The emerging understanding of sickle cell disease

The first indisputable case of sickle cell disease in the literature was described in a dental student studying in Chicago between 1904 and 1907 (Herrick, 1910). Coming from the north of the island of Grenada in the eastern Caribbean, he was first admitted to the Presbyterian Hospital, Chicago, in late December 1904 and a blood test showed the features characteristic of homozygous sickle cell (SS) disease. It was a happy coincidence that he was under the care of Dr James Herrick (Fig 1) and his intern Dr Ernest Irons because both had an interest in laboratory investigation and Herrick had previously presented a paper on the value of blood examination in reaching a diagnosis (Herrick, 1904–05). The resulting blood test report by Dr Irons described and contained drawings of the abnormal red cells (Fig 2) and the photomicrographs, showing irreversibly sickled cells, leave little doubt that the diagnosis was SS disease. The subsequent history of Dr Walter Clement Noel, that first patient, is described in a fascinating account by Dr Todd Savitt (Savitt Mackey, 1949; Raper, 1949; Lehmann, 1951), West Africa (Edington, 1954) and Northern Rhodesia (Beet, 1947). In Uganda, Lehmann and Raper (1949, 1956) found a positive sickling test in 45% of one community, from which homozygous inheritance would have predicted that nearly 10% of children had SS disease, yet not a single case was found. The discrepancy led to a hypothesis that some factor inherited from non-black ancestors in America might be necessary for expression of the disease (Raper, 1950). The explanation for this apparent discrepancy gradually emerged. Working with the Jaluo tribe in Kenya, Foy et al (1951) found five cases of sickle cell anaemia among very young children and suggested that cases might be dying at an age before those sampled in surveys. A similar hypothesis was advanced by Jelliffe (1952) and was supported by data from the then Belgian Congo (Lambotte-Legrand Lambotte-Legrand, 1951, Lambotte-Legrand, 1952, Vandepitte, 1952). Although most cases were consistent with the concept of homozygous inheritance, exceptions continued to occur. Patients with a non-sickling parent of Mediterranean ancestry were later recognized to have sickle cell-β thalassaemia (Powell et al, 1950; Silvestroni Sturgeon et al, 1952; Neel et al, 1953a), a condition also widespread in African and Indian subjects that presents a variable syndrome depending on the molecular basis of the β thalassaemia mutation and the amount of HbA produced. Phenotypically, there are two major groups in subjects of African origin, sickle cell-β+ thalassaemia manifesting 20–30% HbA and mutations at −29(A→G) or −88(C→T), and sickle cell-β0 thalassaemia with no HbA and mutations at IVS2–849(A→G) or IVS2–1(G→A). In Indian subjects, a more severe β thalassaemia mutation IVS1–5(G→C) results in a sickle cell-β+ thalassaemia condition with 3–5% HbA and a relatively severe clinical course. Other double heterozygote conditions causing sickle cell disease include sickle cell-haemoglobin C (SC) disease (Kaplan et al, 1951; Neel et al, 1953b), sickle cell-haemoglobin O Arab (Ramot et al, 1960), sickle cell-haemoglobin Lepore Boston (Stammatoyannopoulos Allison, 1956a) but never convincingly demonstrated. Raper (1949) was the first to suggest that the sickle cell trait might have a survival advantage against some adverse condition in the tropics and Mackey Archibald Edington Gilles et al, 1967) and it is now generally accepted that the sickle cell trait confers some protection against falciparum malaria during a critical period of early childhood between the loss of passively acquired immunity and the development of active immunity (Allison, 1957; Rucknagel Motulsky, 1964). The mechanism of such an effect is still debated, although possible factors include selective sickling of parasitized red cells (Miller et al, 1956; Luzzatto et al, 1970) resulting in their more effective removal by the reticulo-endothelial system, inhibition of parasite growth by the greater potassium loss and low pH of sickled red cells (Friedman et al, 1979), and greater endothelial adherence of parasitized red cells (Kaul et al, 1994). The occurrence of the sickle cell mutation and the survival advantage conferred by malaria together determine the primary distribution of the sickle cell gene. Equatorial Africa is highly malarial and the sickle cell mutation appears to have arisen independently on at least three and probably four separate occasions in the African continent, and the mutations were subsequently named after the areas where they were first described and designated the Senegal, Benin, Bantu and Cameroon haplotypes of the disease (Kulozik et al, 1986; Chebloune et al, 1988; Lapoumeroulie et al, 1992). The disease seen in North and South America, the Caribbean and the UK is predominantly of African origin and mostly of the Benin haplotype, although the Bantu is proportionately more frequent in Brazil (Zago et al, 1992). It is therefore easy to understand the common misconception held in these areas that the disease is of African origin. However, the sickle cell gene is widespread around the Mediterranean, occurring in Sicily, southern Italy, northern Greece and the south coast of Turkey, although these are all of the Benin haplotype and so, ultimately, of African origin. In the Eastern province of Saudi Arabia and in central India, there is a separate independent occurrence of the HbS gene, the Asian haplotype. The Shiite population of the Eastern Province traditionally marry first cousins, tending to increase the prevalence of SS disease above that expected from the gene frequency (Al-Awamy et al, 1984). Furthermore, extensive surveys performed by the Anthropological Survey of India estimate an average sickle cell trait frequency