Clinical and hematologic features of beta0-thalassemia (frameshift 41/42 mutation) in Thai patients.
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BACKGROUND AND OBJECTIVES: Frameshift 41/42 mutation is the most common mutation of beta0-thalassemia found in Thailand. We studied clinical and hematologic features in 84 patients and relatives with frameshift 41/42 to determine whether it is possible to predict phenotypic severity from genetic factors. DESIGN AND METHODS: The clinical phenotypes and hematologic data of Thai patients with frameshift 41/42 were studied. Alpha-thalassemia, Hb Constant Spring (HbCS) genes and the presence of Xmnl-Ggamma polymorphism were studied in patients who had mild symptoms. RESULTS: Homozygotes for frameshift 41/42 and compound heterozygotes for frameshift 41/42 and beta0-thalassemia produced severe symptoms and have a thalassemia major phenotype. Combination of frameshift 41/42 and beta0-thalassemia or Hb E produced mild to moderate symptoms with thalassemia intermedia phenotype and severe symptoms with thalassemia major phenotype. The co-inheritance of beta-thalassemia or HbCS gene or the presence of Xmnl-Ggamma polymorphism was not associated with mild disease in patients with frameshift 41/42 and HbE. INTERPRETATION AND CONCLUSIONS: The clinical phenotype of homozygotes for frameshift 41/42 and compound heterozygotes for frameshift 41/42 and beta0-thalassemia could be used to predict a severe phenotype with thalassemia major. However, the clinical phenotype of compound heterozygotes of frameshift 41/42 and beta0-thalassemia or Hb E were variable and could not be accurately predicted. Associations between concomitant alpha-thalassemia or HbCS of the presence of Xmnl-Ggamma polymorphism and a mild clinical phenotype are not apparent, indicating the involvement of other ameliorating determinants or genetic modifications. (+info)
The effect of platyspondyly and pubertal growth spurt on the stature of patients with beta-thalassaemia major.
(58/842)
OBJECTIVE: To study the effect of the body proportion and pubertal growth spurt on the stature of children with beta-thalassaemia major. METHODS: The height, sitting height, upper to lower segment (U:L) ratio and pubertal development were determined in 71 Chinese children (38 girls and 33 boys) with beta-thalassaemia. The growth patterns of 20 patients with complete growth data between 3 years and final height, were analyzed according to whether they underwent a pubertal growth spurt or not. RESULTS: 27% of the boys and 32% of the girls had a height below the 3rd percentile. About 60% of all the children had a U:L ratio below the 10th percentile for age. Abnormal body proportion was found in patients with or without growth retardation. 34% of the 41 children over the age of 14 years underwent spontaneous puberty. In 28 patients over the age of 16 years, a growth spurt was observed in 46% of the children during spontaneous or induced puberty. The retrospective analysis showed that the height deviation from the mean in adulthood was significantly higher in patients without pubertal growth acceleration than in those with a growth spurt (x = -11.8 cm, s = 7.6 cm vs x = -4.4 cm, s = 4.4 cm; P = 0.02). CONCLUSIONS: An abnormal U:L ratio was commonly observed in patients with beta-thalassaemia major and may be one factor contributing to the short stature of these patients. Abnormal puberty was present in a significant proportion of children and the lack of a pubertal growth spurt was found to be detrimental to adult height. (+info)
betaMinor-globin messenger RNA accumulation in reticulocytes governs improved erythropoiesis in beta thalassemic mice after erythropoietin complementary DNA electrotransfer in muscles.
(59/842)
Mechanisms governing the induction of effective erythropoiesis in response to erythropoietin (Epo) oversecretion have been investigated in beta thalassemic C57Bl/6(Hbbth) mice. Naked DNA encoding an expression vector for mouse Epo was introduced into skeletal muscles by electrotransfer. A transient increase of serum Epo concentrations with a proportional augmentation of hematocrit values was observed. Various parameters relevant to beta thalassemia were surveyed in blood samples taken before treatment, at the peak of Epo secretion, and when the phenotype reverted to anemia. We measured globin messenger RNA (mRNA) levels in reticulocytes by real-time quantitative polymerase chain reaction, globin chain synthesis levels, and several indicators of erythrocyte membrane quality, including bound alpha chains, bound immunoglobulins, main protein components, and iron compartmentalization. Data indicated that high serum Epo levels primarily affect betaminor-globin mRNA accumulation in reticulocytes. Other changes subsequent to intense Epo stimulation, like increased betaminor/alpha-globin chain synthesis ratio, reduced levels of alpha chains and immunoglobulins bound to membranes, improved spectrin/band 3 ratio, increased red blood cell survival, and improved erythropoiesis appeared as consequences of increased betaminor-globin mRNA levels. This conclusion is consistent with models postulating that intense Epo stimulation induces the expansion and differentiation of erythroid progenitors committed to fetal erythropoiesis. Although phenotypic correction was partial in mice, and comparable achievements will probably be more difficult to obtain in humans, naked DNA electrotransfer may provide a safe and low-cost method for reassessing the potentials of Epo as an inducer of fetal erythropoiesis reactivation in patients with beta thalassemia. (+info)
Multiple coronary artery aneurysms combined with abdominal aortic aneurysm.
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Coronary artery aneurysm (CAA) is defined as coronary dilatation which exceeds the diameter of a normal adjacent segment or the diameter of the patients's largest coronary vessel by as much as 1.5 times. It is an uncommon pathology with a frequency of 1-4% in routine autopsies or coronary angiographies. Atherosclerosis plays an important role in the development of CAA, and it may be a predominant cause in the majority of patients. However, the timing of surgical intervention and the treatment options for CAA are still controversial. In this report, we present a patient who had multiple CAAs of all main coronary arteries and abdominal aortic aneurysm. Different treatment modalities and indications are also discussed. (+info)
Erythroid marrow activity and functional anemia in patients with the rare interaction of a single functional a-globin and beta-globin gene.
