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Like other globin gene disorders, alpha-thalassemia is highly prevalent in all tropical and subtropical regions (around 1/10,000), particularly in the African equatorial belt. Intermediate and severe forms of alpha-thalassemia are very rare in North America and Northern Europe (about 1/1,000,000), but predominantly seen in immigrant populations from South-East Asia or Mediterranean countries.

Disease expression varies according to the level of alpha-globin chain deficiency. Alpha thalassemia trait (or alpha thalassemia minor) causes microcytosis and hypochromia with absent or mild anemia (often detected on routine blood tests), generally with no other symptoms. Hemoglobin H disease (HbH) is characterized by moderate hemolytic anemia with variable amounts of hemoglobin H along with occasionally severe splenomegaly, sometimes complicated by hypersplenism. Hb Bart's hydrops fetalis involves a severe deficiency in alpha-globin chains with serious developmental implications.

Alpha globin synthesis is regulated by four alpha-globin genes, two on each copy of chromosome 16 (16p13.3). Alpha-thalassemia most frequently results from deletion of two or more alleles (HBA1 and HBA2). More rarely, point mutations in critical regions of these genes may cause non-deletional alpha-thalassemia. Deletions of regulatory elements located upstream of the alpha-globin genes have also been found. The severity of the clinical picture is correlated with the degree of alpha-globin chain deficiency. It has been found that interactions involving non-deletional forms lead to more severe manifestations than those involving deletional forms. Deletion of 1 allele results in the silent form, 2 alleles in alpha-thalassemia trait, 3 alleles in HbH and 4 alleles in Hb Bart's hydrops fetalis.

Diagnosis is based on hematologic testing of red blood cell (RBC) indices, peripheral blood smear, supravital stain to detect RBC inclusion bodies, and qualitative and quantitative hemoglobin analysis. Confirmation of diagnosis is based on molecular genetic testing.

Differential diagnosis should include iron deficiency anemia and defects in heme synthesis. An acquired form known as alpha-thalassemia-myelodysplastic syndrome (ATMDS) has been described mainly in adult males and should also be considered; it is characterized by myelodysplasia (MD) associated with HbH. A syndromic form, alpha-thalassemia-intellectual deficit syndrome, is characterized by very mild to severe anemia associated with developmental abnormalities.

Prenatal diagnosis is possible when Hb Bart's hydrops fetalis or a severe form of Hb H disease has previously been identified in a family member.

Carriers of a single allelic variant are asymptomatic (silent alpha-thalassemia) but pose a risk of transmission to their offspring. The pattern of inheritance is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.

Patients with silent alpha-thalassemia or thalassemia trait do not require treatment. Specific treatment is however required for other forms of the disease and may include occasional or regular red blood cell transfusions, iron chelation, and other supportive measures.

The prognosis for carriers of silent alpha-thalassemia or alpha-thalassemia trait is very good. Neonates with Hb Bart's hydrops fetalis usually die in the perinatal period. In patients with hemoglobin H disease, the prognosis is usually good, but depends on complications and care.