What is alpha thalassemia?

What is Alpha Thalassemia

Alpha thalassemia is an autosomal recessive inherited blood disorder caused by decreased or absent synthesis of alpha-globin chains due to mutations affecting one to all four alpha-globin genes located on chromosome 16, resulting in a clinical spectrum ranging from asymptomatic carrier states to lethal hemolytic anemia. 1

Genetic Basis and Pathophysiology

• The alpha-globin gene cluster maps to the short arm of chromosome 16, with each chromosome normally containing two alpha-globin genes (α2 and α1), giving a total of four functional alpha-globin genes in diploid cells 2
• Disease severity directly correlates with the number of affected genes: deletion or inactivation of 1,2,3, or all 4 alpha-globin genes produces progressively more severe phenotypes 1
• Most cases result from gene deletions (ranging from 3 to over 100 kb) caused by unequal crossing-over during meiosis, though point mutations affecting mRNA processing or producing unstable polypeptide chains also occur 2
• The fundamental pathophysiology involves imbalanced globin chain production, leading to ineffective erythropoiesis, decreased red blood cell survival, and chronic hemolytic anemia 3

Clinical Phenotypes by Genotype

Silent Carrier (One Gene Deletion: -α/αα)

• Clinically asymptomatic with normal or near-normal hematological parameters 1
• No treatment required 1

Alpha Thalassemia Trait (Two Gene Deletions: --/αα or -α/-α)

• Microcytic hypochromic anemia that does NOT respond to iron supplementation 4
• Mean corpuscular volume (MCV) typically <80 fL with reduced mean corpuscular hemoglobin (MCH) 4
• Generally asymptomatic with only limited alterations in hematological parameters 2
• No treatment required 1

Hemoglobin H Disease (Three Gene Deletions: --/-α)

• Moderate to severe hemolytic anemia with variable degree of ineffective erythropoiesis and splenomegaly 5
• Produces hemoglobin composed entirely of beta chains (HbH), detectable at levels of 0.8-40% 1
• Critical distinction: Nondeletional mutations (e.g., Hb H Constant Spring) cause more severe disease than deletional mutations, with approximately one-third requiring regular transfusions versus uncommon transfusions for deletional types 5
• May require intermittent transfusion therapy, especially during intercurrent illness 1

Hemoglobin Bart's Hydrops Fetalis (Four Gene Deletions: --/--)

• Lethal form with complete absence of alpha-globin synthesis 1
• Distinguished by presence of Hb Bart's and total absence of fetal hemoglobin (HbF) 1
• Most common cause of nonimmune hydrops fetalis in Southeast Asian populations, accounting for 28-55% of cases in these regions 4
• Fetus suffers severe intrauterine hypoxia from early gestational age because Bart's hemoglobin is an ineffective oxygen carrier, typically presenting with hydrops in late second or early third trimester 4
• Most pregnancies are terminated due to increased risk of maternal and fetal morbidity 1

Geographic Distribution and Epidemiology

• Probably the most common monogenic gene disorder worldwide 1
• Highest frequency in Mediterranean countries, Southeast Asia, Africa, the Middle East, and the Indian subcontinent—regions with historical endemic malaria exposure 1
• Incidence has increased in North-European countries and North America due to demographic changes 1

Diagnostic Approach

• All affected individuals demonstrate anemia (low hemoglobin), reduced MCH, reduced MCV, and normal or slightly reduced HbA2 levels 1
• Parents can be screened by evaluating mean cell volume: carriers will have MCV <80 fL 4
• Molecular analysis is usually required to confirm haematological observations, especially in silent carriers and trait forms 1
• Diagnosis of affected fetuses can be made by detection of common DNA deletions or point mutations, or by fetal blood sampling to evaluate for abnormal Bart's hemoglobin 4

Critical Clinical Pitfalls

• Do not prescribe iron supplementation to patients with confirmed alpha thalassemia trait—it provides no benefit and may contribute to unnecessary iron accumulation 6
• Always check serum ferritin to rule out concurrent iron deficiency before attributing microcytic anemia solely to thalassemia trait 6
• Consider ethnicity in the diagnostic approach, as alpha thalassemia is significantly more common in specific populations 6
• In pregnant women of appropriate ancestry with persistent mild anemia unresponsive to prenatal iron supplementation, further evaluation with MCV, RDW, and hemoglobin electrophoresis is indicated 6