(61/842)
BACKGROUND AND OBJECTIVES: The degree of globin chain imbalance and tissue hypoxia are important determinants of clinical severity in thalassemia syndromes. Thus phenotypic expression may be modified by interaction of alpha- and beta-thalassemia defects, level and type of hemoglobin synthesized and oxygen release to the tissues. We evaluated hematology, erythroid marrow activity and functional anemia in patients with the rare interaction of a single a-globin gene and heterozygous beta-thalassemia (HbH/beta-thal trait). DESIGN AND METHODS: In 7 patients characterized by DNA analysis to have HbH disease genotypes with beta-thalassemia trait, we assessed hematologic findings, serum transferrin receptor (sTfR), serum erythropoietin (Epo), red cell 2,3-disphosphoglycerate (2,3-DPG) and whole blood oxygen releasing capability. RESULTS: Patients with HbH/beta-thal trait had moderate anemia, marked hypochromasia and microcytosis, normal or raised HbA2, and no electrophoretically/chromatographically detectable HbH. Epo and sTfR levels were significantly higher than in beta-thalassemia heterozygotes, but lower than in patients with HbH disease; 2,3-DPG levels were highest in HbH/beta-thal trait. Oxygen binding studies and simulations showed reduced oxygen affinity (P50) in HbH/beta-thal trait, resulting in increased oxygen release (O2R). INTERPRETATION AND CONCLUSIONS: Hematologic findings and bone marrow activity in patients with HbH/b-thal trait were consistent with the modified globin chain imbalance and hemoglobin synthesis expected from interaction of HbH disease with heterozygous b-thalassemia, although this rare complex genotype may elude diagnosis based on hematology alone. Significantly higher red cell 2,3-DPG levels were an unexpected finding, and the consequent increase in oxygen release capability resulted in a compensated functional anemia relative to hemoglobin levels. (+info)
Diagnosis of concurrent hemoglobin H disease and heterozygous beta-thalassemia.
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Definitive diagnosis of concurrent hemoglobin (Hb) H disease and heterozygous beta-thalassemia cannot be made from Hb analysis alone, but necessitates genotype analysis and family study. Interactions between alpha- and beta-thalassemia must be considered when investigating moderate to severe hypochromic microcytic anemia of uncertain cause in adult patients from areas with a high prevalence of globin gene mutations. (+info)
Functional requirements for phenotypic correction of murine beta-thalassemia: implications for human gene therapy.
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As initial human gene therapy trials for beta-thalassemia are contemplated, 2 critical questions important to trial design and planning have emerged. First, what proportion of genetically corrected hematopoietic stem cells (HSCs) will be needed to achieve a therapeutic benefit? Second, what level of expression of a transferred globin gene will be required to improve beta-thalassemic erythropoiesis? These questions were directly addressed by means of a murine model of severe beta-thalassemia. Generation of beta-thalassemic mice chimeric for a minority proportion of genetically normal HSCs demonstrated that normal HSC chimerism levels as low as 10% to 20% resulted in significant increases in hemoglobin (Hb) level and diminished extramedullary erythropoiesis. A large majority of the peripheral red cells in these mice were derived from the small minority of normal HSCs. In a separate set of independent experiments, beta-thalassemic mice were bred with transgenic mice that expressed different levels of human globins. Human gamma-globin messenger RNA (mRNA) expression at 7% of the level of total endogenous alpha-globin mRNA in thalassemic erythroid cells resulted in improved red cell morphology, a greater than 2-g/dL increase in Hb, and diminished reticulocytosis and extramedullary erythropoiesis. Furthermore, gamma-globin mRNA expression at 13% resulted in a 3-g/dL increase in Hb and nearly complete correction of red cell morphology and other indices of inefficient erythropoiesis. These data indicate that a significant therapeutic benefit could be achieved with expression of a transferred globin gene at about 15% of the level of total alpha-globin mRNA in patients with severe beta-thalassemia in whom 20% of erythroid precursors express the vector genome. (+info)
The possible role of autoimmunity in the pathogenesis of diabetes in B-thalassemia major.
(64/842)
OBJECTIVE: To evaluate the possible role of autoimmunity in the pathogenesis of diabetes associated with B-thalassemia, we studied a cohort of 53 B-thalassemic individuals, under long term blood transfusion, that included twelve patients with diabetes (22.6%). MATERIAL AND METHODS: To evaluate the activation of an autoimmune response, individuals were tested for islet cell antibodies (ICA), glutamic acid decarboxylase (GAD) autoantibodies, insulin autoantibodies (IAA) and serum anti-nuclear antibodies (ANA). RESULTS: Nine of the total B-thalassemic population (16.98%) were ICA-positive. The frequency of ICA-positive subjects among thalassemic individuals was higher than in the general population. Five (41.6%) of the ICA-positive individuals were diabetic. Of these, three were serum C-peptide-negative (<0.21 nmol/l). HLA class II typing of our thalassemic population did not reveal significantly different allelic frequencies with respect to the control population. CONCLUSIONS: Our study demonstrates evidence of immune system activation against pancreatic B-cells in B-thalassemia and we propose that iron deposition may, through oxidative damage, act as an environmental factor that triggers the autoimmune response. Therefore, we speculate that pancreatic autoimmunity may contribute to selective B-cells damage in the pathogenesis of diabetes associated with B-thalassemia. (+info)