Biology of Disease

Mediterranean sea. However, the thalassemias are also relatively common in

southeastern Asia, the Philippines, China and worldwide and is perhaps the

most common group of hereditary diseases. Cooley first accurately described

them clinically in 1925 and the disease used to be called Cooley’s anemia, a

term now reserved for B-thalassemia.

In the late 1930s, thalassemia was shown to be an inherited disorder. However,

it was not until protein analytical techniques improved in the 1960s that the

disease was shown to be the result of an imbalance in the amounts of A- and

B-globins synthesized. The severe anemias associated with some thalassemias

stimulate the production of erythrocyte precursors. As a result, bone marrow

is able to expand to all areas of the skeleton leading to skeletal deformities.

If this occurs within the spine and compresses the spinal cord it can cause

intense pain. Some forms of the disease are fatal causing death in utero, while

others require copious blood transfusions for the anemia. A-Thalassemia, for

example, is caused by a complete or partial failure to produce A-globin. It is fatal

in its severe form when A-chains are not produced. In B-thalassemia, a partial

or complete failure to produce B-globin means that patients require lifelong

blood transfusions.

There are a number of forms of the disease because there is more than one

gene for the globin polypeptides and a mutation may not affect all of them.

Consequently there may not be complete absence of a given globin chain

and the disease will be less severe. Thalassemias are classified according to

which globin chains are reduced in amount, are mutated or are absent. The

more copies of the gene are missing or inactive, the greater the severity of

the disease. The anemia is caused by an ineffective erythropoiesis and from

precipitation of excess free globin within the erythrocytes. The cells have a

shortened life span and the spleen removes the abnormal erythrocytes leading

to splenomegaly.

A-Thalassemias can vary from a condition in which only one A-globin chain

is missing, producing a ‘silent’ mutation that is practically a symptom-free,

carrier state, to other forms where two, three or all four genes are absent

or inactive (Table 13.6). The presence of a single functional A-globin gene

is usually sufficient to preclude serious morbidity. A decreased synthesis of

A-globin leads to the formation of two abnormal Hb tetramers. Hemoglobin

Barts is found in umbilical cord blood and arises because of a lack of A-chains

but normal production of the fetal G-chains; thus Hb Barts is G 4. If the infant

survives, B-chain synthesis begins and B 4 (HbH) tetramers form. Unfortunately,

neitherG 4 nor B 4 can take up cooperatively O 2 but bind it so tightly it cannot

be delivered to the tissues. Hemoglobin H precipitates in older erythrocytes

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Syndrome Genotype Number of

A-genes

Clinical severity Hemoglobin

Hydrops fetalis ---- 0 lethalin utero mostlyG

littleB 4

HbH disease ---A 1 severe microcytosis about 25%

HbA,

mostlyB 4

A-thalassemia trait --AA

or

• AA-

2 asymptomatic variable

Silent carrier -A/AA 3 none functional

Table 13.6Characteristics ofA-thalassemias

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