Genetics and Pathophysiology of β-thalassaemia
Downregulation of β-globin gene (HBB ) can be caused by a whole
spectrum of mutations. In fact, more than 400 mutations in the β-globin
gene have now been described ranging from point mutations to small
deletions limited to the HBB to extensive deletions of the whole
β globin cluster
(https://ithanet.eu/db/ithagenes?action=list&hem=2).
The non-deletional mutations include single base substitutions, small
insertions or deletions of one to a few bases located within the gene or
its immediate flanking sequences. These mutations can affect every stage
of β-globin expression, from transcription to RNA processing to
translation. Although β-thalassaemia is rarely caused by deletions, a
number of deletions that are restricted to the HBB gene itself
have been described. These deletions range from 25bp up to 6kb [3].
Subjects with a single β-thalassaemia allele are called β-thalassaemia
traits or carriers and they are usually asymptomatic. Such individuals
present with a mild hypochromic, microcytic anaemia and elevated
HbA2. When both β globin gene alleles are affected, no β
globin is produced and these patients are referred to as β-thalassaemia
homozygotes or major. β-thalassaemia major presents itself within the
first 2 years of age with severe anaemia, poor growth and skeletal
abnormalities if left untreated [4]
Due to the imbalance in globin chain synthesis, an excess of freed
α-globin chains accumulates within erythroid cells. Aggregation,
denaturation and degradation of these excess α-chains leads to the
formation of methaemoglobin and insoluble hemichromes resulting in free
iron which catalyses the formation of reactive oxygen species. The
reactive oxygen species damages the cell membrane leading to ineffective
erythropoiesis in the bone marrow and haemolysis of red cells within
circulation. This triggers loss of red blood cells in the spleen due to
the binding of immunoglobulins and complement components to defective
red cell membranes. The resulting severe anaemia leads to reduced tissue
oxygenation, increased erythropoietin and bone marrow expansion. This
leads to skeletal deformities and osteopenia. Substances released from
degenerating red cells increase iron absorption, which contributes to
iron overload which can cause liver and heart disease [5],[6].