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[Current clinical approaches and gene mutation study of beta-thalassemia major]
1Department of Pediatrics, Kaohsiung Medical College, Taiwan, Republic of China.
Insights
Beta-thalassemia major is characterized by specific gene mutations, with compound heterozygotes being more common than homozygotes. Clinical severity correlates with iron overload, transfusion needs, and specific genetic mutations.
Area of Science:
- Hematology
- Genetics
Context:
- Beta-thalassemia major is a severe inherited blood disorder.
- Clinical manifestations and genetic mutations vary among patients.
Purpose:
- To analyze clinical features and gene mutations in beta-thalassemia major patients.
- To identify common mutations and their correlation with disease severity.
Summary:
- This study assessed 41 beta-thalassemia major cases, identifying eight distinct point mutations. The C to T substitution at IVS 2 nt 654 and frameshift codons 41/42 deletion were most prevalent.
- Compound heterozygotes (78%) were more common than homozygotes (22%). Iron overload severity correlated with transfusion amount and age, while splenectomy and iron-chelating agents showed therapeutic benefits.
Impact:
- Identifies key beta-thalassemia major mutations and their prevalence.
- Highlights the significance of compound heterozygosity and specific mutations in disease presentation.
- Correlates iron overload with clinical outcomes and treatment efficacy.
Abstract:
Forty-one cases of beta-thalassemia major were assessed for their clinical manifestations and gene mutation. The age distribution was from 1 to 18 years old. Patient's initial clinical symptoms began mostly before 2 years of age (90.2%). Patient's initial hematological data included mean hemoglobin value, 5.8 +/- 1.2 gm/dl, hemoglobin F value, 85.0 +/- 12.1%, hemoglobin A2 value 2.3 +/- 1.8%, reticulocyte count 9.2 +/- 9.0%. Eight different point mutations were characterized. Of these mutations, C to T substitution at nucleotide (nt) 654 of intervening sequence (IVS) 2, accounting for 46.3% of mutant beta-globin genes, is the most common mutation in our series, followed by frameshift codons 41/42 with a four nucleotides (TCTT) deletion for 31.7%; A to G substitution at position -28 of the promotor area for 8.5%; A to T substitution at codon 17 for 6.1%; frameshift codons 27/28 (insertion of C) for 2.4%; G to T substitution at nucleotide 1 of IVS-1 for 2.4%; frameshift codons 71/72 (insertion of A) and IVS-1 3' end TAG-->GAG for 1.2%. The first four mutations account for 92.6% of all beta-globin gene mutations in our series. As to mutations in each individual, the incidence of compound heterozygotes of two different mutations is much higher than homozygotes of a single mutation, 78.0% vs. 22.0%. Compound heterozygotes of C to T substitution at nt 654 of IVS-2 and frameshift codons 41/42 with a four nucleotides deletion is the most common pattern of beta-thalassemia mutation in our patients (41.5%). Patients with beta(0)/-28 beta(+) compound heterozygote mutation had much delayed initial symptoms than beta (0)/beta(0) homozygote mutation, but clinical manifestation may be aggravated when the mutation combined with glucose-6-phosphate dehydrogenase deficiency. Severity of iron overload was significantly correlated with total transfusion amount and patient's age in simple regression analysis (p < 0.001). Splenectomy may effectively prolong transfusion interval, maintain higher hemoglobin level before each transfusion and palliate clinical symptoms (p < 0.01). Iron-chelating agent therapy can effectively lower the total amount of serum ferritin. Higher severity of iron overload correlates with higher incidence of EKG and cardiac abnormalities in patients with beta-thalassemia major.