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Intersystem > Haemoglobinopathies > Flashcards

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
Q

What is the pathology of thalassemia due to?

A

the homotetramers (beta homotetramers in alpha thalassemia and alpha homotetramers in beta thalassemia)

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26
Q

What mutations causes the majority of alpha thalassemias?

A

deletions

27
Q

What mutations cause the majority of beta thalassemias?

A

point mutations

28
Q

What is the difference between beta + and beta 0 beta thalassemia?

A

beta + means some protein is being made where as beta 0 means no protein is being made - beta + would have a milder phenotype

29
Q

Describe the pathophysiology of untreated beta thalassemia

A

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
Q

What are the complications of the systemic iron overload?

A

the iron accumulates in organs and causes complications such as diabetes, heart failure, cirrhosis, hyper/hypothyroidism, endocrine complications, infertility

31
Q

Why is there splenomegaly in beta thalassemia?

A

because of destruction of red blood cells and extramedullary erythropoiesis

32
Q

Why is there hepatomegaly in beta thalassemia?

A

because of the extramedullary erythropoiesis

33
Q

Why is there skeletal deformities in beta thalassemia?

A

because of the medullary expansion

34
Q

What is seen on a blood smear for beta thalassemia?

A

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
Q

Why is there frontal bossing in beta thalassemia?

A

medullay expansion

36
Q

What is the appearance of the skull on an xray in beta thalassemia?

A

hair on end appearance - due to thinning of cranial bones because of medullary expansion

37
Q

What is the MCV in beta thalassemia?

A

significantly reduced

38
Q

What is the MCHC in beta thalassemia?

A

significantly reduced

39
Q

What is the HbF in beta thalassemia?

A

greatly elevated

40
Q

What are the blood parameters for a carrier of beta thalassemia?

A

moderately reduced/elevated

41
Q

What is the treatment for beta thalassemia?

A

blood tranfusion for the anaemia, splenectomy for the splenomegaly and iron chelation therapy for the iron overload

42
Q

How often are blood transfusions required?

A

every 3-4 weeks

43
Q

What is the risk of a blood transfusion?

A

blood borne infection e.g. HIV or hepatitis B and C

44
Q

What is the risk of a splenectomy?

A

sepsis

45
Q

How is iron chelation therapy given?

A

used to be given with a pump overnight but now there are oral treatments available

46
Q

What is the cure for thalssemia?

A

bone marrow transplant

47
Q

Why is beta thalassemia fatal?

A

because of the complications of the systemic iron overload

48
Q

What is the result if you have 3 functional alpha globin genes?

A

you are a silent carrier

49
Q

What is the result if you have 2 functional alpha globin genes?

A

you have mild anaemia - the two functional genes can either be on one chromosome or on different chromosomes

50
Q

What is the result if you have 1 functional alpha globin gene?

A

you have HbH disease - moderate to severe anaemia

51
Q

What is the result if you have 0 functional alpha globin genes?

A

you have HbBart which causes hydrops fetalis which is fatal before or around birth

52
Q

Why does alpha thalassemia have an effect in utero where as beta thalassemia doesnt?

A

because alpha globin is in the fetal and adult haemoglobin where as beta is just in adult haemoglobin

53
Q

What is the difference between a south east asian mutation and a mediterranean mutation?

A

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
Q

What is mutation causes sickle cell disease?

A

a single base mutation which alters glutamate to valine in the beta globin chain

55
Q

How do the red blood cells sickle in sickle cell disease?

A

when they’re deoxygenated they aggregate which causes sickling - this is initially reversible but becomes irreversible

56
Q

What are the symptoms of sickle cell disease?

A

anaemia and weakness, failure to thrive, splenomegaly, repeated infections, ischaemia, thrombosis, infarctions, iron overload

57
Q

What is seen on a blood film of sickle cell disease?

A

severe normocytic or macrocytic haemolytic anaemia

58
Q

What is the MCV and MCH in sickle cell disease?

A

may be normal if between crisises or may be reduced

59
Q

How do you confirm if someone is a carrier of sickle cell disease?

A

haemoglobin electrophoresis

60
Q

What is the treatment for sickle cell disease?

A

a drug which effects the synthesis of beta globin

61
Q

What is a compound heterozygote?

A

when there are two different types of mutations e.g. two different types of beta globin mutations

62
Q

What is a double heterozygote?

A

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
Q

What are some gene therapies for haemoglobinopathies?

A

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
Q

What is the heterozygote advantage?

A

carriers have some resistance to malaria

Intersystem (14 decks)

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