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Cardiorespiratory 2 > Haemoglobinopathies > Flashcards

Haemoglobinopathies Flashcards

1
Q

what is essential in derteming the ability of the haemoglobin molecule to carry and release oxygen

A

The precise folding of each subunit and the way the four subunits fit together

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2
Q

what can affect the folding and fitting together of the subunits

A

. Slight differences in the amino acid sequence in each subunit affects this folding and fitting together

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3
Q

what is adult haemoglobin made out of

A

two alpha globin subunits and two beta subunits

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4
Q

there are separate genes for..

A

each globing subunit

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5
Q

describe the genes on the alpha subunit and what chromosome they are on

A

There are two genes for the alpha subunit on chromosome 16.

Thus there are four genes for the alpha subunit in normal diploid cells, with two genes maternal in origin and two genes paternal in origin.

there is also a zeta gene that can produce the zeta subunit instead of the alpha subunit

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6
Q

describe the genes on the beta subunit and what chromosome they are on

A

There are five genes for the beta subunit on chromosome 11

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7
Q

name the 5 genes on the beta subunit

A 
epsilon,
gamma A
gamma G 
delta
beta
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8
Q

what chromosome is with alpha genes on

A

chromsome 16

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9
Q

what chromosome is the beta genes on

A

chromsome 11

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10
Q

what is more efficient at binding to oxygen, fetal haemoglobin or adult haemoglobin

A

fetal haemoglobin

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11
Q

what is the haemoglobin that is produced in the first 6 weeks of the foetus life

A
  • produced form the embryonic yolk sac
  • ζ2ε2 (zeta 2 epsilon 2)
  • also known as Hb Gower-1
  • this has a very very high affinity for oxygen
  • this is why we have the zeta gene on chromosome 16
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12
Q

does the fetus have myoglobin

A

Within the fetus, the myoglobin of the fetal muscles has an even higher affinity for oxygen, so oxygen molecules pass from fetal hemoglobin for storage and use in the fetal muscles.

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13
Q

what does Hb Gower -1 enable

A

Within the fetus, the myoglobin of the fetal muscles has an even higher affinity for oxygen, so oxygen molecules pass from fetal hemoglobin for storage and use in the fetal muscles.

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14
Q

what does the haemoglobin switch to after 6 weeks gestation and where does this happen

A
  • starts to make the normal fatal haemoglobin which is 2 alpha and 2 gamma subunits
  • happens in the liver and spleen
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15
Q

describe the order for the affinity of oxygen

A
  1. Hb gower-1
  2. 2 alpha 2 gamma
    3, adult haemoglobin - 2 alpha 2 beta
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16
Q

what is HbA2 made out of

A

alpha 2 delta 2

- this is present in adults as well

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17
Q

where is adult haemoglobin produced

A

bone marrow

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18
Q

when does adult haemoglobin replace fetal haemoglobin

A
  • From 3-6 months after birth HbA [α2β2 ] gradually replaces the fetal haemoglobin; some HbA2 [α2δ2] is also present in the adult
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19
Q

what is thalasemia easily confused with

A

iron deficiency anaemia - cells can be hypo chromic an microcytic which then are not relieved when iron is given

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20
Q

what are the types of thalassemia

A
  • alpha

- beta

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21
Q

how do the types of thalassemia arise

A
  • Alpha thalassaemia results when one or more of the alpha genes on chromosome 16 is delted or faulty
  • Beta thalassaemia results when there is a point mutation on chromosome 11
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22
Q

what is thalassaemia

A
  • Thalassaemia is a genetic defect resulting in inadequate quantities of one or other of the subunits that make up haemoglobin.
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23
Q

what in thalassaemia may the genetic defect be due to

A
  1. A mutation in the noncoding introns of the gene resulting in inefficient RNA splicing to produce mRNA, and therefore decreased mRNA production
  2. The partial or total deletion of a globin gene
  3. A mutation in the promoter leading to decreased expression
  4. A mutation at the termination site leading to production of longer, unstable mRNA
  5. A nonsense mutation
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24
Q

what does the severity of alpha thalassaemia depend on

A

The severity of alpha thalassemia depends on the number of gene alleles defective or missing

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25
Q

what happens when there is one alpha gene defective

A
  • known as alpha thalassemia minima
  • minimal effect
  • 3 alpha globin genes are enough to permit normal haemoglobin production
  • no clinical symptoms
  • silent carrier
  • may have a slightly reduced mean corpuscular volume and mean corpuscular haemoglobin
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26
Q

what happens when there is 2 alpha genes defective

A
  • known as alpha thalassemia minor
  • 2 alpha genes permit nearly normal production of RBC
  • milld microcytic hypo chromic anaemia
  • this is the part of the disease that can be mistaken for iron deficiency anaemia and treated with iron inappropriately
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27
Q

what happens when there is 3 alpha genes defective

A
  • this is haemoglobin H disease
  • Two unstable haemoglobins are present in the blood: Haemoglobin Barts (γ4) and haemoglobin H (β4).
  • both of these haemoglobin have a higher affinity for oxygen that normal haemoglobin - thus this results in poor release of oxygen in tissues
  • there is a microcytic hypo chromic anaemia
28
Q

