Four clinical conditions of increased severity have been described (Table 1). The silent carrier state results from the presence of a single alpha-globin gene defect (—alpha/ alpha alpha) and is characterized in the newborn by a very mild increased percentage (1-2%) of Hb Bart's, a tetramer of globin chains (gamma4), whereas in the adult may be completely silent or associated with a moderate micro-cytosis and hypochromia with normal HbA2.
Subjects with two residual functional alpha genes, either in cis (--/alpha alpha) or in trans (—alpha/
—alpha) clearly show the alpha-thalassemia carrier state, characterized in the newborn by a moderate increase (56%) of Hb Bart's, and in the adult by thalassemia-like red blood cell indices with normal HbA2 and HbF.
HbH disease is a clinical condition resulting from the presence of a single functional alpha globin gene (--/
- alpha) or (--/alphanondeletion alpha). As a consequence there is a relative excess of beta globin chains, which form a beta4 tetramer (HbH). HbH is unstable and precipitates inside the red cells and to some extent in erythroid precursors resulting in premature erythrocyte destruction. The syndrome of HbH disease shows a wide variability in clinical and hematological severity. The most significant features are microcytic and hypochromic hemolytic anemia, hepatosplenomegaly, and jaundice. Subjects with HbH disease may have acute episodes of hemolysis, requiring occasional blood transfusions, in response to oxidant drugs, fever, and infections.
The severity of HbH disease correlates with the degree of alpha chain deficiency. Therefore the more severe phenotypes are associated with interactions involving nondeletion alpha-thalassemia defects of the dominant alpha2 gene including --/alpha Constant Spring alpha,
--/alphaNco1 alpha , --/alphaHphI alpha. In general, patients with HbH disease can survive without any treatment. However, folic acid supplementation is recommended by some clinicians. Oxidant drugs should be avoided because of the risk of hemolytic crisis. In the presence of hypersplenism splenectomy may be performed, but the potential complications of severe life-threatening venous thrombosis should be considered. Two peculiar types of HbH disease have been reported. One is acquired, associated with myelodisplasia, and characterized by the presence of classical HbH inclusion bodies in red blood cells, often detectable levels of HbH and a severe microcytic and hypochromic anemia. The structural analysis of the alpha globin genes and of their flanking regions are normal, and a downregulation of the alpha genes by mutation in trans-acting genes has been proposed. The other is the alpha-thalassemia associated with mental retardation syndromes, which includes two different forms. The first is characterized by a relatively mild mental retardation and variable facial and skeletal abnormalities. This form, known as ATR 16 syndrome, is due to extended deletions (1 to 2 Mb) of the short arm of chromosome 16. A second group of patients has a complex phenotype with quite uniform clinical features (hyper-telorism, flat nasal bridge, triangular upturned nose, wide
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