A number sign (#) is used with this entry because sickle cell anemia is the result of mutant beta globin (HBB; 141900) in which the mutation causes sickling of hemoglobin rather than reduced amount of beta globin which causes beta-thalassemia.
The most common cause of sickle cell anemia is Hb S (141900.0243), with SS disease being most prevalent in Africans.
In many children with sickle cell anemia, functional asplenia develops during the first year of life and septicemia is the leading cause of death in childhood. The risk of septicemia in sickle cell anemia is greatest during the first 3 years of life and is reduced markedly by prophylactic penicillin therapy. Less is known about splenic dysfunction and the risk of overwhelming sepsis in children with sickle cell-hemoglobin C disease (see Hb C; 141900.0038), although functional asplenia has been documented by radionuclide liver-spleen scans in some adult patients (Ballas et al., 1982) and an elevated erythrocyte pit count, a finding that indicates functional asplenia in children with sickle cell anemia, also has been found in some children with SC disease (Pearson et al., 1985). Lane et al. (1994) reported 7 fatal cases of pneumococcal septicemia in children with SC disease. The earliest death occurred in a 1-year-old child who had cyanotic congenital heart; the other children were aged 3.5 to 15 years. Only 1 child had received pneumococcal vaccine or prophylactic penicillin therapy. All 7 children had an acute febrile illness and rapid deterioration despite parenterally administered antibiotic therapy and intensive medical support. Erythrocyte pit counts in 2 patients were 40.3 and 41.7%, respectively (normal, less than 3.6%). Autopsy findings in 5 cases included splenic congestion without infarction in 5, splenomegaly in 4, and bilateral adrenal hemorrhage in 3. Lane et al. (1994) concluded that pneumococcal vaccine should be administered in all children with SC disease. The routine use of prophylactic penicillin therapy in infants and children with SC disease remained controversial.
Morris et al. (1991) reported hematologic findings in 181 patients, aged 40 to 73 years, with SS disease. The studies showed a downward age-related trend in hemoglobin and platelets and falling reticulocyte count consistent with progressive bone marrow failure which could not be explained by renal impairment. Kodish et al. (1991) concluded that despite current rates of mortality and morbidity with bone marrow transplantation, a substantial minority of parents of children with sickle cell disease would consent to bone marrow transplantation for their children.
Adams (1995) reviewed the literature on sickle cell disease and stroke. Previous studies had shown clinically evident cerebral vascular disease in 7 to 8% of cohorts followed during the first 2 weeks of life. However, MRI series demonstrated 11 to 24% of cerebral vascular accidents in patients with sickle cell disease, indicating a large proportion of silent infarctions.
The defect in urine concentrating ability in persons with sickle cell trait is thought to result from intracellular polymerization of Hb S in erythrocytes, leading to microvascular occlusion, in the vasa recta of the renal medulla. Reasoning that the severity of the concentration defect might be related to the percentage of sickle hemoglobin present in erythrocytes, Gupta et al. (1991) studied urine concentrating ability in 3 classes of A/S individuals, those with a normal alpha-globin genotype and those who were either heterozygous or homozygous for the gene-deletion type of alpha-thalassemia. They found a correlation between urine concentrating ability and the percentage of sickle hemoglobin, which was highest in the individuals with normal alpha-globin genotype and lowest in those homozygous for the deletion.
Steinberg (1989) described a 73-year-old black man in Mississippi who had hematologically and genotypically typical sickle cell anemia with, however, very mild clinical manifestations. He had had cholecystectomy for asymptomatic cholelithiasis at the age of about 47. He had had partial priapism. In a large study involving 2,590 patients over 5 years of age at entry and followed for an average of 5.6 years, Milner et al. (1991) found an overall prevalence of osteonecrosis of the femoral head of about 10%. Patients with the hemoglobin SS genotype and alpha-thalassemia and those with frequent painful crises were at highest risk. Osteonecrosis was found in patients as young as 5 years old.
Steinberg et al. (1995) presented 5 cases of sickle cell anemia in individuals in their 70s. They concluded that 'We do not understand why some patients with sickle cell anemia survive their peers by decades just as we have little insight into why occasional normal individuals live far beyond the average number of years.' Sickle cell patients that express gamma-globin at 10 to 20% of the level of sickle globin in most of their red blood cells have greatly improved clinical prognoses (Lan et al., 1998).
