.. LAST PAGE) Inheritance of hemoglobin genes from parents with sickle cell trait and thalassemia trait. As illustrated, the couple has one chance in four that the child will have the genes both for sickle hemoglobin and for thalassemia. The child would have sickle -thalassemia. The severity of this condition is quite variable.

The nature of the thalassemia gene (o or +) greatly influences the clinical course of the disorder. Another disorder that interacts with sickle cell disease is “hemoglobin SC disease”. The abnormal hemoglobin C gene is relatively harmless. Even people with two hemoglobin C genes have a relatively mild clinical condition. When hemoglobin C combines with hemoglobin S, the result is “hemoglobin SC disease”. On average, hemoglobin SC disease is milder than sickle cell disease.

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However, some patients with hemoglobin SC disease have a clinical condition as severe as any with sickle cell disease. The reason for the marked variability in the clinical course of hemoglobin SC disease is unknown. We do know that the tendency of hemoglobin C to produce red cell dehydration is a major reason that the combination of hemoglobins S and C is so problematic. Figure 3. (ABOVE) Inheritance of hemoglobin genes from parents with sickle cell trait and hemoglobin C trait.

As illustrated, the couple has one chance in four that the child will have the genes both for sickle hemoglobin and for hemoglobin C. The child would have hemoglobin SC disease. Most patients with hemoglobin SC disease have a milder condition than occurs with sickle cell disease (two sickle genes). Unfortunately, some patients run a clinical course that is undistinguishable from sickle cell disease. Are There Tests That Can Tell Me Whether I Have Sickle Cell Trait? The answer is yes.

Routine “blood counts” commonly performed in doctors’ offices do not give hints about the presence of sickle cell trait. The blood counts of most people with sickle cell trait are normal. Only a special test, called a “hemoglobin electrophoresis” indicates reliably whether a person has sickle trait. In addition, the hemoglobin electrophoresis will detect hemoglobin C and -thalassemia. How Can I Be Tested for Sickle Cell Trait? Most large hospitals and clinics can perform routine hemoglobin electrophoresis. Smaller laboratories send the test to commercial firms for testing.

If you are concerned about the possibility of having sickle cell trait, you should speak with your doctor. Overview Everyone with sickle cell disease shares the same gene mutation. A thymine replaces an adenine in the DNA encoding the -globin gene. Consequently, the amino acid valine replaces glutamic acid at the sixth position in the -globin protein product. The change produces a phenotypically recessive characteristic.

Most commonly sickle cell disease reflects the inheritance of two mutant alleles, one from each parent. The final product of this mutation, hemoglobin S is a protein whose quaternary structure is a tetramer made up of two normal alpha-polypeptide chains and two aberrant s-polypeptide chains. The primary pathological process leading ultimately to sickle shaped red blood cells involves this molecule. After deoxygenation of hemoglobin S molecules, long helical polymers of HbS form through hydrophobic interactions between the s-6 valine of one tetramer and the -85 phenylalanine and -88 leucine of an adjacent tetramer. Deformed, sickled red cells can occlude the microvascular circulation, producing vascular damage, organ infarcts, painful crises and other such symptoms associated with sickle cell disease.

Although everyone with sickle cell disease shares a specific, invariant genotypic mutation, the clinical variability in the pattern and severity of disease manifestations is astounding. In other genetic disorders such as cystic fibrosis, phenotypic variability between patients can be traced genotypic variability. Such is not the case, however, with sickle cell disease. Physicians and researchers have sought explanations of the variability associated with the clinical expression of this disease. The most likely causes of this inconstancy are disease-modifying factors.

I have reviewed the role of some of these factors, and tried to ascertain the clinical importance of each. Fetal Hemoglobin Augmented post-natal expression of fetal hemoglobin is perhaps the most widely recognized modulator of sickle cell disease severity. Fetal hemoglobin, as its name implies is the primary hemoglobin present in the fetus from mid to late gestation. The protein is composed of two alpha-subunits and two gamma-subunits. The gamma-subunit is a protein product of the -gene cluster.

