22nd May 2020, Dr Chee L Khoo
Let’s imagine we have a pregnant woman who tested positive for β-thalassaemia trait (minor) on antenatal screening blood tests. If both partners carry the same thalassaemia trait, there is a 25% chance of having a baby with thalassaemia major. Thus, we are advised to screen her partner for thalassaemia as well. Say, the partner’s blood picture is normal with no microcytosis and high performance cation-exchange chromatography (HPLC) shows normal levels of HbA2 and HbF. The partner’s test is therefore negative for beta thalassaemia. Great news but can they exclude α-thalassaemia? Does it matter since the mother only has beta thalassaemia trait?
There are two main types of thalassaemias, α-thalassaemia and β-thalassaemia. Carriers of thalassaemia are usually asymptomatic. Screening for thalassaemia is suggested for all women who are pregnant but is that enough reassurance to your patients? What if the mother carries two thalassaemia traits? Does haemoglobin electrophoresis screen for both types of thalassaemias?
Normal haemoglobin molecule
Normal adult haemoglobin consists of pairs of α and β chains (a2 β 2), and foetal haemoglobin has two α-chains and two γ -chains (α2 γ 2). The genes for the α chains and γ chains are duplicated (αα/αα, γγ/γγ), whereas the ß chains are encoded by a single gene locus (β/β). In the foetus, defective production of α-chains is reflected by the presence of excess γ-chains, which form γ4 tetramers called haemoglobin Bart’s. The number of missing or faulty genes for either globin can vary and this gives rise to a whole host of combinations and permutations of phenotypes of thalassaemia.
α-thalassaemia
There is decreased α-globin production, therefore fewer α-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers called haemoglobin H (HbH) of four beta chains. The excess γ chains form tetramers which are poor carriers of O2 since their affinity for O2 is too high. The severity of this disorder is related to the number of non-functional copies of the α-globin genes. α-thalassaemias are classified into two main subgroups: α+-thalassaemia, in which one pair of the genes is deleted or inactivated by a point mutation (-α/αα or ααND/αα, with ND denoting nondeletion) and α0-thalassemia, in which both pairs of α-globin genes on the same chromosome are deleted (–/αα).
β-thalassaemia
This is caused by reduced (β+) or absent (β0) synthesis of the β-globin chains of haemoglobin. Three clinical and haematological conditions of increasing severity are recognised: the β- thalassaemia carrier state, thalassaemia intermedia, and thalassaemia major. The severity of disease expression is related to the degree of α-globin chain excess, which precipitates in the red blood cell precursors, causing both mechanic and oxidative damage. Any mechanism that reduces the number of unbound α-globin chains in the red cells may ameliorate the detrimental effects of excess α-globin chains. This include co-inheritance of alpha thalassaemia, so-called double thalassaemia.
Diagnostic tests
We start considering thalassaemia when we see microcytosis in the blood picture and the patient is NOT iron deficient. Individuals with β-thalassemia trait usually have microcytosis and increased levels of HbA2. HbF is sometimes elevated as well. Unfortunately, in mild cases of beta thalassaemia, the HbA2 can be normal.
Individuals with α-thalassemia trait also have microcytosis and normal levels of HbA2 and HbF. However, α-thalassaemia trait status cannot be determined by these screening tests alone. DNA testing that directly examines the alpha and/or beta globin genes is the only way to determine silent α-thalassemia trait.
The mother
We assume that in a woman who has β-thalassaemia, the microcytosis is from her β-thalassaemia. What if she also has α-thalassaemia trait as well? Unless we do genetic testing, we cannot exclude her having double thalassaemia. Does it matter since she only has thalassaemia minor for both types of thalassaemia? Well, that depends on her partner’s thalassaemia status.
It’s relatively easy to exclude β-thalassaemia in her partner. However, without DNA testing, we are not able to exclude α-thalassaemia. Let’s say, her partner does have α-thalassaemia trait but has normal blood cell indices (which is not uncommon).
Scenario 1
Mother has β-thalassaemia trait (minor) and does NOT have α-thalassaemia but her partner has α-thalassaemia trait. Couples in whom one partner is heterozygous for α-thalassaemia and the other is heterozygous for β- thalassaemia are often assumed not to be at risk of having offspring with homozygous states of the disease.
Scenario 2
Mother has both β-thalassaemia trait and α-thalassaemia. Partner also has α-thalassaemia trait. Now, there is a 25% chance of a homozygous α-thalassaemia baby which could be a disaster.
Is double thalassaemia common? During a 12-year prenatal screening program in Guangdong, China, a total of 158 couples (3.2%) were diagnosed to be the discordant α- and β-thalassemia carriers. Of the 158 β-thalassemia partners, seven (4.4%) were found to have co-inheritance of α0-thalassemia, and three (1.9%) found to have co-inheritance of α+-thalassemia. Three pregnancies affected with Hb Bart’s hydrops fetalis were terminated in the 158 couples (1).
Thalassaemia is prevalent in the Mediterranean region and Southeast Asia. In Southeast China, α-thalassemia and β-thalassemia constitute the majority of monogenetic disorders, with the average carrier rates being as high as 10.3% and 8.53% for the two diseases, respectively [2, 3].
Screening tests for thalassaemia do not adequately exclude α-thalassaemia. Women who have microcytosis on blood tests and tests positive for beta thalassaemia may harbour an alpha thalassaemia trait as well. If a woman tests positive for beta thalassaemia, should we refer their partners to genetic services to exclude alpha thalassaemia as a pre pregnancy work up?
References:
- Dongzhi Li,Can Liao, Jian Li, Xingmei Xie, Yining Huang, Huizhu Zhong. Detection of a-halassemia in b-thalassemia carriers and prevention of Hb Bart’s hydrops fetalis through prenatal screening. haematologica 2006; 91(5)
- Cai R, Li L, Liang X, et al. Prevalence survey and molecular characterization of alpha and beta thalassemia in Liuzhou city of Guangxi. Zhong Hua Liu Xing Bing Xue Za Zhi. 2002;23(4):281–5.
- Xu XM, Zhou YQ, Luo GX, et al. The prevalence and spectrum of alpha and beta thalassemia in Guangdong Province: implications for the future health burden and population screening. J Clin Pathol. 2004;57:517–9.
- Xiaoting Shen & Yanwen Xu & Yiping Zhong et al. Preimplantation genetic diagnosis for α-and β-double thalassemia. J Assist Reprod Genet (2011) 28:957–964 DOI 10.1007/s10815-011-9598-5