Alpha Thalassaemia Flashcards
Thalassaemia
Thalassaemia refers to a group of disorders characterised by reduced or absent globin chain production.
Thalassaemia is one of the haemoglobinopathies, which refers to a group of autosomal recessive inherited disorders that affect the globin chains that form the protein component of haemoglobin.
Haemglobinopathies can be broadly divided into two types:
Haemoglobin variants: mutant forms of haemoglobin that affect the structure. Sickle cell disease is most well recognised.
Thalassaemia: reduced or absent globin chain production due to underlying mutations.
Thalassaemia can be further divided depending on the type of globin chain affected:
Alpha thalassaemia: reduced or absent production of the alpha globin chains
Beta thalassaemia: reduced or absent production of the beta globin chains
Haemoglobin is the main oxygen-carrying molecules within our red blood cells.
Haemoglobin (Hb) is essential for the transport of oxygen around the body. It is composed of four globin chains and four heme molecules, which are the actual oxygen-binding structures that contain iron.
In the human body, there are two major gene clusters important for the synthesis of globin chains in the formation of haemoglobin:
Alpha globin gene cluster: located on chromosome 16. Contains the embryonic globin genes zeta and two copies of the alpha globin gene (alpha-1 and alpha-2).
Beta globin gene cluster: located on chromosome 11. Contains the embryonic globin gene epsilon, fetal globin genes and the adult beta globin and delta globin gene.
When we look at abnormal mutations seen in thalassaemia, we use the following denotation:
Mutation leading to absent production (0)
Mutation leading to reduced production (+)
Alpha thalassaemia is one of the most common single gene disorders worldwide.
Anyone may be a carrier of an alpha thalassaemia gene, but is it most prevalent in sub-Saharan Africa, the Middle East, Mediterranean regions and areas of Asia (South and South-East).
Globally, it is estimated that 3 in 100 of the world’s population will have a thalassaemia gene (alpha or beta).
Alpha thalassaemia is one of the most common single gene disorders worldwide.
We each have four alpha globin genes. The severity of alpha thalassaemia therefore depends on how many genes are affected and whether the mutations leads to reduced, or absent, production. In general, there are two clinically significant forms of alpha thalassaemia that occur if three or four of the genes are affected.
Numerous genetic mutations may occur in the alpha globin genes leading to thalassaemia. Deletions of the alpha globin genes are the most commonly seen mechanisms accounting for alpha thalassaemia, particularly in Asian and Mediterranean populations.
Mutations seen can include:
Deletions
Genetic rearrangements
Mutations affecting transcription (due to mutations that affect promotors or enhancers)
Mutations affecting splicing (splicing is form of mRNA processing that removes introns)
Premature stop codons (affects mRNA translation leading to truncated proteins)
Other rarer mechanisms
Alpha thalassaemia can be considered an autosomal recessive disorder. However, because there are two genes on each chromosome that encode the alpha globin chains, there are multiple types of alpha thalassaemia.
Inheritance of three normal copies (aa/a-): known as alpha thalassaemia minima. Patients are asymptomatic.
Inheritance of two normal copies (a-/a- OR aa/–): known as alpha thalassaemia trait. Minimal anaemia.
Inheritance of one normal copy (a-/–): known as haemoglobin H disease (HbH). HbH is composed of tetramers of beta globin chains. Moderate to severe haemolytic anaemia.
Inheritance of no normal copies (–/–): known as Hb Barts syndrome. Incompatible with extrauterine life.
In the absence of alpha globin chains, normal haemoglobin A, A2 and fetal haemoglobin cannot be formed.
The severity of thalassaemia depends on both the number, and how, the genes are affected.
Alpha thalassaemia trait
Patients with alpha thalassaemia trait are usually asymptomatic. There may be evidence of mild microcytic anaemia on routine blood testing. There are no specific treatments required. The condition is clinically relevant for offspring. If two patients with alpha thalassaemia trait or minima have a child, there is a risk of HbH or Hb Barts syndrome.
Haemoglobin H (HbH) disease
Patients with HbH disease inherit three abnormal copies of the alpha globin chain. These may be deletional or non-functional mutations. Without alpha globin chains, there are two major consequences:
Neonatal period: formation of abnormal haemoglobin composed of four gamma chains. Known as Hb Barts.
Adult period: formation of abnormal haemoglobin composed of four beta chains. Known as HbH.
The consequence of the abnormal HbH is a reduced red cell survival with a hypochromic microcytic anaemia. These cells are also removed from the circulation at an increased rate by the spleen. The severity of anaemia is variable depending on the mutation.
The HbH haemoglobin is at increased risk of oxidative stress and is ineffective as an oxygen delivering molecule. This is because, like myoglobin, it holds onto oxygen with higher affinity. It is estimated to have an affinity for oxygen at least 10 times that of HbA (normal haemoglobin).
Patients with HbH disease inherit … abnormal copies of the alpha globin chain
Patients with HbH disease inherit three abnormal copies of the alpha globin chain
Haemoglobin Barts
This is the most severe form of alpha thalassaemia that results from inheritance of four abnormal copies of the alpha globin gene. The condition is incompatible with extrauterine life.
