What is thalassemia? causes, symptoms, clinical features?
Thalassemia
Thalassemias are inherited disorders caused by mutations in globin genes that decrease the synthesis of α- or β-globin. Decreased synthesis of one globin results not only in a deficiency of Hb but also in red cell damage that is caused by precipitates formed from excess unpaired "normal" globin chains. The mutations that cause thalassemia are particularly common in Mediterranean, African, and Asian regions in which malaria is endemic. As with HbS, it is hypothesized that globin mutations associated with thalassemia protect against falciparum malaria.
Pathogenesis
A diverse collection of α-globin and β-globin mutations underlies the thalassemias, which are autosomal codominant conditions.
Adult hemoglobin (HbA) is composed of two α chains and two β chains.
α chains are encoded by two α-globin genes on chromosome 16.
β chains are encoded by a single β-globin gene on chromosome 11.
Clinical features vary widely depending on the combination of mutated alleles inherited.
β-Thalassemia
Mutation Categories:
β⁰: No β-globin chains are produced.
β⁺: Reduced but detectable β-globin synthesis.
Types:
β-thalassemia minor (trait): One abnormal allele, asymptomatic or mildly symptomatic.
β-thalassemia major: Two abnormal alleles, severe disease.
β-thalassemia intermedia: Milder disease with at least one β allele.
Mutation Effects:
Most mutations disrupt β-globin synthesis via abnormal RNA splicing, promoter issues, or coding errors.
Mechanism of Anemia:
Inadequate HbA formation → Microcytic, hypochromic red cells.
Excess unpaired α-globin chains form toxic precipitates → Red cell and precursor damage.
Ineffective erythropoiesis leads to apoptosis of erythroid precursors.
Iron overload due to decreased hepcidin and increased iron absorption.
α-Thalassemia
Mainly caused by deletions involving one or more α-globin genes.
Severity depends on the number of deleted genes:
1 gene: Silent carrier.
2 genes: α-thalassemia trait.
3 genes: HbH disease (excess β or γ chains).
4 genes: Lethal in utero (Hb Bart).
Tetramers:
HbH (β₄) and Hb Bart (γ₄) have high oxygen affinity → Poor oxygen delivery.
Less ineffective erythropoiesis than in β-thalassemia.
Morphology
β-thalassemia minor & α-thalassemia trait:
Peripheral smear: Microcytic, hypochromic, regular red cells.
Target cells are common.
β-thalassemia major:
Marked microcytosis, hypochromia.
Poikilocytosis, anisocytosis.
Nucleated red cells (normoblasts).
Anatomical Changes in β-thalassemia major:
Profound erythroid hyperplasia.
Bone marrow expansion, skeletal deformities.
Extramedullary hematopoiesis: Splenomegaly, hepatomegaly, and lymphadenopathy.
Growth retardation, cachexia.
Hemosiderosis if untreated.
β-thalassemia intermedia & HbH disease:
Intermediate findings.
Moderate splenomegaly, erythroid hyperplasia.
Growth retardation.
Clinical Features
β-thalassemia trait & α-thalassemia trait:
Typically asymptomatic.
Mild microcytic hypochromic anemia.
Must distinguish from iron deficiency anemia.
β-thalassemia major:
Manifests postnatally as HbF synthesis decreases.
Growth retardation from infancy.
Requires regular transfusions.
Iron overload develops from transfusions and low hepcidin.
Without chelation therapy, iron-induced cardiac dysfunction is fatal.
Stem cell transplantation is the best early treatment option.
HbH disease & β-thalassemia intermedia:
Moderate anemia.
Typically do not require transfusions.
Less severe iron overload.
Diagnosis:
β-thalassemia major:
Clinical signs + Hb electrophoresis.
Reduced/absent HbA, elevated HbF.
HbA2: Normal or increased.
β-thalassemia minor:
Hb electrophoresis: Low HbA, high HbA2.
HbH disease:
Electrophoresis: Detects β₄ tetramers.
Prenatal diagnosis:
DNA analysis in specialized centers.
First disease diagnosed via DNA-based testing.
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