what happens when there is 4 alpha genes defective

A
  • foetus can’t live outside the uterus
  • may not survive gestation
  • most are born with hydros fetallis
  • they have little circulating haemoglobin and the haemoglobin that is present is all tetrameric gamma chains ( haemoglobin parts)
29
Q

describe how the severity of haemoglobin H disease can change

A
  • HbH caused by deletion of three genes is less server than cases in which two genes are delated and the third gene has a point mutation (non deletional HbH)
  • HbH constant spring (HCS) is the most common from of non deletional HbH
30
Q

describe the genetics of beta thalassaemia

A

caused by mutations in the haemoglobin β gene on chromosome 11, inherited in an autosomal recessive disease

31
Q

what does the severity of beta thalassaemia depend upon

A

the nature of the mutation.

32
Q

what are the two main genotypes of beta thalassemia

A

heterozygous (thalassaemia trait, beta thalasaemia minor, β+)

homozygous (beta thalassaemia major, βo).

33
Q

what is beta thalassaemia also know as

A

Beta thalassemia major is known in the USA as Cooley’s anemia.

34
Q

what is beta thalassemia intermedia

A

occurs when both of the beta globin genes are mutated, but still able to make some beta chains

35
Q

when does beta thalassemia become apparent

A
  • after the 3-6 months after birth when the haemoglobin is changing from the gamma chains to beta chain synthesis
36
Q

what is a sign that beta thalasemia is present

A
  • There may be a compensatory increase in g and d chain synthesis resulting in increased levels of Hb F and A2 in a blood test
37
Q

what is beta thalassaemia major

A

the body’s inability to construct beta-globins leads to the underproduction of Haemoglobin A (HBA).

Reductions in HBA available to fill the red blood cells in turn leads to microcytic anaemia

38
Q

what is the pathological effects of beta thalassaemia

A
  1. Due to loss of synthesis of beta globins, excess alpha globins are produced in developing erythroblasts in marrow. The alpha tetramers are unstable and precipitate on the erythrocyte membrane
  2. This causes intra-medullary destruction of developing erythroblasts, erythroid hyperplasia and ineffective erythropoiesis- causes damage of the bone marrow in this condition,
  3. Result: (severe) hypochromic microcytic anaemia
  4. This is mild in heterozygous disease but severe in homozygous disease
39
Q

what is more sever in beta thalassemia heterozygous disease or homozygous disease

A

homozygous disease

40
Q

what are the effects of untreated beta thalassemia

A
  • Hypochromic, Microcytic Anaemia.
  • Bone marrow expansion, splenomegaly
  • Bone deformity, extramedullary erythropoietic masses
  • Failure to thrive from about 6 months of age
  • Heart failure and death by age 3-4
41
Q

how do you treat both alpha and beta thalassameia

A
  • Regular transfusions (but can cause iron overload)
  • Iron chelation therapy
  • Splenectomy (not usually necessary now)
  • Allogeneic bone marrow transplant (for young children if sibling donor available)
  • Alternative treatments under trial: HbF modulating agents,
  • The future: Gene therapy
42
Q

what is the difference between deficiency caused by iron deficiency and that caused by thalassaemia in

  • MCV
  • Serum iron
  • TIBC (total iron binding capacity)
  • serum ferritin
  • bone marrow iron
A

iron deficiency

  • MCV - Decreased
  • Serum iron - decreased
  • TIBC - increased
  • serum ferritin - decreased
  • bone marrow iron = absent

thalassaemia

  • MCV - very decreased
  • Serum iron - normal
  • TIBC - normal
  • serum ferritin - normal
  • bone marrow iron - normal
43
Q

when can iron overload happen

A

With excess haemolysis some free iron may be released from the haem and enter the blood

44
Q

why is iron overload bad

A

With excess haemolysis some free iron may be released from the haem and enter the blood.

If hydrogen peroxide is present the Fenton reaction can occur which produces hydroxyl radicals which oxidise and damage all biological tissues.

.

45
Q

what is the Fenton reaction responsible for

A

the cirrhosis,
diabetes,
glandular dysfunction (especially growth hormone deficiency)
and other effects of chronic iron overload.

