Thalassemia

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Introduction

Thalassemias are a heterogenous group of genetic disorders of hemoglobin synthesis. They are characterized by a reduced rate of synthesis of one or more alpha/beta globin chains.

Thalassemias are the most common inherited abnormalities of hemoglobin. Beta thalassemia is most common in Mediterranian populations, while alpha thalassemia is most common in southeast Asian populations.

Not structural abnormality of hemoglobin, but rather disruption of amounts of hemoglobins.

There is important stochiometry between alpha and beta globin.

Thalassemias can be deficiencies in alpha or beta, leading to abnormal tetramers.

The Case of...

a simple case introducing clincial presentation and calling for a differential diagnosis to get students thinking.

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Causes and Risk Factors

Beta thalassemia

major is severe, leading to dependence on transfusions
intermedia causes moderate to severe anemia
minor can cause asymptomatic or mild anemia

typically presents when fetal hemoglobin transitions to

Alpha thalassemia:

Can present in newborn period

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Pathophysiology

There are two beta genes and four alpha genes that code for hemoglobin production, with is composed of two copies of each protein.

Alpha thalassemia is usually an autosomal recessive disease. There are two alpha globin genes on chromosome 16, with four loci total. Disease depends on the number of loci affected:

1: silent
2: trait
3: Hemoglobin H disease
4: hydrops fetalis (barts)

Decreased α chain production leads to decreased hemoglobin synthesis and also β chain tetramers. As these are fairly soluble (though abnormal), there is decreased hemolysis with alpha thalassemia.

Beta thalassemia comes about due to mutations in the beta globin gene. It also is an autosomal recessive disease. β⁰ is a nonsense mutation in the coding region, leading to no gene expression. A homozygous β⁰ leads to thalassemia major.

β⁺ is a mutation leading to altered mRNA splicing and decreased gene expression.

Decreased β chain production leads to decreased hemoglobin synthesis and also α chain tetramers. These are poorly soluble, leading to hemolysis. An intense bone marrow expansion leads to skeletal abnormalities. Hemolysis leads to massive liver and splenic enlargement.

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