The inherited disorders of haemoglobin

Introduction T he in h e r ite d d iso rd ers of haem oglob in , com prising th e s tru c tu ra l haemoglobin variants and the thalassaem ias, are the commonest monogenic diseases in man. Their study, though they are relatively rare diseases in richer W estern countries, has greatly increased our understanding of the nature and control of genetic disorders in general. Paradoxically, however, these conditions are likely to pose an increasing world health problem in the new m illennium by developing in transition countries, as rates of neonatal and childhood m ortality decline because of better sanitation, nutrition and control of infection. Babies with serious genetic diseases like the haemoglobinopathies will then survive the first few months of life; throughout Africa, the Middle East, the Indian subcontinent and Southeast Asia, thousands of children will be born annually with these conditions, many of whom will live long enough to require treatm ent (W eatherall and Clegg 1996).The effects of these dem ographic changes were graphically illustrated in Cyprus, a country that underwent such a demographic transition shortly after World War II (Fawdry 1944, W eatherall and Clegg 1981). Thalassaem ia was not recognised on the island until 1944, when, as the result of a m alaria eradication programme and related improvements in public health, it became clear that among the children there was a common form of anaem ia with enlargem ent of the spleen that was not due to infection. This turned out to be thalassaem ia. By the early 1970s it was reckoned that, if steps were not taken to reduce the prevalence of the disease, in about 40 years the blood required to trea t these children would am ount to 78,000 units per year, about 40 per cent of the population would need to be donors and the total cost of treatm ent would equal or exceed the island’s health budget.Because of m ajor population m ovements over the second half of the tw entieth century, the inherited disorders of haem oglobin have become disseminated widely in the richer countries of the West (Weatherall and Clegg 1996). In the U nited Kingdom, for example, they now constitute the second com m onest genetic diseases and affect a wide range of the im m igran t population. In this chapter I shall outline the major clinical problems posed by these diseases and how their control is being envisaged, and to what extent

these m easures have been successful to date. In the context of this volume on ethnicity and health, thalassaem ias represent largely genetic variations in disease between subgroups within a m ulticultural W estern population. This chap te r also highlights how m onogenic diseases in m an, such as thalassaem ias, are quite heterogenous in their clinical presentation and m anifestations. Normal human haemoglobin synthesis H um an adult haemoglobin is a m ixture of proteins consisting of a major component, haemoglobin A, and a minor component, haemoglobin A2, the la tte r making up about 2.5 per cent of the total. In in trauterine life, the m ain haemoglobin is haemoglobin F. The structure of these haemoglobins is similar; each consists of two separate pairs of identical globin chains. Except for some of the embryonic haemoglobins, which will not be considered here, all the normal hum an haemoglobins have one pair of a-chains: in haemoglobin A these are combined with (3-chains (a 2p2), in haemoglobin A2 with 5-chains (a282), and in haem oglobin F with y-chains (cx2y2). A fter the decline of embryonic haemoglobin synthesis, haemoglobin F is the main oxygen carrier of fetal life. Its synthesis starts to decline shortly before term , and by the end of the first year after birth it is almost entirely replaced by haemoglobins A and A2.The structure of the OC-and non-a-globin chains is directed by two gene clusters, the a-gene cluster on chromosome 16 and the (3-gene cluster on chromosome 11. These clusters and the genes that they contain have been completely sequenced and much is known about the regulation of individual globin genes, but less is known about the control of the transition from embryonic to fetal and fetal to adult haemoglobin synthesis (Grosveld et al. 1993). The haemoglobinopathies The inherited disorders of haemoglobin fall into two groups. First, there are over 700 structural haemoglobin variants, most of which result from single amino acid substitutions in the (X-or P-globin chains. The only variants, which reach polymorphic frequencies, are haemoglobins S, C and E. Second, there are the thalassaem ias, disorders which result from a reduced rate of synthesis of either the a-, p-, or 5-and p-globin chains; hence they are subdivided into the a-, P-and 5p-thalassaem ias. There are over 170 different m utations that underlie P-thalassaemia (Thein 1993). The bulk of them are point m utations, which result in p rem atu re chain term ination , fram eshifts or defects in splicing. A nother set involves the prom oter regions of the P-globin genes.The genetics of the a-thalassaem ias is more complex (Higgs 1993). There are two a-globin genes per haploid genome, w ritten aa/aa. There are two

major classes of a-thalassaem ia, called a+- and a°-thalassaem ia. The a+- thalassaem ias result from either deletions of the a-globin genes, w ritten in the heterozygous and homozygous states as -a/aa or -a/-a, respectively, or from point m utations which inactivate these genes, which are designated aTa/aa or aTa/aTa. The a°-thalassaem ias result from long deletions, which either remove both a-globin genes, or key regulatory regions upstream from the a-globin gene cluster. Clinical features The sickling disorders The sickling disorders consist of the homozygous state for the sickle cell gene, SS, and the compound heterozygous states for the sickle cell and haemoglobin C genes, SC, or p-thalassaem ia, S-p-thalassaemia.The homozygous state for the sickle cell gene, sickle cell anaem ia, is characterised by chronic anaem ia and tissue damage resulting from blockage of small blood vessels. The glutamic acid to valine substitution at position 6 in the p-globin chain results in the form ation of stacks of haem oglobin m olecules, which cause the sickling deform ation of the red cell in the deoxygenated state. The pathophysiology of sickling is extrem ely complex and has been the subject of several extensive reviews (Bunn and Forget 1986, W eatherall et al. 1995). O ne of the problem s w ith this condition is its extraordinary clinical heterogeneity. In the steady state patients are anaemic bu t adap t well because of the righ t shift in th e ir whole-blood oxygen dissociation curves associated with sickle cell haemoglobin. However, they are prone to severe infections because their spleens atrophy as a result of repeated minor infarction and to a variety of acute episodes called ‘sickling crises’. These include widespread bone pain, sequestration of sickle cells into the lungs with respiratoryfailure, strokes, and massive sequestration of sickle cells into the spleen with profound anaemia.There is rem arkable variation in the severity of sickle cell anaem ia among different racial groups. In Africa the disease still kills large numbers of infants early in life, whereas in the Caribbean it seems to run a less severe course. The reasons for this discrepancy are unknown. There is an even milder form of the disease, which occurs in Saudi Arabia and parts of India, which is associated with unusually high levels of fetal haemoglobin production. Fetal haem oglobin protects against sickling and this, together with the high frequency of a-thalassaem ia, which is also known to am eliorate the disease, may be a t least p a rtly responsib le for the m ild phenotypes in these populations. However, this is only a partia l exp lanation for its clinical h e te ro g en e ity and m uch rem ain s to be le a rn t w h e th e r th is re flec ts predom inantly genetic or environm ental factors.