Duplicate genes duplicate upstream of the -globin gene encodes fetal globin. Fetal hemoglobin binds oxygen more tightly than does adult hemoglobin A. The characteristic allows the developing fetus to extract oxygen from the mother’s blood supply. After birth, this trait is no longer necessary and the production of the gamma-subunit decreases as the production of the -globin subunit increases. The -globin subunit replaces the gamma-globin subunit in the hemoglobin tetramer so that eventually adult hemoglobin replaces fetal hemoglobin as the primary component red cells.

HbF levels stabilize during the first year of life, at less than 1% of the total hemoglobin. In cases of hereditary persistence of fetal hemoglobin, that percentage is much higher. This persistence substantially ameliorates sickle cell disease severity. Mechanism of Protection Two properties of fetal hemoglobin help moderate the severity of sickle cell disease. First, HbF molecules do not participate in the polymerization that occurs between molecules of deoxyHbS. The gamma-chain lacks the valine at the sixth residue to interact hydrophobically with HbS molecules.

HbF has other sequence differences from HbS that impede polymerization of deoxyHbS. Second, higher concentrations of HbF in a cell infer lower concentrations of HbS. Polymer formation depends exponentially on the concentration of deoxyHbS. Each of these effects reduces the number of irreversibly sickle cells (ISC). Hemoglobin F Levels and Amelioration of Sickle Cell Disease The level of HbF needed to benefit people with sickle cell disease is a key question to which different studies supply varying answers. Bailey examined the correlation between early manifestation of sickle cell disease and fetal hemoglobin level in Jamaicans.

They concluded that moderate to high levels of fetal hemoglobin (5.4-9.7% to 39.8%) reduced the risk for early onset of dactylics, painful crises, acute chest syndrome, and acute splenic sequestration. Platt examined predictive factors for life expectancy and risk factors for early death (among Black Americans). In their study, a high level of fetal hemoglobin (*8.6%) augured improved survival. Koshy et al. reported that fetal hemoglobin levels above 10% were associated with fewer chronic leg ulcers in American children with sickle cell disease.

Other studies, however, suggest that protection from the ravages of sickle cell disease occur only with higher levels of HbF. In a comparison of data from Saudi Arabs and information from Jamaicans and Black Americans, Perrine et al. found that serious complications occurred only 6% to 25% as frequently in Saudi Arabs as North American Blacks. In addition mortality under the age of 15 was 10% as great among Saudi Arabs. Further, these patients experienced no leg ulcers, reticulocyte counts were lower and hemoglobin levels were higher on average.

The average a fetal hemoglobin level in the Saudi patients ranged between 22-26.8%. This is more than twice that reported in studies mentioned above. Kar et al. compared patients from Orissa State, India to Jamaican patients with sickle cell. These patients also had a more benign course when compared with Jamaican patients.

The reported protective level of fetal hemoglobin in this study was on average 16.64%, with a range of 4.6% to 31.5%. Interestingly, -globin locus haplotype analysis shows that the Saudi HbS gene and that in India have a common origin (see below). These studies suggest that the level of fetal hemoglobin that protects against the complications of sickle cell disease depend strongly on the population group in question. Among North American blacks, fetal hemoglobin levels in the 10% range ameliorate disease severity. The higher average level of fetal hemoglobin could contribute to the generally less severe disease in Indians and Arabs. Another study that suggests only a small role at best for fetal hemoglobin as a modifier of sickle cell disease severity was reported by El-Hazmi.

The subjects were Saudi Arabs in whom a variety of symptoms associated with sickle cell disease were assessed to form a “severity” index. The author concluded that among his patients, no correlation existed between HbF and the severity index. However, his analysis has a fundamental flaw. El-Hazmi failed to examine the effect of HbF on each of these symptoms individually. Their important information and an association between fetal hemoglobin levels specific disease manifestations could be concealed in his data.

