The body has quite a complicated way of making globin. ordinary hemoglobin is made from two alfa chains and two beta chains. Alfa chains are coded on chromosome 16. There are two alfa genes which are clustered with a gene for the zeta chain, an alfa chain equivalent produced in early embryonic life when blood is made in yolk sac. Both alfa chain genes are active in fetal and adult life and necessary to produce enough alfa chains.
Beta chains are coded on chromosome 11 along with a cluster of beta-like genes, including epsilon, gamma and delta chain genes. Epsilon genes are used by the embryo during yolk sac hemopoiesis. Embryonic hemopoiesis produces Hb Gower 1 and Gower 2 as well as Hb Portland. (Gower 1 is zeta 2, epsilon 2; Gower 2 is alfa 2, epsilon 2; Portland is zeta 2, gamma 2) The fetus uses the gamma chain gene to make HbF (alfa 2, gamma 2) and the adult uses mainly the beta chain gene, with small amounts of delta and gamma chains (HbA is alfa 2, beta 2; HbA2 is alfa 2, delta 2).
This is all very wonderfully designed with the appropriate hemoglobin being made at the different stages of development. For example, baby red blood cells need to snatch oxygen molecules from the mother's blood while the baby is in the womb. It so happens that HbF has a higher affinity for oxygen than HbA, and this is how the baby does it.
For the most part, individuals carrying thalassemia genes suffer no ill effects, but they are protected against malaria. You can usually tell that the individual has it because the red cells are smaller than usual. When we were dealing with iron deficiency we said that a red cell consists mainly of hemoglobin, so the amount of hemoglobin controls the size of the red cell. To little iron means not enough heme and therefore small red cells. In the thalassemias, not enough globin is made and therefore not enough hemoglobin and therefore small red cells result. These individuals are said to have thalassemia trait, meaning that they have inherited a thalassemia gene from only one parent. They are not anemic but they have microcytosis (small red cells).
If you inherit thalassemia genes from both parents then you are probably in real trouble with what is usually a severe illness, but it does depend on whether you inherit the same abnormal gene or a different one. Sometimes inheriting different thalassemia genes can actually make the condition less severe, but the various combinations give a wide variety of conditions from no illness to a fatal one.
There are four clinical states of thalassemia. The most severe is death in the womb. This is called hydrops fetalis - the fetus gets severe heart failure because it isn't making any blood and dies. The second most severe is thalassemia major, in which anemia develops at the age of about 6 months. The body strains to make blood, but hardly succeeds. In the normal adult blood making takes place in the flat bones of the body only - the skull, ribs, sternum, pelvis and spine, but in children it is also made in the bones of the arms and legs. In the fetus it is in addition made in the liver and spleen. In thalassemia major, blood is made in all these places and even in lymph nodes. So, big livers and spleens are the order of the day and the bone marrow so expands that the walls of the bones become very thin. The shape of the face is distorted with prominence of the frontal and maxillary bones, and fractures of the other bones are common.
X-ray of the skull demonstrates the expansion of the medulla and thinning of the cortex and the picture is often referred to a the hair on end appearance. (Picture from medispot123.blogspot.com).
These children have to be treated by blood transfusion. In fact they are heavily transfused to try and suppress the growth of the bone marrow. All this transfusion overloads them with iron which has to be removed or else it gets stuck in various organs, causing staining of the skin, arthritis, and damage to the liver and heart, as well as failure of a host of endocrine organs including the pancreas causing diabetes, the thyroid causing myxedema, the parathyroids causing a low calcium, the testes causing failure of puberty and the pituitary causing small stature.
Removal of iron used to involve nightly subcutaneous infusions of desferrioaxamine which itself was unpleasant and cause cataracts and damage to the retina as well as increasing susceptibility to infections, particularly with salmonella and yersinia. Happily we now have XJade an oral and more efficient chelator.
The least severe form of thalassemia, thalassemia minor, is totally asymptomatic with only a funny blood count to let you know it is there. Between major and minor, there is thalassemia intermedia in which there is anemia and a big spleen, but usually transfusions are not necessary.