Langdown et al. (1989) described a doubly substituted sickling hemoglobin, called Hb S (Oman) (141900.0245). The higher expressors of Hb S (Oman) had a sickle cell anemia clinical syndrome of moderate intensity, whereas the lower expressors had no clinical syndrome and were comparable to the solitary case first described in Oman.
Popp et al. (1997) stated that the sickle cell anemia syndrome produced by Hb S Antilles (141900.0244) is a more severe phenotype than that produced by Hb S. Humans heterozygous for Hb S have RBCs that contain approximately 40% Hb S, but do not exhibit clinical symptoms of sickle cell disease. In comparison, humans heterozygous for Hb S Antilles have RBCs that contain approximately 40% Hb S Antilles, but these individuals exhibit clinical symptoms of sickle cell disease that are similar in severity to those in persons who are homozygous for Hb S. This is because Hb S Antilles is less soluble and has a right shift in its oxygen association-dissociation curve, properties that favor deoxygenation and polymerization of Hb S Antilles.
Rey et al. (1991) described sickle cell/hemoglobin E (SE) disease (141900.0071) in 3 black American children of Haitian origin. They pointed out that the disorder is probably more benign than SC disease, SC (Arab) disease (141900.0202), and SC (Harlem) disease (141900.0039), all of which have increased risk of the complications of sickling including pneumococcal sepsis.
Walker et al. (2000) studied the prevalence, incidence, risk factors, clinical associations, and morbidity of gallstones in 311 patients with homozygous sickle cell disease and 167 patients with sickle cell-hemoglobin C disease in a cohort studied from birth. Gallstones developed in 96 patients with SS disease and 18 patients with SC disease; specific symptoms necessitating cholecystectomy occurred in only 7 patients with homozygous SS disease.
Adler et al. (2001) described a patient with mild Hb SC disease who, after administration of granulocyte colony-stimulating factor (GCSF; 138970) for collection of peripheral stem cells, developed sickle cell crisis and died within 36 hours. The case strongly suggested a role for granulocytes in acute sickle cell complications and a need for caution in the use of GCSF in this disorder. The patient was a 47-year-old African American woman who had learned she had Hb SC disease only 6 weeks earlier. She had no history of sickle cell crisis. Hb SC disease was diagnosed after a hemoglobinopathy evaluation at the time of HLA typing, done in preparation for her to become a stem cell donor for her sister, who had chronic myeloid leukemia and mild Hb SC disease. The patient was the only sib and had a 6 of 6 antigen match.
Thomas et al. (2000) presented growth curves for children aged 0-18 years with homozygous sickle cell disease. These were derived from 315 participants in a longitudinal cohort study in Kingston, Jamaica.
Ashley-Koch et al. (2001) performed population-based surveillance of children aged 3 to 10 years from metropolitan Atlanta to determine if stroke-related neurologic damage in children with sickle cell disease is associated with developmental disabilities. Children with sickle cell disease had an increased risk for developmental disabilities of 3.2, with a P value of less than 0.0001, particularly mental retardation (RR = 2.7, P = 0.0005) and cerebral palsy (RR = 10.8, P less than 0.0001). This risk was confined to developmental disabilities associated with stroke (RR = 130, P less than 0.0001; for developmental disabilities without stroke the relative risk was only 1.3 with a P value of 0.23).
Friedman and Trager (1981) reviewed the mechanism of resistance of SA cells to falciparum malaria. The cell infected by the falciparum but not by the other malarial parasites develops knobs in its surface which leads to its sticking to the endothelium of small blood vessels such as those in the brain. In such sequestered sites sickling takes place because of the low oxygen concentration. Perforation of the membranes of the parasite as a result of physical injury and perforation of the red cell membrane occur with loss of potassium. In an in vitro test system, death of the parasites can be prevented by high potassium in the medium. The infected red cell is more acidic than the uninfected cell so that the rate of sickling is increased by this factor also.
