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1Principles of Biomedicine - MD1 > 66 - Haemoglobinopathies > Flashcards

66 - Haemoglobinopathies Flashcards

1
Q

Inheritance pattern of most haemoglobin disorders

A

Autosomal recessive

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2
Q

Proportion of world-s population that are carriers of haemoglobinopathies

A

4.5%

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3
Q

Where are alpha globin genes clustered?

A

Chromosome 16

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4
Q

Where are beta globin genes clustered?

A

Chromosome 11

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5
Q

Alpha globin gene cluster architecture

A

5’->3’ LCR, zeta, 2xphi (pseudogenes), alpha2, alpha1 (these are identical)

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6
Q

Beta globin gene cluster architecture

A

5’->3’ LCR, epsilon, Ggamma, A gamma, phiB, delta, beta

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7
Q

LCR

A

Locus control region. Essential for regulation of beta-like globin genes

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8
Q

*Regulation of globin-like genes over lifespan

A
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9
Q

Proportion of HbF in an adult

A

0.5%

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10
Q

Types of haemoglobinopathies 1) 2) 3)

A

1) Alpha and beta thalassaemias 2) Structural variants 3) Hereditary persistence of foetal haemoglobin

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11
Q

Definition of thalassaemias

A

Decreased synthesis of one or more globin chains

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12
Q

Definition of structural variants (haemoglobinopathies)

A

Altered globin polypeptide sequence, without altering rate of synthesis. Over 500 variants (EG: sickle cell anaemia)

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13
Q

Alpha thalassaemia distribution

A

South-East Asia

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14
Q

Beta-thalassaemia distribution

A

Global distribution. Increased freq in Southern European, Middle Eastern, North African, SE Asian, Indian Subcontinental populations

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15
Q

Sickle cell disease distribution

A

Malaria zones. West, Central Africa, Middle East, Indian Subcontinent

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16
Q

Basis for pathology of thalassaemias

A

Imbalance in relative numbers of alpha and beta chains leads to formation of homotetramers instead of heterotetramers. These aggregate within RBCs and damage them. Severity relates to degree of imbalance.

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17
Q

Mutations leading to alpha thalassaemias

A

Large deletions

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18
Q

Mutations leading to beta-thalassaemias

A

Majority caused by point mutations

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19
Q

Different types of beta thalassaemias

A

B+ (beta-globin produced at reduced rate), B- (no beta-globin produced)

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20
Q

Another name for a homozygous thalassaemia

A

Thalassaemia major

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21
Q

Type of anaemia from thalassaemia

A

Haemolytic anaemia

22
Q

Thalassaemia present at birth

A

Alpha

23
Q

Thalassaemia that presents a few months after birth

A

Beta

24
Q

Pathophysiology of untreated beta-thalassaemia 1) 2) 3) 4)

A

1) Swelling of bone marrow from increased erythropoiesis (skeletal deformities). 2) Leads to increased Fe absorption, buildup (no mechanism for Fe excretion), which damages heart and liver. 3) Extramedullary erythropoiesis in liver and spleen, leads to hepatosplenomegaly 4) Destruction of RBC aggregates in spleen also leads to splenomegaly

25
Q

Gross appearances of untreated beta-thalassaemia 1) 2) 3) 4)

A

1) Frontal bossing (protruding forehead) from intramedullary erythropoiesis 2) Thinning of long bones 3) ‘Hair-on-end’ appearance of skull due to thinning of cranial bones 4) Hepatosplenomegaly

26
Q

Appearance of RBCs on beta-thalassaemia blood film 1) 2) 3) 4)

A

1) Microcytic, hypochromic anaemia 2) Anisocytic (irregular size) 3) Poikilocytic (abnormal shape) 4) Tear-drop shaped cells

27
Q

Blood parameters in beta-thalassaemia 1) 2) 3) 4)

A

1) Mean corpuscular volume significantly decreased 2) Mean corpuscular Hb significantly decreased 3) Greatly elevated HbF 4) These are much less severe in heterozygous

28
Q

Treatment of beta-thalassaemia 1) 2) 3)

A

1) Chelation therapy for Fe 2) Splenectomy, if spleen is in danger of bursting 3) Regular blood transfusions are only long-term treatment

29
Q

Frequency of blood transfusions for beta-thal

A

Every 3-4 weeks.

30
Q

Cost of transfusions plus chelation

A

$120,000 per year

31
Q

Cure for beta-thal

A

Bone marrow transplant

32
Q

Number of alpha-thalassaemias

A

Five phenotypes

33
Q

Genotype of normal alpha globin

A

aa/aa

34
Q

Genotype of an alpha-thalassaemia carrier (thal minor)

A

aa/a-

35
Q

Genotype of a mild anamia alpha thalassaemia

A

a-/a- or aa/–

36
Q

Genotype of HbH disease

A

a-/–

37
Q

Genotype of hydrops fetalis

A

–/– (lethal at birth)

38
Q

How is haemoglobin measured?

A

Hb electrophoresis, high performance liquid chromatography (HPLC)

39
Q

How is Fe chelation therapy administered?

A

Initially was injected by pump, 6-7 nights per week. Now is orally administered once per day

40
Q

South-East Asian alpha globin mutation

A

aa/–

41
Q

Mediterranean alpha globin mutation

A

a-/a-

42
Q

Mutation that can result in hydrops fetalis, and why.

A

South East Asian mutation in alpha globin gene (aa/–). If both parents are carriers, can have a child with –/–, which results in hydrops fetalis.

43
Q

Why is the South East Asian alpha globin mutation more severe for offspring than the Mediterranean?

A

Mediterranean (a-/a-) carriers can only give rise to other carriers (a- is only allele possible). SE Asian (aa/–) can either give rise to normal, carrier or hydrops fetalis (aa/aa, aa/– or –/–), because possible alleles are either aa or –.

44
Q

Number of alpha globin genes in a normal person

A

Four. Two identical genes on each chromosome

45
Q

Which type of mutation leads to sickle cell disease?

A

Point mutation

46
Q

Sickle cell pathology 1) 2)

A

1) Repeated cycles of deoxygenation make RBC become more sickle-shaped, as deoxy-HbS polymers form. 2) Sickle cell increases adherence to endothelium, forms thromboses.

47
Q

Type of anaemia from sickle cell disease

A

Severe normocytic or macrocytic haemolytic anaemia

48
Q

Blood parameters in heterozygous sickle cell disease 1) 2) 3)

A

1) Mean corpuscular volume, mean corpuscular Hb normal, slightly reduced 2) Hb slightly reduced 3) HbS seen on Hb electrophoresis or high performance liquid chromatography

49
Q

Blood parameters in homozygous sickle cell disease 1) 2) 3) 4)

A

1) Mean corpuscular volume and mean corpuscular Hb normal or reduced. 2) Hb significantly decreased (60-80g/L) 3) HBS seen on Hb electrophoresis, HPLC. 4) HbA absent

50
Q

Name for someone with two different mutant alleles

A

Compound heterozygote

51
Q

Name for someone with a beta globin mutation and an alpha globin mutation

A

Double heterozygote

52
Q

Why can some compound heterozygous thalassaemias be less severe?

A

Thalassaemia pathology arises from imbalance in alpha and beta globins, leading to formation of homomultimers. If both alpha and beta globin production is reduced, then less severe pathology could be caused.

1Principles of Biomedicine - MD1 (157 decks)

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