Those are the clinical conditions; what are the genetic lesions that cause them?
Hydrops fetalis is caused by a complete absence of alfa chains - they are needed for both HbA and HbF. You have four genes coding for alfa chains, two from each parent. For Hydrops all four have to be missing. If it is recognized early by genetic testing, the baby's life can be saved by intra-uterine transfusion, but the baby will never make its own blood and it will be totally reliant on transfusions unless it could have a stem cell transplant. This sequence of treatments is seldom undertaken and termination of pregnancy is a more likely outcome.
Thalassemia major is usually beta thalassemia major, where a point mutation on both maternal and paternal chromosomes has prevented the production of beta chains. Since you don't need HbA until after birth it does not cause hydrops, but it gradually develops in the first six months of life. Free alfa chains are toxic to the red cell, shortening its survival. Production of other chromosome 16 globin chains, gamma and delta, means that there are increased amounts of HbF and HbA2, which help to soak up the excess alfa chains. If there is a degree of alfa thalassemia, this can lessen the severity of the condition. Rare individuals posess three copies of the alfa chain on chromosome 11 and this makes the condition worse. In some forms of beta thalassemia, small amounts of beta chains are produced which help to ease the condition slightly. Although beta thalassemia major is mainly a sign of two defective beta chains, sometimes the patients are double heterozygotes for beta thalassemia and another hemoglobinopathy.
Thalassemia trait is the non-significant form of thalassemia, only picked up on the blood count.
The blood picture is of a microcytosis with prominent target cells. With beta-thalassemia trait the diagnosis can be confrimed by Hb electrophoresis, though not with alfa thalassemia trait.
Here is is necesary to look for HbH inclusions by incubating the blood with brilliant cresyl blue. If only one alfa gene is missing then the incidence of the 'golf ball' inclusions may be as small as 1 cell in 50,000.though with two genes missing they are a bit commoner.
Thalassemia intermedia may have many causes. The patients are moderately anemic and have large spleens but they don't require regular transfusions. It may be caused by homozygous beta thalassemia - if the gene inherited from both parents allows for the production of some beta chains, or if alfa thalassemia is also inherited, or if a condition called hereditary persistence of fetal hemoglobin (which allows the gamma chains to soak up the excess alfa chains) coexists. Or it might be caused by the asociation of beta thalassemia trait and three (rather than 2) alfa chains on each chromosome 11. Or it could be HbH disease, where three of the four alfa chains have gone missing. Or it could be delta beta thalassemia (where no HbA2 is made). Or it could be Hb Lepore. This is a strange molecule made from the fusion of parts of the beta genes and the delta genes. Homozygotes show intermedia and heterozygotes the trait.
Most forms of alfa thalassemia are caused by deletion of one or more alfa chain gene. Hb Constant Spring is an alfa chain varient in which a mutation affects the termination code so that an elongated chain is produced. this fails to function as a proper alfa chain and effectively produces one of the forms of alfa thalassemia, though these non-deletional forms of alfa thalassemia (and there others with strange names like Hb Quong Sze) tend to be more severe than the deletional forms.
Hemoglobin E is now the commonest form of thalassemia in North America. Newer migrants from South-East Asia have carried the gene. HbE is caused by a substitution of glutamic acid by lysine at codon 26 of the beta chain. This mutation activates a cryptic mRNA splice site which results in reduced synthesis of the mutant beta chain, leading to a thalassemic phenotype. It also interferes with the interface with the alfa chain, leading to increased susceptibility to oxidative stress. Although individuals with homozygous HbE may be similar to Thlassemia trait patients, the condition is variable. Double heterozygotes with HbE and beta thalassemia tend to have thalasemia intermedia with hemolytic crises, though some have a thalassemia major picture. Some patients have benefited from hydroxycarbamide treatment which raises HbF levels.
The thalassemic syndromes are very common throughout the Mediterranean world and in South East Asia. With the migration consequent on war we are seeing and understanding more about these strange conditions.
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