Page 338 - Textbook of Pathology, 6th Edition

322 By deletion of a single α-chain gene causing heterozygous
α-thalassaemia trait called heterozygous α-thalassaemia.
CLINICAL FEATURES. α-thalassaemia trait due to two
α-chain gene deletion is asymptomatic. It is suspected in a
patient of refractory microcytic hypochromic anaemia in
whom iron deficiency and β-thalassaemia minor have been
excluded and the patient belongs to the high-risk ethnic
group. One gene deletion α-thalassaemia trait is a silent
carrier state.
LABORATORY FINDINGS. The patients of α-thalas-
saemia trait may have the following haematological
findings:
1. Haemoglobin level normal or mildly reduced.
2. Blood film shows microcytic and hypochromic red cell
morphology but no evidence of haemolysis or anaemia.
3. MCV, MCH and MCHC may be slightly reduced.
4. Haemoglobin electrophoresis reveals small amount of
SECTION II
Hb-Bart’s in neonatal period (1-2% in α-thalassaemia 2
and 5-6% in α-thalassaemia 1) which gradually disappears
by adult life. HbA is either normal or slightly decreased
2
(contrary to the elevated HBA levels in β-thalassaemia
2
trait).
Figure 12.31 Pathogenesis of β-thalassaemia major.
β β β β β-THALASSAEMIAS
ii) Translation defect: Mutation in the coding sequence causing
MOLECULAR PATHOGENESIS. β-thalassaemias are stop codon (chain termination) interrupting β-globin
caused by decreased rate of β-chain synthesis resulting in messenger RNA. This would result in no synthesis of β-globin
reduced formation of HbA in the red cells. The molecular chain i.e. β° thalassaemia.
pathogenesis of the β-thalassaemias is more complex than iii) mRNA splicing defect: Mutation leads to defective mRNA
that of α-thalassaemias. In contrast to α-thalassaemia, gene processing forming abnormal mRNA that is degraded in the
deletion rarely ever causes β-thalassaemia and is only seen nucleus. Depending upon whether part of splice site remains
in an entity called hereditary persistence of foetal haemoglobin intact or is totally degraded, it may result in β thalassaemia
+
(HPFH). Instead, most of β-thalassaemias arise from different or β° thalassaemia.
types of mutations of β−globin gene resulting from single Depending upon the extent of reduction in β-chain
base changes. The symbol β° is used to indicate the complete synthesis, there are 3 types of β-thalassaemia:
+
absence of β-globin chain synthesis while β denotes partial
synthesis of the β-globin chains. More than 100 such 1. Homozygous form: β-Thalassaemia major. It is the most
mutations have been described affecting the preferred sites severe form of congenital haemolytic anaemia. It is further
in the coding sequences e.g. in promoter region, termination of 2 types (Fig. 12.31):
region, splice junctions, exons, introns. Some of the important i) β° thalassaemia major characterised by complete absence
Haematology and Lymphoreticular Tissues
ones having effects on β-globin chain synthesis are as under of β-chain synthesis.
+
(Fig. 12.30): ii) β thalassaemia major having incomplete suppression of
i) Transcription defect: Mutation affecting transcriptional β-chain synthesis.
promoter sequence causing reduced synthesis of β-globin 2. β-Thalassaemia intermedia: It is β-thalassaemia of
chain. Hence the result is partially preserved synthesis i.e. intermediate degree of severity that does not require regular
β thalassaemia. blood transfusions. These cases are genetically heterozygous
+
+
(β°/β or β /β).
3. Heterozygous form: β-Thalassaemia minor (trait). It is
a mild asymptomatic condition in which there is moderate
suppression of β-chain synthesis.
Besides β-thalassaemia minor, a few uncommon globin
chain combinations resulting in β-thalassaemia trait are as
under:
i) δβ-thalassaemia minor in which there is total absence of
both β and δ chain synthesis and is characterised by elevated
Figure 12.30 Schematic representation of sites of β-globin gene HbF level but unlike β-thalassaemia minor there is normal
mutation in chromosome 11 giving rise to β-thalassaemia. or reduced HbA level.
2