Genetic Mutations in Beta vs Alpha Thalassemia
Beta-thalassemia is caused by mutations in the HBB gene on chromosome 11, while alpha-thalassemia is caused by mutations in the alpha-globin genes on chromosome 16.
Beta-Thalassemia Genetic Basis
Beta-thalassemia results from mutations in the HBB gene (hemoglobin subunit beta gene) located on chromosome 11. 1 Humans have only two beta-globin genes (one on each chromosome 11), making the condition particularly impactful even with heterozygous mutations. 1
Types of HBB Mutations
The molecular heterogeneity is extensive, with the following mutation patterns:
- Point mutations are the most common cause, including single nucleotide substitutions that affect beta-globin synthesis 2, 3
- Small deletions or insertions leading to frameshift mutations 3
- Pre-terminating mutations that create premature stop codons (e.g., c.271 G>T creating a stop codon at amino acid 90) 4
- Gross gene deletions occur rarely 3
- Over 200 disease-causing mutations have been identified, with more than 350 mutations documented in the β-globin gene 3, 5
Beta-Thalassemia Phenotypes
The severity depends on the specific mutation type:
- β⁰ mutations result in complete absence of beta-globin chain production 6
- β⁺ mutations cause reduced but not absent beta-globin production 7
- The clinical severity correlates with the extent of imbalance between alpha and non-alpha globin chains 3
Inheritance Pattern
Beta-thalassemia follows an autosomal recessive inheritance pattern:
- Heterozygous mutations (beta-thalassemia trait) cause detectable hematologic changes with persistent microcytic anemia 1, 5
- Homozygosity or compound heterozygosity results in thalassemia major, requiring lifelong transfusions 7, 1
- When two carriers reproduce, there is a 25% chance of thalassemia major and 50% chance of carrier offspring 5
Alpha-Thalassemia Genetic Basis
While the provided evidence focuses primarily on beta-thalassemia, the fundamental distinction is clear: alpha-thalassemia is caused by mutations or deletions in the alpha-globin gene cluster on chromosome 16 (general medical knowledge, as specific evidence for alpha-thalassemia genetics was not provided in the references).
Key Genetic Differences
The critical distinction between these conditions:
- Beta-thalassemia: HBB gene on chromosome 11 (predominantly point mutations) 1, 3
- Alpha-thalassemia: Alpha-globin genes on chromosome 16 (predominantly gene deletions)
- Humans have two beta-globin genes but four alpha-globin genes (two on each chromosome 16), making alpha-thalassemia phenotypically variable depending on how many genes are affected
Clinical Implications of Genetic Differences
Timing of Presentation
Infants with beta-thalassemia are healthy at birth because fetal hemoglobin (HbF) does not require beta-globin chains. 7, 1 Symptoms emerge at 1-2 years of age as the switch from fetal to adult hemoglobin occurs. 7, 1
Diagnostic Approach
Both conditions present with microcytic hypochromic anemia, but genetic testing confirms the specific diagnosis:
- MCV typically <80 fL in both conditions 1
- Hemoglobin electrophoresis shows elevated HbA2 (>4.0%) in beta-thalassemia trait 5
- Genetic testing definitively distinguishes beta from alpha thalassemia 1
Common Pitfall
Do not prescribe iron supplementation to patients with confirmed thalassemia trait—it provides no benefit and may contribute to unnecessary iron accumulation. 1 Always check serum ferritin to rule out concurrent iron deficiency before attributing microcytic anemia solely to thalassemia trait. 1