The inherited disorders of haemoglobin are the commonest single-gene disorders in the world. They cause much morbidity and mortality in those individuals who are severely affected, and place a major burden on health services in some places, in particular the Mediterranean region, sub-Saharan Africa, and South-East Asia, when economic conditions improve and infant and childhood death rates fall. Mass migrations of populations from high-incidence areas for the haemoglobin disorders, together with the general ease of international travel, means that these conditions are being seen with...
The inherited disorders of haemoglobin are the commonest single-gene disorders in the world. They cause much morbidity and mortality in those individuals who are severely affected, and place a major burden on health services in some places, in particular the Mediterranean region, sub-Saharan Africa, and South-East Asia, when economic conditions improve and infant and childhood death rates fall. Mass migrations of populations from high-incidence areas for the haemoglobin disorders, together with the general ease of international travel, means that these conditions are being seen with increasing frequency in parts of the world where they have not been recognized previously.
Structure, function, and genetic control of the synthesis of haemoglobin
Structure—human haemoglobins have a tetrameric structure made up of two different pairs of globin chains, each attached to one haem molecule. Adult and fetal haemoglobins have α chains combined with β chains (Hb A, α2β2), δ chains (Hb A2, α2δ2), or γ chains (Hb F, α2γ2); other forms of haemoglobin are found in embryos.
Function—the sigmoid shape of the oxygen dissociation curve ensures that oxygen is rapidly taken up at high oxygen tension in the lungs, and that it is released readily at the lower tensions encountered in the tissues.
Genetic control—there are linked clusters of β-like globin genes on chromosome 11, and of α-like globin genes on chromosome 16; various regulatory elements interact to promote erythroid-specific gene expression and to coordinate changes in globin gene activity during development.
Classification of the disorders of haemoglobin
These can be (1) genetic—including thalassaemia, structural variants, hereditary persistence of fetal haemoglobin; or (2) acquired—including methaemoglobin, carbonmonoxyhaemoglobin, sulphaemoglobin, defective synthesis (e.g. haemoglobin H/leukaemia, other neoplastic disorders).
This heterogeneous group of genetic disorders all result from a reduced rate of production of one or more of the globin chains of haemoglobin: they are divided into the α, β, δβ, or εγδβ thalassaemias, according to which globin chain is produced in reduced amounts. They are inherited in a simple mendelian fashion. Heterozygotes are usually symptomless; more severely affected patients are either homozygotes for α or β thalassaemia, compound heterozygotes for different molecular forms of α or β thalassaemia, or compound heterozygotes for thalassaemia and a structural haemoglobin variant. They are clinically classified into major, intermediate, and minor forms according to severity.
These are most important types of thalassaemia because they are very common and produce severe anaemia in their homozygous and compound heterozygous states. They occur widely in a broad belt ranging from the Mediterranean and parts of North and West Africa, through the Middle East and Indian subcontinent, to South-East Asia.
Molecular pathology and pathophysiology—can be caused by more than 200 different mutations in the β globin gene, most of which are single base changes or small deletions or insertions of one or two bases, resulting in absent or reduced β chain production. In the absence of their partner chains the excess α chains are unstable and precipitate in the red cell precursors, leading to both ineffective erythropoiesis and shortened red-cell survival. The anaemia acts as a stimulus to increased erythropoietin production, causing massive expansion of the bone marrow which may lead to serious deformities of the skull and long bones, and splenic uptake of abnormal red cells leads to splenomegaly.
Clinical features—(1) Severe homozygous or compound heterozygous forms—usually present within the first year of life with failure to thrive, poor feeding, intermittent bouts of fever, or failure to improve after an intercurrent infection. Progress then depends on management: (a) well transfused—early growth and development is normal, but without adequate iron chelation complications due to iron overloading arise, most notably progressive cardiac damage that is eventually fatal; (b) inadequately transfused—growth and development are markedly retarded; there is progressive splenomegaly, with hypersplenism sometimes causing a worsening of anaemia; other complications include bone marrow expansion that leads to deformities of the skull with marked bossing and overgrowth of the zygomata. (2) Carriers for β thalassaemia—are usually well except from symptoms of mild anaemia.
Investigation—(1) Severe homozygous or compound heterozygous forms—haemoglobin values on presentation range from 2 to 8 g/dl, with the red cells showing marked hypochromia and variation in shape and size. In βº thalassaemia there is no haemoglobin A and the haemoglobin consists of F and A2 only; in β+ thalassaemia the level of haemoglobin F ranges from 30 to 90% of the total haemoglobin. (2) Carriers for β thalassaemia—haemoglobin values are typically 9 to 11 g/dl, with the red cells showing hypochromia and microcytosis. Haemoglobin A2 is elevated to 4 to 6%.
β thalassaemia in association with other haemoglobin variants—in many populations it is common for an individual to inherit a β thalassaemia gene from one parent and a gene for a structural haemoglobin variant from the other, with clinically important conditions being sickle cell β thalassaemia, haemoglobin C β thalassaemia, and haemoglobin E β thalassaemia.