Studying transgenic mice expressing the human A-gamma and G-gamma globin chains and challenged with rodent malaria, Shear et al. (1998) found that the mice cleared the infection and survived even if splenectomy had been performed. Light microscopy showed that intraerythrocytic parasites developed slowly in Hb F erythrocytes, and electron microscopy showed that hemozoin formation was defective in transgenic mice. Digestion studies of Hb F by recombinant plasmepsin II demonstrated that Hb F is digested only half as well as hemoglobin A (HBA). Shear et al. (1998) concluded that Hb F provides protection from Plasmodium falciparum malaria by the retardation of parasite growth. The mechanism involves resistance to digestion by malarial hemoglobinases based on the data presented and with the well-known properties of Hb F as a super stable tetramer. In addition, the resistance of normal neonates for malaria can now be explained a by double mechanism: increased malaria invasion rates, reported in neonatal RBC, will direct parasites to fetal cells, as well as F cells, and less to the approximately 20% of cells that contain Hb A, thus amplifying the antimalarial effects of Hb F.
In Denver, Lane and Githens (1985) observed the splenic syndrome (severe left-upper-quadrant abdominal pain) in 6 nonblack men with sickle cell trait who developed symptoms within 48 hours of arrival in Colorado from lower altitudes. The authors discussed the possibility that nonblacks may be at greater risk of trouble because of lack of other genetic make-up that through evolution has come to ameliorate the effects of the sickle gene in Africans.
Kark et al. (1987) studied the frequency of sudden unexplained death among enlisted recruits during basic training in the U.S. Armed Forces from 1977 to 1981. They found that death rates per 100,000 were 32.2 for sudden unexplained deaths, 2.7 for sudden explained deaths, and zero for nonsudden deaths among black recruits with hemoglobin AS, as compared with 1.2, 1.2, and 0.7 among black recruits without hemoglobin S and 0.7, 0.5 and 1.1 among nonblack recruits without hemoglobin S. Among black recruits the relative risk of sudden unexplained death (hemoglobin AS vs nonhemoglobin S) was 27.6, whereas among all recruits this risk was 39.8.
The acute chest syndrome is a leading cause of death among patients with sickle cell disease. In a 30-center study, Vichinsky et al. (2000) analyzed 671 episodes of the acute chest syndrome in 538 patients with sickle cell disease to determine the cause, outcome, and response to therapy. They found that among patients with sickle cell disease, the acute chest syndrome is commonly precipitated by fat embolism and infection, especially community-acquired pneumonia. Among older patients and those with neurologic symptoms, the syndrome often progressed to respiratory failure. Treatment with transfusions and bronchodilators improved oxygenation, and with aggressive treatment most patients who had respiratory failure recovered.
Platt (2000) commented on the acute chest syndrome in sickle cell disease. A good working definition of the acute chest syndrome is the presence of a new pulmonary infiltrate, not atelectasis, involving at least one complete lung segment, with chest pain, a temperature of more than 38.5 degrees C, tachypnea, wheezing, or cough in a patient with sickle cell disease. As reported by Charache et al. (1995), there is a 50% reduction in both painful crises and episodes of the acute chest syndrome with long-term treatment with hydroxyurea which results in increased production of fetal hemoglobin and decreased polymerization. The positive effect on the acute chest syndrome probably results from the fact that there are fewer episodes of bone marrow ischemia and embolization. Another explanation may be that the small reduction in white cell count associated with hydroxyurea therapy enhances the effect of increased fetal hemoglobin by dampening the inflammatory response that promotes polymerization.
As indicated by Hebbel (1997), a factor contributing to the vasoocclusive process in sickle cell disease is abnormal adhesion of sickle cells (even oxygenated ones) to the vascular endothelium. Kaul et al. (2000) explored experimentally in animals the use of monoclonal antibodies to block adhesion of sickle cells to endothelium. This approach was evaluated by Hebbel (2000).
As a preliminary step to preimplantation diagnosis of sickle cell disease in unfertilized eggs or 8-cell embryos of heterozygous parents, Monk et al. (1993) established quality control by detection of the mutant and normal alleles of the HBB gene using single buccal cells. Efficient PCR amplification of a 680-bp sequence of the HBB gene spanning the site of the Hb S mutation was obtained for 79% of single heterozygous cells. In 71% of cases, both alleles were detected. Monk et al. (1993) predicted that with that level of efficiency, a clinical preimplantation diagnosis at the 8-cell embryo stage could be carried out safely and reliably for a couple at risk of transmitting sickle cell disease to their children.
