thalassemia
there is reduced beta globin synthesis which results in too much alpha globin which forms aggregates which are insoluble and damages the membrane of the red blood cells. the red blood cells mostly die in the bone marrow but the few that enter the circulation are destroyed in the spleen. the red blood cells which are broken down release their iron so there is a systemic iron overload
30
What are the complications of the systemic iron overload?
the iron accumulates in organs and causes complications such as diabetes, heart failure, cirrhosis, hyper/hypothyroidism, endocrine complications, infertility
31
Why is there splenomegaly in beta thalassemia?
because of destruction of red blood cells and extramedullary erythropoiesis
32
Why is there hepatomegaly in beta thalassemia?
because of the extramedullary erythropoiesis
33
Why is there skeletal deformities in beta thalassemia?
because of the medullary expansion
34
What is seen on a blood smear for beta thalassemia?
hypochromic microcytic anaemia as well as anisocytotic cells (irregular in size) and poikilocytotic cells (irregular in shape) and tear drop shaped cells and target cells
35
Why is there frontal bossing in beta thalassemia?
medullay expansion
36
What is the appearance of the skull on an xray in beta thalassemia?
hair on end appearance - due to thinning of cranial bones because of medullary expansion
37
What is the MCV in beta thalassemia?
significantly reduced
38
What is the MCHC in beta thalassemia?
significantly reduced
39
What is the HbF in beta thalassemia?
greatly elevated
40
What are the blood parameters for a carrier of beta thalassemia?
moderately reduced/elevated
41
What is the treatment for beta thalassemia?
blood tranfusion for the anaemia, splenectomy for the splenomegaly and iron chelation therapy for the iron overload
42
How often are blood transfusions required?
every 3-4 weeks
43
What is the risk of a blood transfusion?
blood borne infection e.g. HIV or hepatitis B and C
44
What is the risk of a splenectomy?
sepsis
45
How is iron chelation therapy given?
used to be given with a pump overnight but now there are oral treatments available
46
What is the cure for thalssemia?
bone marrow transplant
47
Why is beta thalassemia fatal?
because of the complications of the systemic iron overload
48
What is the result if you have 3 functional alpha globin genes?
you are a silent carrier
49
What is the result if you have 2 functional alpha globin genes?
you have mild anaemia - the two functional genes can either be on one chromosome or on different chromosomes
50
What is the result if you have 1 functional alpha globin gene?
you have HbH disease - moderate to severe anaemia
51
What is the result if you have 0 functional alpha globin genes?
you have HbBart which causes hydrops fetalis which is fatal before or around birth
52
Why does alpha thalassemia have an effect in utero where as beta thalassemia doesnt?
because alpha globin is in the fetal and adult haemoglobin where as beta is just in adult haemoglobin
53
What is the difference between a south east asian mutation and a mediterranean mutation?
south east asian mutation is where the two functional alpha globin genes are on the same chromosome whereas mediterranean is where the two functional alpha globin genes are on different chromosomes - this has an impact on the next generation - south east asian mutation couples have a 1/4 chance of having an HbBart child whereas mediterranean mutation couples cant have an HbBart child
54
What is mutation causes sickle cell disease?
a single base mutation which alters glutamate to valine in the beta globin chain
55
How do the red blood cells sickle in sickle cell disease?
when they're deoxygenated they aggregate which causes sickling - this is initially reversible but becomes irreversible
56
What are the symptoms of sickle cell disease?
anaemia and weakness, failure to thrive, splenomegaly, repeated infections, ischaemia, thrombosis, infarctions, iron overload
57
What is seen on a blood film of sickle cell disease?
severe normocytic or macrocytic haemolytic anaemia
58
What is the MCV and MCH in sickle cell disease?
may be normal if between crisises or may be reduced
59
How do you confirm if someone is a carrier of sickle cell disease?
haemoglobin electrophoresis
60
What is the treatment for sickle cell disease?
a drug which effects the synthesis of beta globin
61
What is a compound heterozygote?
when there are two different types of mutations e.g. two different types of beta globin mutations
62
What is a double heterozygote?
when there are two completely different mutations e.g. a beta globin mutation and an alpha globin mutation - may result in a milder phenotype because of the relative imbalance
63
What are some gene therapies for haemoglobinopathies?
knock down the relative amounts of the other globin gene to create balance using interfering RNAs, upregulate the amount of HbF, gene therapy using pluripotent stem cells
64
What is the heterozygote advantage?
carriers have some resistance to malaria

Intersystem (14 decks)

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