20.04.10 Haemoglobinopathies - sickle cell, thalassemia's Flashcards

1
Q

What are haemoglobinopathies

A

Disorders caused by pathogenic sequence variants which affect the genes that synthesize globin chains of haemoglobin.

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2
Q

What is haemoglobin

A

Iron containing oxygen-transport metalloprotein in the red blood cells of all vertebrates.

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3
Q

Normal red blood cells contain 3 types of haemoglobin

A
  1. HbA (86-98%) α2beta2
  2. HbA2 (1.5-3.2%). α2delta2
  3. HbF (0.5-0.8%). α2gamma2
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4
Q

What encodes the 2 α globin genes

A
  • HBA1 and HBA2 (chr 16)
  • Different expression levels: α2:α1 is 3:1
  • Expression is controlled by locus control region (LCR)
  • earliest embryonic forms are closest to LCR, so HBA2 is closer to LCR
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5
Q

What is alpha-thalassemia

A
  • Includes all conditions with a deficit in alpha globin chain production
  • Most prevalent in regions where malaria is endemic as it confers some protection.
  • Frequency of alpha-thalassemia alleles in Mediterranean basin= 5-10%, West Africa= 20-30%, Saudi Arabia, Papua New guinea, Thailand and India= as high as 60-80%
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6
Q

What is the most common cause of α thalassemia

A
  • Deletion of 1 or both alpha genes (90% cases)
  • 10% cases caused by point mutations in HBA2 (α+α) or HBA1 (αα+), from promoter to polyadenylation site
  • α0 indicates no HBA expression from the allele
  • α+ indicates some α-globin is produced from affected allele.
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7
Q

Is there are correlation between phenotype and degree of α-globin chain deficiency

A

Yes

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8
Q

What causes the majority of deletion type α-thalassemia

A

Reciprocal recombination between the two chromosome 16. Due to the high degree of sequence homology within α globin gene cluster.

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9
Q

What produces -α3.7

A
  • Rightward crossover due to mispairing of Z boxes during meiosis.
  • Fusion protein has 3 α globin genes, reciprocal is an allele with 1 α globin gene
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10
Q

What produces -α4.2

A
  • Leftward crossover due to mispairing of X boxes during meiosis.
  • Fusion protein has 3 α globin genes, reciprocal is an allele with 1 α globin gene
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11
Q

When are α globin genes most active

A

Early in fetal life. Therefore alpha-thalassemia is an issue for an unborn child

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12
Q

What are the 4 α -thalassemia syndromes

A
  1. Hemoglobin Bart hydrops fetalis (Hb Bart) syndrome. Most severe
  2. Hemoglobin H (HbH) disease.
  3. α-thalassemia trait.
  4. α-thalassemia silent carrier.
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13
Q

What is Hemoglobin Bart hydrops fetalis

A
  • Most severe α -thalassemia syndrome.
  • Due to loss of all 4 α-globin genes
  • Usually results in still birth or neonatal death. Only HbH formed.
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14
Q

What is Hemoglobin H (HbH) disease

A
  • Loss of 3 alpha-globin genes.
  • Body produces HbH (beta-globin tetramers instead to compensate but unstable and forms Heinz bodies (red blood cell inclusions)
  • Patients also have microcytic anaemia, moderate extravascular hemolysis, splenomegaly
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15
Q

What is α-thalassemia trait

A

Loss of 2 alpha globin genes either in cis (–/αα, α0 carrier) or in trans (-α/-α). Asymptomatic but may have microcytic anaemia. Important in antenatal setting to know which to assess risk to unborn child.

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16
Q

What is an α-thalassemia silent carrier

A

Loss of 1 α-globin gene (-α/αα, α+ carrier). Asymptomatic,

17
Q

Example of other alpha-thalassemia syndromes

A
  • Alpha-thalassemia retardation 16 (ATR-16) syndrome. Since alpha-globin genes are located at tip of 16p, they are vulnerable to translocation. ART-16 occurs when other adjacent genes are involved. Short stature, reduced IQ, hypospadias and cryptorchidism.
  • Alpha-thalassemia retardation X (ART-X), Due to mutations in ATRX gene. Appearance of het alpha-thalassemia but normal alpha-globins. Patients also have dysmorphic features and profound dev delay
18
Q

What is beta thalassemia

A
  • Blood disorder where reduced/absent beta globin chain synthesis results in reduction/absence of adult haemoglobin (HbA).
  • 1.5% global population are thought to be carriers.
  • Prevalent in countries where falciparum malaria is endemic.
19
Q

What encodes beta globin

A

HBB gene. Chr 11

20
Q

What kind of mutations are common in beta-thalassemia

A

-Single nucleotide substitutions, small deletions, insertions or frameshift mutations. Large gene deletions are rare.