As a substitute for obtaining fetal cells for genetic diagnosis by the invasive procedures of amniocentesis, chorionic villus sampling, and fetal blood sampling, Cheung et al. (1996) reported a method for detecting point mutations in single gene disorders by enriching fetal cells from maternal blood by magnetic cell sorting followed by isolation of pure fetal cells by microdissection. In 2 pregnancies at risk for sickle cell anemia and beta-thalassemia, they successfully identified the fetal genotypes.
Xu et al. (1999) performed preimplantation genetic diagnosis (PGD) for sickle cell anemia on 7 embryos produced by in vitro fertilization for a couple who were both carriers of the sickle cell gene. PGD indicated that 4 were normal and 2 were carriers; diagnosis was not possible in 1. The embryos were transferred to the uterus on the fourth day after oocyte retrieval. A twin pregnancy was confirmed by ultrasonography, and subsequent amniocentesis showed that both fetuses were unaffected and were not carriers of the sickle cell mutation. The patient delivered healthy twins at 39 weeks' gestation.
In a report on a sickle cell workshop, Luzzatto and Goodfellow (1989) reviewed current treatment of this disease. The lessons learned from sickle cell anemia will be applicable in other genetic diseases.
Stimulating fetal hemoglobin by increasing gamma-globin synthesis in patients with sickle cell disease would be expected, if the production of sickle hemoglobin is decreased concomitantly, to reduce the formation of intracellular S polymer and improve the acute and chronic hemolytic and vasoocclusive complications of the disease. Azacytidine and hydroxyurea have been shown to increase fetal hemoglobin levels in some patients with sickle cell disease (Charache et al., 1983; Dover et al., 1986). Rodgers et al. (1993) found that administration of intravenous recombinant erythropoietin with iron supplementation alternating with hydroxyurea elevated fetal hemoglobin levels more than hydroxyurea alone. The increases reduced intracellular polymerization of hemoglobin S. The program reduced the myelotoxic effects of hydroxyurea and was beneficial in patients who had not been helped by hydroxyurea alone. Not only does fetal hemoglobin inhibit the polymerization of hemoglobin S but it also can function as a substitute for the beta-globin chains that are defective or absent in patients with the beta-thalassemias. Butyrate has also been tried for the stimulation of fetal hemoglobin synthesis (Perrine et al., 1993). The trial with butyrate was based on the observation by Perrine et al. (1985) that infants who have high plasma levels of alpha-amino-n-butyric acid in the presence of maternal diabetes do not undergo the normal developmental gene switch from the production of predominantly gamma-globin to that of beta-globin before birth. Since other developmental processes were not delayed, the use of butyric acid as a safe and fairly specific agent was suggested. Butyrate may act through sequences near the transcriptional start site to stimulate the activity of the promoter of the gamma-globin genes. Perrine et al. (1993) showed that butyrate can significantly and rapidly increase fetal globin production to levels that can ameliorate beta-globin disorders.
On the basis of a double-blind, randomized clinical trial, Charache et al. (1995) reported that hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in adults with 3 or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects did not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia was uncertain. No neoplastic disorders developed during the study, but hydroxyurea does have a potential for inducing malignancy. This is a nice example of the modulation of expression of endogenous genes to abrogate pathophysiologic processes in the treatment of a genetic disorder. Bone marrow or hematopoietic stem cell transplantation are proven methods of treatment which may be considered a reasonable alternative to long-term drug therapy in some patients.
Charache et al. (1996) gave a comprehensive report on the results of a multicenter study of hydroxyurea in sickle cell anemia.