46
Q

what can prevent the Fenton reaction

A
  • iron chelating compounds
47
Q

name three iron chelation therapies which prevent iron overload

A

1, desferoxamine
2, deferiprone
3, deferasirox

48
Q

describe how the three iron chelation therapies work

A

1, desferoxamine “desferal”

  • 8-12 hours subcutanouse infusion 5-7 days per week
  • Chelation enhanced with ascorbate
  • Toxicity with higher doseases e.g. diarrhoea, vomiting, fever, hearing loss and eye problems

2, Deferiprone

  • Oral iron chelator
  • Licensed in EU as second-line agent
  • Dosage 75-100mg/kg/day
  • Agranulocytosis/neutropenia may occur: Not to be used in pregnancy

3, Deferasirox
- A once daily oral iron chelator: but can cause GI bleeding and kidney or liver failure

49
Q

what is sickle cell disease

A
  • this is a genetic condition where there is a mutation on one of the beta subunits causing the RBC to become sickle shaped
50
Q

what can sickle cell cause to happen

A
  • These cells obstruct capillaries and restrict blood flow to an organ resulting in ischaemia, pain, and organ damage
51
Q

why is sickle cells such as problem

A

they can carry oxygen reasonably well but they are destroyed at a greater rate than normal cells therefore you have an haemolytic anaemia
- In deoxygeneated blood haemoglobin S may precipitate or crystallize, distorting the red blood cells into a sickle shape, making them fragile and easily destroyed, leading to anaemia.

52
Q

what are the signs of sickle cell disease

A
  • Haemolytic anaemia: haemoglobin levels in the range of 6–8 g/dL
  • Microvascular occlusion: rigid sickle cells adhere to endothelium, interact with white cells and vessel wall, cause nitric oxide depletion
  • Large vessel damage
53
Q

what is the mutation that causes sickle cell disease

A
  • The sickle mutation is a glutamic acid to valine (GAG-GTG) substitution at codon 6 of the beta globin chain. An abnormal beta chain is produced (βS)
  • This produces an abnormal type of haemoglobin, called haemoglobin S. (α2βS2)
54
Q

what haemoglobin chain is produced in sickle cell disease

A
  • This produces an abnormal type of haemoglobin, called haemoglobin S. (α2βS2)
55
Q

what tests can you do to confirm sickle cell anaemia

A
  • Complete blood coutn and blood film
  • Sickle solubility test ( a mixture of HbS in reducing solution gives a turbid appearance whereas nomoral Hb gives a clear solution
  • Hb electrophoresis
  • Hb HPLC
56
Q

what are the major clinical consequences of sickle cell disease

A
  1. Anaemia
  2. Increased susceptibility to infection (particularly encapsulated bacteria)
  3. Vaso-occlusive crises (commonest is painful crisis)
  4. Chronic tissues damage (eg stroke, avascular necrosis of hip, retinopathy
57
Q

what is the treatment of sickle cell disease

A
  • Infection prophylaxis
  • Analgesics for painful crises
  • Education, life style, avoidance of precipitants
  • Transfusions for specific acute and chronic complications
  • Hydroxyurea (Increases HbF, reduces painful crises)
  • Bone marrow transplantation (few have been done in UK)
58
Q

what happens during screening for sickle cell disease

A
  • Carrier screening enables identification of couples at risk of producing affected offspring
  • Individuals or couples can then be counselled about the genetic risk, the consequences of having an affected child, and the options for avoiding an affected pregnancy
  • Carrier screening is generally easily done with a simple blood analysis (Full blood count and haemoglobinopathy screen)
  • Very occasionally interpretation of results is problematic
  • Carrier screening can be done early in pregnancy (ante-natal), or better, before pregnancy (eg pre-marital in Cyprus, school age screening in some areas of high prevalence)
59
Q

why is it important to identify sickle cell disease early

A
  • Infancy (6 months-2 years) is a high risk time for sickle cell complications
  • Diagnosis of sickle disorders soon after birth can reduce morbidity and mortality
  • Enables treatment with antibiotic prophylaxis, parental education, and early intervention for complications
60
Q

what is haemoglobin c

A
  • Haemoglobin C is a mutation in which there is an abnormal beta subunit
61
Q

What does haemoglobin C cause

A
  • Haemoglobin C is a mutation in which there is an abnormal beta subunit.
  • This causes reduced plasticity and flexibility of the erythrocytes.
  • This causes excess red cell destruction (haemolysis).
62
Q

what is the difference between homozygous and heterozygous form of haemoglobin C

A

In those who are homozygotes, nearly all Hb is in the HbC form, resulting in mild haemolytic anemia.
- In those who are heterozygous for the mutation, only about 1/3 of total haemoglobin is in the form of HbC, and no anaemia develops.

63
Q

what is haemoglobin E

A
  • Haemoglobin E (HbE) is an abnormal hemoglobin with a single point mutation in the β chain.
  • Haemoglobin E disease results when the offspring inherits the gene for HbE from both parents
64
Q

when does haemoglobin E present itself

A
  • At birth, babies homozygous for the haemoglobin E allele do not present symptoms due to the fetal hemoglobin they still have.
  • However after 3-6 months , fetal hemoglobin disappears and the amount of hemoglobin E increases, so the subjects start to have a mild β-thalassemia
65
Q

what is a GP6D deficiency

A

An X-linked recessive inborn error of metabolism that causes haemolysis and jaundice

66
Q

what can cause a GP6D deficiency

A
  • food such as broad lava beans
  • drugs such as oxidative drugs
  • viral or bacterial infections
67
Q

what are carries of the G6PD gene protected against

A

. Carriers of the G6PD allele appear to be partially or fully protected against malaria

Cardiorespiratory 2 (43 decks)

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