Thalassemia is an inherited blood disorder that results in the production of abnormal red blood cells, resulting in the inefficient transport of oxygen around the body. In severe cases, babies carrying the genetic changes that cause the disease rarely survive to birth and the health of the mother is also affected. However, recent improvements in medical care mean that now, babies with this rare form of severe anaemia can survive and this presents a need for sharing resources and expertise between doctors throughout the world to ensure these patients are properly cared for throughout life. To coincide with Rare Disease Day, Dr Duantida Songdej (a consultant haematologist in Thailand) and her DPhil co-supervisor Dr Chris Babbs tell us about their work creating a registry of survivors of this rare form of anaemia – a project that Duantida initiated during her DPhil studies with Doug Higgs here at the MRC WIMM.
Red blood cells are responsible for carrying oxygen to body tissues. The major component inside red blood cells that allows them to perform this essential task is the protein haemoglobin.
Normal haemoglobin is composed of two α-globin and two β-globin protein chains. Insufficient production of either α-globin or β-globin because of a genetic defect can lead to the globin present in excess (either α or β) abnormally binding together. This abnormality results in the premature destruction and rupture of red blood cells and is known as thalassemia, an inherited form of anaemia.
Thalassemia occurs more frequently in regions where malaria is endemic, such as South East Asia, China and the Mediterranean. This is thought to be because people carrying thalassemia genes have some resistance to malaria. It is believed that thalassemia mutations became common approximately 10,000 years ago after humans learnt to farm and coincidentally provided mosquitoes with breeding grounds.
Patients carrying the abnormal globin genes that result in decreased α-globin chain production have α-thalassemia and those carrying abnormal β-globin genes have β-thalassemia. The most severe form of α-thalassemia results from complete absence of all the α-globin genes and the red blood cells of affected fetuses contain only aggregations of β-like globin chains, termed haemoglobin Bart’s (so called because this abnormal haemoglobin type was first described at St. Bartholomew’s hospital in London).
Haemoglobin Bart’s binds oxygen so tightly that it cannot release it to body tissues, resulting in severely decreased tissue oxygenation. Moreover, Haemoglobin Bart’s aggregates lead to massive red blood cell destruction and severe anemia. These combined effects are devastating for the fetus and the knock-on consequences include heart failure, fluid accumulation around the lungs, heart and abdomen and skin swelling.
The vast majority of affected fetuses die during the late stages of pregnancy or immediately after birth, therefore this severe form of α-thalassemia has long been regarded as a universally fatal disorder. However, over the last thirty years improvements in antenatal and neonatal care has resulted in a small number of individuals who have survived with this disease. Survivors are often reported to have congenital abnormalities, growth retardation and developmental delay and the overwhelming majority of patients are dependent on blood transfusions for their entire lives. Mothers carrying affected fetuses also have increased risk of serious complications during pregnancy.
Because survival with severe α-thalassemia is still a recent phenomenon there is very little information on how best to counsel and manage mothers carrying affected fetuses. To address this issue and provide a resource for doctors and patients we have recently initiated an international registry of long-term survivors with severe α-thalassemia. The predominant aim of the registry is to provide information on the long-term outcomes of patients who survive, such that counseling to the rare mothers who may wish to continue their pregnancy may be offered.
We find that the complex clinical outcomes of these patients, even when treated in expert centers, underscores the need for an improved program for prevention worldwide. However, the work also highlights an important area of research, which investigates ways that would allow reactivation of dormant α-globin genes and thereby offer a potential cure for this devastating disease.
This post was edited by Chris Babbs and Philippa Pettingill.