of 15% across the states of Orissa, Madhya Pradesh and Masharastra which, with the estimated population of 300 million people, implies that there may be more cases of sickle cell disease born in India than in Africa. The Asian haplotype of sickle cell disease is generally associated with very high frequencies of alpha thalassaemia and high levels of fetal haemoglobin, both factors believed to ameliorate the severity of the disease. The promotion of sickling by low oxygen tension and acid conditions was first recognized by Hahn Allison, 1956b; Harris et al, 1956). The morphological and some functional characteristics of irreversibly sickled cells were described (Diggs Shen et al, 1949), but the essential features of the polymerization of reduced HbS molecules had to await the developments of electron microscopy (Murayama, 1966; Dobler Bertles White Perutz et al, 1951). The early observations on the inducement of sickling by hypoxia led to the first diagnostic tests utilizing sealed chambers in which oxygen was removed by white cells (Emmel, 1917), reducing agents such as sodium metabisulphite (Daland Feldman Huisman et al, 1955). Analyses of terminal amino acids also failed to reveal differences, although an excess of valine in HbS was noted but considered an experimental error (Havinga, 1953). The development of more sensitive methods of fingerprinting combining high voltage electrophoresis and chromatography allowed the identification of the essential difference between HbA and HbS. This method enabled the separation of constituent peptides and demonstrated that a peptide in HbS was more positively charged than in HbA (Ingram, 1956). This peptide was found to contain less glutamic acid and more valine, suggesting that valine had replaced glutamic acid (Ingram, 1957). The sequence of this peptide was shown to be Val-His-Leu-Thr-Pro-Val-Glu-Lys in HbS instead of the Val-His-Leu-Thr-Pro-Glu-Glu-Lys in HbA (Hunt Graham, 1924). The bone changes of medullary expansion and cortical thinning were noted in early radiological reports (Vogt LeWald, 1932; Grinnan, 1935). Drawing on a comparison of sickle cell disease and hereditary spherocytosis, Sydenstricker (1924) introduced the term 'haemolytic crisis' that has persisted in the literature to this day, despite the lack of evidence for such an entity in sickle cell disease. The increased requirements of folic acid and the consequence of a deficiency leading to megaloblastic change was not noted until much later (Zuelzer Jonsson et al, 1959; MacIver Seakins et al, 1973) that HbS within the red cell with a low oxygen This patients at their haemoglobin levels of anaemia and fail to from blood to oxygen of bone marrow by of from the blood and a haemoglobin termed the was first recognized by et al case report contained many features characteristic of this a a became and the haemoglobin from to g/dl within 3 and were examination revealed an of red cell which was replaced 9 later by with an of and into the was admitted to with similar on the same The for to predominantly to occur in and to siblings was consistent with an but it was not until a chance observation in et al, that the of the was shown to be et al, marrow after and, oxygen is by the is has never been The and in several early reports (Washburn, Graham, et al, The lack of data on the history of led to from and a to However, data from the report a prevalence of by the age of 25 years, and no differences between patients with and without or within patients with before and after their development et al, of asymptomatic and has been by in only of SS patients with known The of was recognized more areas of were described by (1924) and & may be by in early childhood et al, et al, and by at later and effective to survival et al, These may in the with the of and the development of a that may be effective when at and 6 A occurred in a reported by Sydenstricker et al (1923) and the first major review et al, 1940) described patients and 25 cases from the This review the early age of and the high frequency of features in subsequent & et al, A mechanism was proposed and confirmed by et al and or of major occurred in of seven children et al, clinical features of in SS disease the young age of age 6 the of in children and of in and a to within 3 years of the et al, et al, 1992). of of the primary not and is confined to of by early of of by and of has reduced et al, but the many with changes The first review of bone changes (Diggs et al, was followed by reports of the bone changes associated with et al, cortical & & 1948) and of the & & 1947). of active bone marrow for and of the of the and in children under years syndrome or and a similar the areas of and in children and young the The features of were first by et al and the of in the by & bone marrow is to by despite several reports & Diggs et al, the association was not until & The is the most frequent of in SS disease and for of sickle in the UK and the its high it is remarkable that studies have only and factors et al, et al, clinical features et al, mechanism & associated et al, and et al, Although to be in origin the term the frequency of as a factor et al, greater prevalence in with less sickling disease and homozygous thalassaemia and sickle cell-β0 and and distribution are to on this basis, leading to the hypothesis that this may a syndrome & may be by and of which is the most frequent in The of a high haemoglobin as a factor et al, et al, for but only data are and Although most attention has been to the of it is clear that a to with is determined by many of which and around the occurred in all of the first four case reports despite a of cases presented at the of & and the it was not until that became recognized as a of the disease & occur in other hereditary suggesting common although they are almost with contributions from and