These are commoner than the β thalassaemias, but pose less of a public health problem because their severe forms only occur in a few regions. They occur widely through the Mediterranean region, parts of West Africa, the Middle East, parts of the Indian subcontinent, and throughout South-East Asia in a line stretching from southern China through Thailand, the Malay peninsula, and Indonesia to the Pacific island populations.
Molecular pathology and pathophysiology—normal individuals receive two linked α globin genes from each of their parents (genotype αα/αα), with loss of both copies on an affected chromosome (genotype – –) causing more severe disease than loss or mutation of one (genotype –α or αTα). Deficiency of α chains leads to the production of excess γ chains in the fetus, which form γ4 tetramers (haemoglobin Bart’s), and excess of β chains in the adult, which form β4 tetramers (haemoglobin H). These both have very high oxygen affinity and are physiologically useless, and haemoglobin H is unstable and precipitates in red cells as they age leading to a shortened red-cell survival.
Clinical features and investigation—(1) haemoglobin Bart’s hydrops syndrome (– –/– –)—infants are usually stillborn at 28 to 40 weeks; (2) haemoglobin H disease (usually –α/– – or αTα/– –)—there is variable anaemia and splenomegaly; haemoglobin values range from 7 to 10 g/dl, with the blood film showing typical thalassaemic changes; patients usually survive into adult life.
α Thalassaemia and mental retardation—also characterized by dysmorphic features, these conditions are usually caused by mutations that involve the α globin gene cluster on chromosome 16 (ATR-16) or mutations on the X chromosome (ATR-X).
Thalassaemias—prevention and treatment
Prevention—since there is no definitive treatment, most countries in which the disease is common are putting a major effort into programmes for its prevention, most often by offering prenatal diagnosis to couples at risk for having children with severe forms of β thalassaemia.
Treatment—symptomatic management of severe β thalassaemia requires regular blood transfusion, the judicious use of splenectomy if hypersplenism develops, and the administration of chelating agents to reduce iron overload.
Structural haemoglobin variants—general considerations
There are more than 400 structural haemoglobin variants, most of which result from single amino acid substitutions and cause clinical disorders only if they alter the stability or functional properties of the haemoglobin molecule. Manifestations include (1) haemolysis and tissue damage—haemoglobin S (sickling disorders); (2) drug-induced and chronic haemolysis—various haemoglobins; (3) congenital polycythaemia—high affinity variants; (4) congenital cyanosis—haemoglobin(s) M, low affinity variants; (5) hypochromic thalassaemic phenotypes.
These occur very frequently in African populations and, sporadically, throughout the Mediterranean region, the Middle East, and in India. The high frequency of the sickle cell gene occurs because carriers are more resistant than normal individuals to Plasmodium falciparum malaria.
Molecular pathology and pathophysiology—haemoglobin S differs from haemoglobin A by the substitution of valine for glutamic acid at position 6 in the β chain. Sickling disorders are caused by the heterozygous state for haemoglobin S (sickle cell trait, AS), the homozygous state (sickle cell disease, SS), and the compound heterozygous state for haemoglobin S together with haemoglobins C, D, E, or other structural variants. The sickling phenomenon appears to be due to the unusual solubility characteristics of haemoglobin S, which undergoes liquid crystal (tactoid) formation as it becomes deoxygenated.
Clinical features and investigation—(1) Sickle cell trait—causes no clinical disability except in conditions of extreme hypoxia. Diagnosed by the finding of a positive sickling test together with haemoglobins A and S on electrophoresis. (2) Sickle cell disease—typical presentations in infancy include symptoms related to anaemia or infection, and infarction of bones in the hands or feet causes dactylitis (‘hand and foot’ syndrome). The haemoglobin level is typically 6 to 8 g/dl with a reticulocyte count of 10 to 20%, and examination of the peripheral blood film shows anisochromia and poikilocytosis with a variable number of sickled erythrocytes, with diagnosis confirmed by a positive sickling test and typical appearances on haemoglobin electrophoresis. Acute exacerbations (‘crises’) can be (1) thrombotic—generalized or localized bone pain, abdominal, pulmonary, neurological; (2) aplastic; (3) haemolytic; (4) sequestration—spleen, liver, lung; (5) various combinations of (1) to (4). Chronic complications include (1) aseptic necrosis of bone; (2) chronic leg ulceration; (3) chronic kidney disease; (4) recurrent priapism.
Treatment—babies of ‘at risk’ pregnancies should be screened at birth to establish the diagnosis as early as possible because early deaths due to infection and the frequency of crises may be reduced by oral penicillin. Patients should be given folate supplements. Painful crises require adequate rehydration, oxygen, antibiotics where appropriate, and—in particular—analgesia. Patients with sequestration crises can be extremely ill, requiring intensive support including oxygen and exchange or top-up transfusion. Hydroxyurea can reduce infarction crises, possibly by favouring release of erythrocytes with a greater content of fetal haemoglobin which inhibits the sickling tendency.
Chapter. 20344 words. Illustrated.
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