66 - Haemoglobinopathies Flashcards
Inheritance pattern of most haemoglobin disorders
Autosomal recessive
Proportion of world-s population that are carriers of haemoglobinopathies
4.5%
Where are alpha globin genes clustered?
Chromosome 16
Where are beta globin genes clustered?
Chromosome 11
Alpha globin gene cluster architecture
5’->3’ LCR, zeta, 2xphi (pseudogenes), alpha2, alpha1 (these are identical)
Beta globin gene cluster architecture
5’->3’ LCR, epsilon, Ggamma, A gamma, phiB, delta, beta
LCR
Locus control region. Essential for regulation of beta-like globin genes
*Regulation of globin-like genes over lifespan
Proportion of HbF in an adult
0.5%
Types of haemoglobinopathies 1) 2) 3)
1) Alpha and beta thalassaemias 2) Structural variants 3) Hereditary persistence of foetal haemoglobin
Definition of thalassaemias
Decreased synthesis of one or more globin chains
Definition of structural variants (haemoglobinopathies)
Altered globin polypeptide sequence, without altering rate of synthesis. Over 500 variants (EG: sickle cell anaemia)
Alpha thalassaemia distribution
South-East Asia
Beta-thalassaemia distribution
Global distribution. Increased freq in Southern European, Middle Eastern, North African, SE Asian, Indian Subcontinental populations
Sickle cell disease distribution
Malaria zones. West, Central Africa, Middle East, Indian Subcontinent
Basis for pathology of thalassaemias
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.
Mutations leading to alpha thalassaemias
Large deletions
Mutations leading to beta-thalassaemias
Majority caused by point mutations
Different types of beta thalassaemias
B+ (beta-globin produced at reduced rate), B- (no beta-globin produced)
Another name for a homozygous thalassaemia
Thalassaemia major
Type of anaemia from thalassaemia
Haemolytic anaemia
Thalassaemia present at birth
Alpha
Thalassaemia that presents a few months after birth
Beta
Pathophysiology of untreated beta-thalassaemia 1) 2) 3) 4)
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
Gross appearances of untreated beta-thalassaemia 1) 2) 3) 4)
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
Appearance of RBCs on beta-thalassaemia blood film 1) 2) 3) 4)
1) Microcytic, hypochromic anaemia 2) Anisocytic (irregular size) 3) Poikilocytic (abnormal shape) 4) Tear-drop shaped cells
Blood parameters in beta-thalassaemia 1) 2) 3) 4)
1) Mean corpuscular volume significantly decreased 2) Mean corpuscular Hb significantly decreased 3) Greatly elevated HbF 4) These are much less severe in heterozygous
Treatment of beta-thalassaemia 1) 2) 3)
1) Chelation therapy for Fe 2) Splenectomy, if spleen is in danger of bursting 3) Regular blood transfusions are only long-term treatment
Frequency of blood transfusions for beta-thal
Every 3-4 weeks.
Cost of transfusions plus chelation
$120,000 per year
Cure for beta-thal
Bone marrow transplant
Number of alpha-thalassaemias
Five phenotypes
Genotype of normal alpha globin
aa/aa
Genotype of an alpha-thalassaemia carrier (thal minor)
aa/a-
Genotype of a mild anamia alpha thalassaemia
a-/a- or aa/–
Genotype of HbH disease
a-/–
Genotype of hydrops fetalis
–/– (lethal at birth)
How is haemoglobin measured?
Hb electrophoresis, high performance liquid chromatography (HPLC)
How is Fe chelation therapy administered?
Initially was injected by pump, 6-7 nights per week. Now is orally administered once per day
South-East Asian alpha globin mutation
aa/–
Mediterranean alpha globin mutation
a-/a-
Mutation that can result in hydrops fetalis, and why.
South East Asian mutation in alpha globin gene (aa/–). If both parents are carriers, can have a child with –/–, which results in hydrops fetalis.
Why is the South East Asian alpha globin mutation more severe for offspring than the Mediterranean?
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 –.
Number of alpha globin genes in a normal person
Four. Two identical genes on each chromosome
Which type of mutation leads to sickle cell disease?
Point mutation
Sickle cell pathology 1) 2)
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.
Type of anaemia from sickle cell disease
Severe normocytic or macrocytic haemolytic anaemia
Blood parameters in heterozygous sickle cell disease 1) 2) 3)
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
Blood parameters in homozygous sickle cell disease 1) 2) 3) 4)
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
Name for someone with two different mutant alleles
Compound heterozygote
Name for someone with a beta globin mutation and an alpha globin mutation
Double heterozygote
Why can some compound heterozygous thalassaemias be less severe?
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.
