66 - Haemoglobinopathies

Question 1

Inheritance pattern of most haemoglobin disorders

Answer 1

Autosomal recessive

Question 2

Proportion of world-s population that are carriers of haemoglobinopathies

Answer 2

4.5%

Question 3

Where are alpha globin genes clustered?

Answer 3

Chromosome 16

Question 4

Where are beta globin genes clustered?

Answer 4

Chromosome 11

Question 5

Alpha globin gene cluster architecture

Answer 5

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

Question 6

Beta globin gene cluster architecture

Answer 6

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

Question 7

LCR

Answer 7

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

Question 8

*Regulation of globin-like genes over lifespan

Answer 8

Question 9

Proportion of HbF in an adult

Answer 9

0.5%

Question 10

Types of haemoglobinopathies 1) 2) 3)

Answer 10

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

Question 11

Definition of thalassaemias

Answer 11

Decreased synthesis of one or more globin chains

Question 12

Definition of structural variants (haemoglobinopathies)

Answer 12

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

Question 13

Alpha thalassaemia distribution

Answer 13

South-East Asia

Question 14

Beta-thalassaemia distribution

Answer 14

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

Question 15

Sickle cell disease distribution

Answer 15

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

Question 16

Basis for pathology of thalassaemias

Answer 16

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.

Question 17

Mutations leading to alpha thalassaemias

Answer 17

Large deletions

Question 18

Mutations leading to beta-thalassaemias

Answer 18

Majority caused by point mutations

Question 19

Different types of beta thalassaemias

Answer 19

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

Question 20

Another name for a homozygous thalassaemia

Answer 20

Thalassaemia major

Question 21

Type of anaemia from thalassaemia

Answer 21

Haemolytic anaemia

Question 22

Thalassaemia present at birth

Answer 22

Alpha

Question 23

Thalassaemia that presents a few months after birth

Answer 23

Beta

Question 24

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

Answer 24

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

Question 25

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

Answer 25

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

Question 26

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

Answer 26

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

Question 27

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

Answer 27

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

Question 28

Treatment of beta-thalassaemia 1) 2) 3)

Answer 28

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

Question 29

Frequency of blood transfusions for beta-thal

Answer 29

Every 3-4 weeks.

Question 30

Cost of transfusions plus chelation

Answer 30

$120,000 per year

Question 31

Cure for beta-thal

Answer 31

Bone marrow transplant

Question 32

Number of alpha-thalassaemias

Answer 32

Five phenotypes

Question 33

Genotype of normal alpha globin

Answer 33

aa/aa

Question 34

Genotype of an alpha-thalassaemia carrier (thal minor)

Answer 34

aa/a-

Question 35

Genotype of a mild anamia alpha thalassaemia

Answer 35

a-/a- or aa/--

Question 36

Genotype of HbH disease

Answer 36

a-/--

Question 37

Genotype of hydrops fetalis

Answer 37

--/-- (lethal at birth)

Question 38

How is haemoglobin measured?

Answer 38

Hb electrophoresis, high performance liquid chromatography (HPLC)

Question 39

How is Fe chelation therapy administered?

Answer 39

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

Question 40

South-East Asian alpha globin mutation

Answer 40

aa/--

Question 41

Mediterranean alpha globin mutation

Answer 41

a-/a-

Question 42

Mutation that can result in hydrops fetalis, and why.

Answer 42

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

Question 43

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

Answer 43

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 --.

Question 44

Number of alpha globin genes in a normal person

Answer 44

Four. Two identical genes on each chromosome

Question 45

Which type of mutation leads to sickle cell disease?

Answer 45

Point mutation

Question 46

Sickle cell pathology 1) 2)

Answer 46

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.

Question 47

Type of anaemia from sickle cell disease

Answer 47

Severe normocytic or macrocytic haemolytic anaemia

Question 48

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

Answer 48

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

Question 49

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

Answer 49

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

Question 50

Name for someone with two different mutant alleles

Answer 50

Compound heterozygote

Question 51

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

Answer 51

Double heterozygote

Question 52

Why can some compound heterozygous thalassaemias be less severe?

Answer 52

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.