Steinberg (1999) provided a detailed and highly useful exposition on the management of sickle cell disease. Hydroxyurea, properly used and monitored, is an established form of therapy. Early interruption of the vasoocclusive process that underlies the clinical manifestations of sickle cell disease may prevent damage to the central nervous system, lungs, kidneys, and bones. Two important caveats tempered this hope. The long-term effects of hydroxyurea are unknown. Is it mutagenic, carcinogenic, or leukemogenic? Steinberg (1999) stated that leukemia or cancer had not occurred in patients with sickle cell anemia who had been treated with hydroxyurea, but fewer than 300 patients had been treated for 5 years. It is also not known whether its use in children will have an adverse effect on growth and development.
Treatment with hydroxyurea is associated with cutaneous side effects. Chaine et al. (2001) evaluated 17 adult patients with SCD who were undergoing long-term treatment with hydroxyurea. They found that 5 (29%) had disabling leg ulcers. Four of the 5 had a history of leg ulcers prior to initiating hydroxyurea treatment. Chaine et al. (2001) concluded that caution should be observed when giving hydroxyurea to patients with SCD with previous ulcers as well as in older patients with SCD.
Ferster et al. (2001) reported results in the treatment of sickle cell disease in children and young adults with hydroxyurea, based on a Belgian registry. The median follow-up of the 93 patients was 3.5 years. On hydroxyurea, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirmed a significant difference in the number of hospitalizations and days in hospital throughout the treatment when compared to prior to hydroxyurea therapy.
As indicated earlier, the genetic basis of sickle cell disease is an A-to-T transversion in the sixth codon of the HBB gene. The intricacies of globin gene expression make the development of treatments for hemoglobinopathies based on gene therapy difficult. Lan et al. (1998) used an alternative genetic approach to sickle cell therapy based on RNA repair. They used a trans-splicing group I ribozyme to alter mutant beta-globin transcripts in erythrocyte precursors derived from peripheral blood from individuals with sickle cell disease. Sickle beta-globin transcripts were converted into mRNAs encoding the anti-sickling protein gamma-globin. In this splicing reaction, the ribozyme recognized the sickle beta-globin transcript by basepairing to an accessible region of the RNA upstream of the mutant nucleotide via an internal guide sequence (IGS), cleaved the sickle beta-globin RNA, released the cleavage product containing the mutation, and spliced on the revised sequence for the globin transcript. Lan et al. (1998) generated erythrocyte precursors from normal umbilical cord blood and from peripheral blood from patients with sickle cell disease by culturing the blood cells in medium without serum supplemented with erythropoietin, FLT3 (600007), and IL3 (147740). RNA repair may be a particularly appropriate genetic approach with which to treat sickle cell disease because the process should restore the regulated expression of anti-sickling versions of beta-globin and simultaneously reduce the production of sickle beta-globin. The efficiency of beta-globin RNA repair probably does not have to be 100% to benefit patients.
Pawliuk et al. (2001) designed a beta-A globin gene variant that prevents HbS polymerization and introduced it into a lentiviral vector that they optimized for transfer to hematopoietic stem cells and gene expression in the adult red blood cell lineage. Long-term expression (up to 10 months) was achieved without preselection in all transplanted mice with erythroid-specific accumulation of the antisickling protein in up to 52% of total Hb and 99% of circulating red blood cells. In 2 mouse SCD models, Berkeley and SAD, inhibition of red blood cell dehydration and sickling was achieved with correction of hematologic parameters, splenomegaly, and prevention of the characteristic urine concentration defect.
Shesely et al. (1991) corrected the human beta-S-globin gene by homologous recombination in a mouse-human hybrid cell line that is derived from a mouse erythroleukemia cell line and carries a single human chromosome 11 with the beta-S-globin allele. The corrected gene retained the proper regulation of induction of human beta-globin expression. The targeting construct contained 1.2 kb of prokaryotic sequence 5-prime to the normal beta-A-globin sequence for use in selecting and identifying targeted clones.
Fabry et al. (1996) succeeded in creating an improved transgenic mouse model for sickle cell disease. Previous transgenic models had expressed residual levels of mouse globins which complicated the interpretation of experimental results. They reported on a mouse expressing high levels of human sickle beta chains and 100% human alpha-globin. These mice were created by breeding the alpha-globin-knockout mouse and the mouse with deletion of the beta(major)-deletion to homozygosity, the same mice expressing human alpha- and beta(S)-transgenes (see 141900.0243). The animals were considered important for testing strategies for gene therapy and for testing new noninvasive diagnostic procedures such as magnetic resonance imaging techniques.