However, the study reinforces the conclusion that fetal hemoglobin levels most likely work in conjunction with other moderating factors to determine clinical severity in-patients with sickle cell disease. Alpha-Thalassemia Concurrent alpha-thalassemia has also been examined as a modifier of sickle cell disease severity. Alpha-thalassemia, like sickle cell disease, is a genetically inherited condition. The loss of one or more of the four genes encoding the alpha globin chain (two each on chromosome 16) produces alpha-thalassemia. A gene deletion most commonly is at fault.

The deletion results from unequal crossover between adjacent alpha-globin genes during the prophase I of meiosis I. Such a crossover leaves one gamete with one alpha-gene and the other gamete with three alpha genes. Upon fertilization the zygote can have 2, 3, 4, or 5 alpha genes depending on the make up of the other parental gamete. In people of African descent, the most common haploid gamete of this type is alpha-thal-2 in which there is one deletion on each of the number 16 chromosomes in the patient. Heterozygotes for this allele, therefore, have three alpha genes (one alpha gene on one of the number 16 chromosomes, two alpha genes on the other). Embury et al.

(1984) examined the effect of concurrent alpha-thalassemia and sickle cell disease. Based on prior studies, they proposed that alpha-thalassemia reduces intraerythrocyte HbS concentration, with a consequent reduction in polymerization of deoxyHbS and hemolysis. They investigated the effect of alpha gene number on properties of sickle erythrocytes important to the hemolytic and rheological consequences of sickle cell disease. Specifically they looked for correlations between the alpha gene number and irreversibly sickled cells, the fraction of red cells with a high hemoglobin concentration (dense cells), and red cells with reduced deformabilty. The investigators found a direct correlation between the number of alpha-globin genes and each of these indices. A primary effect of alpha-thalassemia was reduction in the fraction of red blood cells that attained a high hemoglobin concentration.

These dense cells result from potassium loss due to acquired membrane leaks. The overall deformability of dense RBCs is substantially lower than normal. This property of alpha-thalassemia was confirmed by comparison of red cells in people with or without 2-gene deletion alpha-thalassemia (and no sickle cell genes). The cells in the nonthalassemic individuals were denser than those from people with 2-gene deletion alpha-thalassemia. The difference in median red cell density produced by alpha-thalassemia was much greater in-patients sickle cell disease.

Reduction in overall hemoglobin concentration due to absent alpha genes is not the only mechanism by which alpha-thalassemia reduces the formation of dense and irreversibly sickled cells. In reviewing the available literature, Embry and Steinburg suggested that alpha-thalassemia moderate’s red cell damage by increasing cell membrane redundancy. This protects against sickling-induced stretching of the cell membrane. Potassium leakage and cell dehydration would be minimized. These two papers by Embury et al.

give some insight into the moderation of sickle cell disease severity by alpha thalassemia. Some deficiencies exist, nonetheless. The first paper makes no mention of the patient pool. Unspecified are the number of patients used, their ethnicity, or their state of health when blood samples were taken. This information would help establish the statistical reliability of the data, and its applicability across patient groups.

Despite these limitation, the work provides important insight into the mechanisms by which alpha-thalassemia ameliorates sickle cell disease severity. Ballas et al reached different conclusions regarding alpha thalassemia and sickle cell disease than did Embury et al . They reported that decreased red blood cell deformability was associated with reduced clinical severity of sickle cell disease. Patients with more highly deformabile red cells had more frequent crises. They also found that fewer dense cells and irreversible sickle cells correlated inversely with the severity of painful crises. Like Embury et al., Ballas and colleagues found alpha thalassemia was associated with fewer dense red cells. In addition, Ballas’ group found that alpha thalassemia was associated with less severe hemolysis.

However they reached no clear conclusion concerning alpha gene number and deformability of RBC except to note that the alpha thalassemia was associated with less red cell dehydration. The two studies are not completely at odds. Both state that concurrent alpha-thalassemia reduces hemolytic anemia. They agree that this occurs through reduction in the number of dense cells, a number directly related to the fraction of irreversibly sickled cells. Embury et al. concludes that through this mechanism red blood cell deformability is increased.

The investigators diverge, however, on the relationship to clinical severity of dense cells and rigid cells. Ballas et al. asserts that both the reduction of dense cells and rigid cells contribute to disease severity.


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