21
Q

What two types of mutant alleles are there in beta thalassemia

A
  • Beta zero: no output from affected allele. i.e. caused by nonsense, frameshift, deletion, splice variant
  • Beta plus: variable output
22
Q

What can alter disease severity in beta thalassemia

A
  • Type of mutation in HBB
  • Genetic modifiers that reduce alpha/ non alpha chain imbalance. i.e. co-inheritance of alpha thalassemia lessens imbalance by reducing alpha-globin gene output. Conversly duplicated alpha globin genes may cause beta-thalassemia intermedia
  • modifiers that increase gamma globin production or to continue production of gamma globins in adulthood (persistence of fetal Hb).
23
Q

What are the different sub types of beta thalassemia

A
  1. Beta thalassemia major (most severe)
  2. Beta thalassemia intermedia
  3. Beta thallassemia trait
24
Q

What is beta thalassemia major

A
  • Patients have severe anaemia, hepatosplenomegaly, diarrhoea, fever.
  • Patients will have increased HbF (alpha2 gamma2) and no HbA.
  • Treatment: regular transfusions.
25
Q

What is beta thalassemia intermedia

A
  • Later onset, mild-to-moderate anaemia. Rarely splenomegaly.
  • Higher amount of HbA compared to beta thalassemia major
  • Need occasional transfusion (during illness or pregnancy)
26
Q

What is beta thalassemia trait/minor

A

-Heterozygotes. Asymptomatic but may have microcytic RBCs and elevated HBA2 (delta globin genes)

27
Q

What is dominant beta thalassemia

A
  • Due to rare mutations resulting in the synthesis of unstable beta globin, leading to ineffective erythropoiesis
  • Heterozygotes with beta thalassemia
28
Q

What is Sickle cell disease

A
  • Autosomal recessive disorder characterised by RBCs with an abnormal rigid sickle shape.
  • Caused by HBB c.20A>T p.(Glu6Val)
  • Highest prevalence in West Africa (1 in 4 are carriers) as hets have a protective advantage from malaria
  • In low oxygen (hypoxia), acid conditions, polymerisation of HbS leads to sickle shape.
  • Vascular occlusions cause a sickle crisis (bone pain, chest disease, damage to major organs, anaemia, stroke.
29
Q

Common type of sickle cell disease

A
  • Sickle cell anaemia
  • Homozygous for c.20A.T p.(Glu6Val) in HBB gene, aka HbSS
  • Het carriers are usually asymptomatic with no anaemia
30
Q

Other types of sickle cell disease

A

-Inheritance of HbS (c.20A>T p.(Glu6Val) with a second HBB variant

31
Q

Treatment of sickle cell disease

A

Blood transfusion, prophylactic antibiotics, bone marrow transplant

32
Q

What methods are used to test for haemoglobinopathies

A
  • Haematology: full blood count, microscopic analysis. Hb pattern analysis using HPLC (high performance liquid chromatography), isoelectric focussing.
  • Genetics: Used for more complicated cases, if there is likely to be a prenatal, or to get a definitive diagnosis of alpha thalassemia.
33
Q

What antenatal screening is done for haemoglobinopathies

A
  • If a woman is identified as a carrier of significant haemoglobinopathy then baby’s father is also tested
  • Screening differs in high and low prevalence areas.
  • Aim is to identify high risk couples early enough so prenatal testing can be offered by the end of 13 weeks pregnancy.
34
Q

Why is bone marrow transplantation a high risk treatment

A

5-10% mortality rate and limited success due to graft vs host disease. Used for only the most severe cases or where there is difficulty finding HLA matched donors.

35
Q

Novel therapies for haemoglobinopathies

A
  • Gene therapy using lentiviral vectors to introduce wild type exogenous beta or gamma globin, epigenetic reactivation of fetal Hb expression.
  • Activin receptor ligand traps: mitigates disease complications of ineffective erythropoiesis.
  • Macrophage targeting. Macrophages found to have a negative effect on haematopoiesis in thalassaemia.