Evolution of Thalassaemia Management Four Decades in Thalassaemia Care – Our Achievements and Challenges
Prevention of serious form of thalassaemia
Despite high prevalence of thalassaemia carrier rate (1 in 8 persons) in Hong Kong, preventive measure by antenatal screening has dramatically reduced the birth rate of severe forms of thalassaemia. The carrier screening is normally done by examining MCV (Mean cell volume) of red blood cells. If MCV is low compared with normal reference range, true thalassaemia carrier can be done by hematological testing (Hb pattern) and then confirmed by molecular test.
Local data shows that employing MCV <80 fl or MCH <27 pg as cutoff value for thalassemia screening detects all heterozygous carriers of SEA deletion α-thalassemia and the important common β-thalassemia mutations. Two less common carrier state, namely: 1) compound heterozygosity for SEA deletion α-thalassemia and triplicated α-globin genes and 2) concurrent SEA deletion α-thalassemia and β-thalassaemia carrier, are covered. However, using the above cutoff values will not detect: 1) around 50% carriers of Hb E; 2) around 50% carriers of single α-globin gene deletion and non-deletional α-globin gene mutations; and 3) the rare silent β-thalassemia carriers.
The screening is usually done on pregnant woman during antenatal checkup. It a woman is confirmed to be thalassemia carrier, the husband will be screened. A couple has sought screening testing before marriage or before conception of an offspring so that they get information in advance before conception. If both partners are found to be thalassaemia carriers, the fetus may be affected by serious form of thalassaemia if thalassaemia genes are passed onto them by parents. The fetus can be confirmed by a procedure called amniocentesis or chronic villus biopsy (CVS). The tissues and cells thus obtained from the fetus could be tested by molecular testing. The first amniocentesis for α-thalassaemia was done in 1983 and for β-thalassaemia in 1985. The first CVS for α-thalassaemia was performed in 1987, and for β-thalassaemia in 1989. These procedures have become the standard preventive measures for many years. In recent years, fetal DNA in maternal blood can also be employed to diagnosis whether a fetus is affected by the serious form of thalassaemia. This non-invasive new method can be used However occasional couples with affected fetus have decided to carry on the pregnancy after being counselled on the current state of thalassaemia care. Some of the patients with Hb Bart diseases were born this way and they were given intra-uterine transfusion which reduces the detrimental effects of severe anaemia.
In prenatal diagnosis, the prediction of the phenotype from genotype information is useful information that may be provided for the couple to make an informed decision on pregnancy outcome. Therefore, genotype phenotype correlation study is clinically relevant under this setting. The nature of the beta-thalassaemia mutation is an important factor to determine disease severity. Beta-thalassaemia mutations can be divided into beta-zero β0 (severe and no residual beta-chain production) and beta-plus β+ (less severe and shows residual beta-chain production). Local data shows that patients who are homozygous for β0/β0-thalassaemia show β-thalassaemia major phenotype with few exceptions. Compound heterozygous β0/β+-thalassaemia shows considerable phenotypic heterogeneity. Approximately two-thirds of patients behave as β-thalassaemia major and the remaining one-third behaving as β-thalassaemia intermedia. The genotypic finding of β0/β+-thalassaemia without other alleviating factor therefore cannot be used to predict β-thalassaemia intermedia phenotype in our patients. On the other hand, homozygosity for β+-thalassaemia is predictive of β-thalassaemia intermedia phenotype.
Another important genetic factor is the amelioration effect of concurrent alpha-thalassaemia that improves the globin chain imbalance. For example, local data shows that the SEA deletion α-thalassaemia ameliorates the clinical phenotype of β0/β+-thalassaemia but not necessarily β0/β0-thalassaemia. Finally, co-inheritance of genetic factors that enhances gamma chain production may also correlate with a milder phenotype in patients. Overall information on genetic factors of the genotype is clinically useful to predict disease severity, which has important implications in prenatal diagnosis and future patient treatment decision.