8.1 - Haemoglobinopathies Flashcards
what is a haemoglobinopathy
inherited disorders to do with defects in globin chain synthesis
→ typically autosomal recessive
abnormal globin chain variants with altered stability and/or function
* sickle cell disease
* globin gene mutations alter structure/function/stability of haemoglobin tetramer
reduced or absent expression of normal globin chains
* thalassaemias types α and β
* globin gene mutations reduce expression of specific individual globin proteins resulting in an imbalance in composition of haemoglobin tetramer
what is a haemoglobinopathy
inherited disorders to do with defects in globin chain synthesis
→ typically autosomal recessive
abnormal globin chain variants with altered stability and/or function
* sickle cell disease
* globin gene mutations alter structure/function/stability of haemoglobin tetramer
reduced or absent expression of normal globin chains
* thalassaemias types α and β
* globin gene mutations reduce expression of specific individual globin proteins resulting in an imbalance in composition of haemoglobin tetramer
what is the normal structure of haemoglobin
- haemoglobin is tetramer of 4 globin polypeptide chains
- should have 2 α and two non-α chains (β, δ or γ)
- each globin chain is complexed with haem group containing ferrous iron
- it is haem group that binds to oxygen → oxyhaemoglobin
what are the different types of haemoglobin and when are they expressed
- different haemoglobins expressed during development
- adaptive response to variations in O2 requirements
- different characteristics eg oxygen affinity
HbA
* 2 α and 2 β globin chains
* main proportion of total Hb in adult
* HbA commences before birth and and steadily increases to become dominant by about 6 months after birth
HbA2
* 2α and 2δ globin chains
* about 3% of total Hb in adult
HbF
* 2α and 2γ globin chains
* main form just before birth
* makes less than 1% of total Hb in adult
note: several embryonic forms expressed in early development
the globin gene clusters
- chromosome 16 and 11 control haemoglobin expression
- duplicated α globin gene complex on c16… total of 4 (2 on maternal, 2 paternal)
- single β globin gene complex on c11… total of 2 (1 on maternal, 2 on paternal)
- also have γ, δ, ε globin genes on c11
- on c11 is also β-LCR regions (locus control regions)
- these β-LCR regions control globin gene expression
- expression varies during development, leading to production of different haemoglobin tetramers and globin combination
thalassaemias
in general
- normal expression of globin genes is under tight control to ensure 1:1 ratio of α to non-α globin chain proteins
- defects in this regulation of expression of globin genes results in abnormalites in both the relative and absolute amounts of globin chain proteins… results in α and β thalassaemia
- thalassaemias are heterogenous group of genetic disorders
- β thalassaemia more prevalent in south asian, mediterranean and middle eastern populations
- α thalassaemia more prevalent in far east populations
α-thalassaemia
different types
usually occurs by deletion of gene. α globin genes affected. Humans have 4 α globin genes (2 on maternal, 2 on paternal)
silent carrier state - 1 α globin gene deleted
asymptomatic, carrier of disease with no symptoms
α thalassaemia trait - 2 α globin genes deleted
* minimal or no anaemia
* microcytosis: cells will keep dividing and getting smaller to compensate for less haemoglobin
* hyperchromia: reduction in haemoglobin
* resembles β thalassaemia minor
haemoglobin H (HbH disease) - 3 α globin genes deleted
* moderately severe disease
* resembles β thalassaemia intermedia
* tetramers of β globin (HbH) form due to excess of β globin
* results in microcytic, hypochromic anaemia
* abnormal RBCs taken out by spleen
* target cells and heinz bodies present
hydrops fetalis - 4 α globin genes deleted
* severe, usually results in intrauterine death
* excess γ globin forms tetramers in foetus (Hb Bart)
* not enough haemoglobin being made
* Hb Bart unable to deliver oxygen to tissues
β thalassaemia
- β-globin gene on c11 - disease often caused by mutation rather than deletion.
- β0 = total absence of production
- β+ = reduction of globin production
β-thal minor or β-thal trait
* usually asymptomatic with mild anaemia
* very microcytic and hypochromic RBCs
* heterozygous with 1 normal and one abnormal gene (β0/β or β+/β)
* resembles α-thal trait
β-thal intermedia
* severe anaemia, but not enough to require regular blood transfusions
* genetically heterogenous
* genotype may be mild variants of homozygous (β+/β+) or compound heterozygous states, and sometimes (β0/β+)
β-thal major
* severe transfusion-dependent anaemia
* manifests 6-9 months after birth as HbF → HbA
* homozygous genotype (β0/β0 or β+/β+)
note: names relate to clinical presentation
what will peripheral blood smear form patient with severe thalassaemia typically show
- hypochromic RBCs due to lack of haemoglobin
- microcytic RBCs as they will get smaller when dividing to compensate for lack of haemoglobin
- anisopoikilocytosis (RBCs of different shapes)
- frequent target cells, circulating nucleated RBCs and heinz bodies
why are insoluble aggregates produced in thalassaemia
- relative excess of unaffected globin chain
- eg insoluble aggregates of α chains form in β-thal
- sometimes can see this in different stains
- haemoglobin aggregates get oxidised, causing toxicity and damage, resulting in…
→ premature death of erythroid precursors, leading to innefective eryhtropoiesis
→ excessive destruction of mature red cells in spleen, leading to shortened red blood cell survival
why is thalassaemia also classified as a haemolytic anaemia?
- haemoglobin aggregates get oxidised
- causes damange to red blood cell
- excessive destruction of mature red cells in spleen
- red cells are destroyed
- red cells get removed too early
consequences of thalassaemia
extramedullary haemopoiesis occurs in an attempt to compensate, but results in splenomegaly, hepatomegaly (tissues are overworked) and expansion of haemopoiesis into the bone cortex (impairs growth and causes skeletal abnormalities)
further stimulation of EPO
reduced oxygen delivery (due to anaemia, as red cells are getting destroyed by spleen too early) further stimulates the bone marrow, contributing to the drive to make more defective red cells
iron overload
* excessive absorbtion of dietary iron due to ineffective haematopoiesis, as body tries to compensate
* more severe forms of thalassaemia (eg β-thal major) require repeated blood transfusions to treat the anaemia
reduced life expectancy
eg due to cardiac complications of iron overload
thalassaemia major treatments
- red cell transfusion from childhood
- iron chelation (delays iron overload by binding to the iron and allowing body to excrete bound particles)… might need to wear iron chelation pump
- folic acid, as bone marrow runs out of this (help support erythropoiesis)
- holistic care to manage complications - cardiology, endocrine, psychological and opthalmology
- stem cell transplantation in some - replace defective red cell production (the only ‘cure’ but are risky)
- pre-conception counselling for at-risk couples and antenatal screening
sickle cell disease
in general
- due to mutation in globin chain
- globin chain still produced at same amount, but globin chain abnormal
- these mutations alter the structure/function/stability of the haemoglobin tetramer
- autosomal recessive disease resulting from mutation of β-globin gene
- GAG (glutamic acid) → GTG (valine)
- mutant haemoglobin containing mutated β-globin protein called HbS
- heterozygous HbS carrier state = mild asymptomatic anaemia
- HbSS = homozygous is most common cause of severe sickling syndrome
- HbS can also be co-inherited with another normal Hb (eg HbC or β-thal) to cause sickling disorder
why does sickle cell disease persist in population if it can cause severe disease
- HbS gene found in large proportion of West African population
- protection against malaria
- therefore ‘beneficial’ to population and continues to persist in population
