Page 325 - Concise Pathology for Exam Preparation ( PDFDrive )

310 SECTION II Diseases of Organ Systems

Common Types of Thalassaemias

1. a-Thalassaemia: Affects the synthesis of a chains and its severity depends on the num-
ber of a genes deleted. Based on the number of dysfunctional a genes, a-thalassaemia is
classified into
(a) a-thalassaemia trait: One or two a genes are deleted or dysfunctional. Majority of
the patients are asymptomatic; some show reduced MCV and MCH and a micro-
cytic hypochromic anaemia.
(b) Haemoglobin H disease: This is caused by functional inactivation of 3–4 a
genes. There is microcytic hypochromic anaemia (Hb-7–11 g/dL); hepato-
splenomegaly, jaundice, gall stones and leg ulcers. Haemoglobin electrophoresis
shows 4–10% HbH (b4 haemoglobin). No bony deformities or features of iron
overload are evident.
(c) Haemoglobin Bart’s (hydrops fetalis): All four a genes are inactive. There
is inability to make either HbA or HbF. The excess b chains form Hb Bart’s.
There is intrauterine death at 25–40 weeks or the fetus dies immediately
after birth.
2. b-Thalassaemia: Also called Cooley anaemia or Mediterranean anaemia, b-thalassaemia
is characterized by a total lack or reduction in the synthesis of structurally normal b-
globin chains with normal synthesis of a chains resulting in reduced levels of HbA.
b-thalassaemia is a common blood disorder, which occurs most frequently in Mediter-
ranean countries, North Africa, the Middle East, India, Central and Southeast Asia.
Depending on the severity it is classified into
(a) b-Thalassaemia minor (trait)
(b) b-Thalassaemia intermedia
(c) b-Thalassaemia major

Molecular Pathology of b-Thalassaemia
Based on molecular pathology b-thalassaemia is classified into
0
• b -Thalassaemia: Total absence of b chains (homozygous state)
1
• b -Thalassaemia: Reduced synthesis of b chains (homozygous state)
• b-Thalassaemia is mainly due to point mutations (in contrast to gene deletion in
a-thalassaemia).
1
• Promoter region mutations lead to b -thalassaemia.
0
• Chain terminator mutations lead to b -thalassaemia. These result from either of the
two following mechanisms:
• Frame shift mutation (introduction of stop codon)
• Point mutation (introduction of stop codon)
• Splicing mutations (most common cause of thalassaemia) may occur:
0
• At the junction of exon and intron: b -thalassaemia
• In intron: b -thalassaemia
1
0
• Translation defect of exon leads to b -thalassaemia.
• b-Thalassaemia major may be
0
0
0
• Homozygous b -thalassaemia (b /b )
1
• Homozygous b -thalassaemia (b /b )
1
1
0
• Double heterozygous (b /b ) thalassaemia.
1
• b-Thalassaemia minor/trait is
0
• Heterozygous (b /b, b /b)
1

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