Ryan et al. (1997) and Paszty et al. (1997) created transgenic knockout mouse models of sickle cell disease. In both cases the model was produced by mating transgenic mice that expressed human sickle hemoglobin with mice having knockout mutations of the mouse alpha- and beta-globin genes. Similar to human patients with sickle cell disease, the mice developed hemolytic anemia and extensive organ pathology. Although chronically anemic, most animals survived 2 to 9 months and were fertile. Thus, this mouse model of sickle cell disease should be useful for trial of drug and genetic therapies.
Chang et al. (1998) created transgenic knockout mice expressing human hemoglobin S by transfer of a 240-kb yeast artificial chromosome carrying the beta-sickle gene. The transgenic lines were produced by coinjection of human alpha-, gamma-, and beta-globin constructs. Thus, all of the transgenes were integrated at a single chromosomal site. Studies in transgenic mice had demonstrated that the normal gene order and spatial organization of the members of the human beta-globin gene family are required for appropriate developmental and stage-restricted expression of the genes. The mice produced by transfer of the YAC had hemolytic anemia, 10% irreversibly sickled cells in their peripheral blood, reticulocytosis, and other phenotypic features of sickle cll anemia.
Popp et al. (1997) bred 2 homozygous viable Hb S Antilles transgene insertions into a strain of mice that produce hemoglobins with a higher affinity for oxygen than normal mouse Hb. The rationale was that the high oxygen affinity hemoglobin, the lower oxygen affinity of Hb S Antilles, and the lower solubility of deoxygenated Hb Antilles than Hb S would favor deoxygenation and polymerization of human Hb S Antilles in the red cells of the high-oxygen-affinity mice. The investigators found that the mice produced a high and balanced expression of human alpha and human beta (S Antilles) globins, that 25 to 35% of their RBCs were misshapen in vivo, and that in vitro deoxygenation of their blood induced 30 to 50% of the RBCs to form classic elongated sickle cells with pointed ends. The mice exhibited reticulocytosis, an elevated white blood cell count, and lung and kidney pathology commonly found in sickle cell patients, which should make these mice useful for experimental studies on possible therapeutic intervention of sickle cell disease.
Using a transgenic mouse model of sickle cell disease, Blouin et al. (2000) assessed in vivo the potential curative threshold of fetal hemoglobin using mating with mice expressing the human fetal A-gamma-globin gene (HBG1; 142200). With increasing levels of Hb F, the transgenic mice showed considerable improvement in all hematologic parameters, morphopathologic features, and life span/survival. Correction was observed by increasing fetal hemoglobin to about 9 to 16% in this mouse model.
Savitt and Goldberg (1989) gave a delightful account of investigations into the story of Walter Clement Noel, the first-to-be-described case of sickle cell anemia (Herrick, 1910). Noel, a first-year dental student at the Chicago College of Dental Surgery, was admitted to the Presbyterian Hospital in late 1904 where Ernest E. Irons, a 27-year-old intern, obtained a history and performed routine physical, blood, and urine examinations. He noticed that Noel's blood smear contained 'many pear-shaped and elongated forms' and alerted his attending physician, James B. Herrick, to the unusual blood findings. Irons drew a rough sketch of these erythrocytes in the hospital record. Herrick and Irons followed Noel over the next 2.5 years through several episodes of severe illness as he continued his dental studies. Thereafter, Noel returned to Grenada to practice dentistry. He died 9 years later at the age of 32. Curiously, Irons, who lived from 1877 to 1959, was not included by Herrick, who lived from 1861 to 1964, in the authorship.
Gary A. Bellus - updated : 4/8/2002Ada Hamosh - updated : 1/9/2002Ada Hamosh - updated : 12/18/2001Victor A. McKusick - updated : 10/12/2001Victor A. McKusick - updated : 8/23/2001Victor A. McKusick - updated : 2/26/2001Ada Hamosh - updated : 9/15/2000Paul Brennan - updated : 5/3/2000Victor A. McKusick - updated : 4/11/2000Victor A. McKusick - updated : 7/7/1999
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