Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A young American woman of Thai ancestry living in Ohio and a man of Vietnamese origin living in Iowa are believed to be the first recognized hemoglobin E homozygotes residing in the western hemisphere. Both were clinically well and exhibited neither pallor nor icterus nor splenomegaly. Their blood exhibited marked microcytosis and mild erythrocytosis. Hemoglobin was 99% E and 1% F, 97% E and 3% F, respectively. These features were similar to those previously reported from Southeast Asia and Madagascar in the few well-documented reports of homozygous hemoglobin E. A 51Cr erythrocyte survival study indicated a normal t1/2 of 28 days. Also demonstrated were minimal decrease in whole blood O2 affinity and increased ratio of alpha/non-alpha globin chain synthesis. Mild hemolytic anemia is not, as usually stated, a feature of this condition, which closely mimics a very mild thalassemia minor. Anemia, when found with high proportions of hemoglobin E, should not be attributed to the homozygous hemoglobinopathy. Persons with homozygous hemoglobin E should be reassured as to its benign implications.
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PMID:Homozygous hemoglobin E mimics beta-thalassemia minor without anemia or hemolysis: hematologic, functional, and biosynthetic studies of first North American cases. 739 58

Three clinical parameters - average steady-state haematocrit (ASSH), number of crises per year (Cr/Y), and number of transfusions per year (Tx/Y) - were evaluated in 52 patients with sickle-cell anaemia in relation to their foetal haemoglobin (HbF) levels. No correlation was observed between HbF and any of these parameters. A comparison of these three clinical parameters and the alpha globin gene status was also made in 28 of these patients. The relationships between (ASSH) or (Cr/Y) and alpha globin gene status were not significantly different (p > 0.05) but a significantly different value (p < 0.05) was observed between (Tx/Y) and the alpha globin gene status in these patients. It is concluded that, although HbF levels did not affect any of these parameters, alpha thalassaemia deletion significantly reduces the transfusion requirements of these patients.
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PMID:Effects of alpha thalassaemia and haemoglobin F (HbF) level on the clinical severity of sickle-cell anaemia. 750 64

A Leu-->Pro substitution at position 129 of the alpha 1 globin gene was detected in three members of a Tunisian family by sequencing the whole alpha 2 and alpha 1 DNA. The mutation was verified by dot-blot allele-specific hybridization as well as by digestion of PCR and RT-PCR products with Nci I, since the alpha 1(129) T-->C mutation creates an additional recognition site for the above-mentioned enzyme. The alpha 1(129)(H12)Leu-->Pro substitution disturbs helix H resulting in alpha-thal trait most probably because the unstable alpha-globin chain variant cannot form alpha beta dimers. A search for the abnormal Hb and for the abnormal alpha globin chain by isoelectric focusing, carboxymethyl cellulose chromatography and electrospray ionization mass spectrometry was negative. In the heterozygous state, the alpha 1(129)(H12) Leu-->Pro variant is manifested by microcytosis (MCV approximately 73 fl), whereas in the homozygous state there is moderate anaemia with marked microcytosis (Hb 11.6 g/dl, MCV 65 fl).
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PMID:Haemoglobin Tunis-Bizerte: a new alpha 1 globin 129 Leu-->Pro unstable variant with thalassaemic phenotype. 778 98

The life threatening anemia in beta-thalassemia major (Cooley's anemia) is characterized by profound intramedullary lysis, the cause of which is incompletely understood. Using marrow obtained from beta thalassemia major patients undergoing allogeneic bone marrow transplantation in Pesaro Italy, it became possible to directly study the mechanism of the intramedullary hemolysis. Based on our previous studies, we hypothesized that the unmatched alpha globin chains would interfere with normal assembly of erythroid precursor membrane proteins. Patient and control erythroid precursors were reacted with monospecific polyclonal rabbit antibodies directed against spectrin, band 3, and band 4.1 and with a monoclonal anti-alpha globin chain antibody. Using laser confocal fluorescence microscopy, normal erythroid precursors show no alpha globin chain accumulation and exhibited uniformly smooth rim fluorescence of the three membrane proteins. In some thalassemic precursors, spectrin appeared to interact with large alpha globin accumulations, and in many of these cells the spectin appeared clumped and discontinuous. Band 4.1 interacted strongly with accumulations of alpha globin in thalassemic precursors to produce bizarrely clumped zones of abnormal band 4.1 distribution. Band 3 was incorporated smoothly into thalassemic erythroblast membranes. However, the proerythroblasts and basophilic erythroblasts were significantly deficient in band 3. Thus, accumulations of alpha globin in beta-thalassemia major colocalized with and disrupt band 4.1 and spectrin assembly into the membrane. The cause of deficient band 3 incorporation into thalassemic proerythroblast membranes remains unknown. These profound membrane alterations would likely contribute to the intramedullary lysis seen in Cooley's anemia.
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PMID:Abnormal assembly of membrane proteins in erythroid progenitors of patients with beta-thalassemia major. 863 56

Cardiac function was measured at rest and during exercise in 9 patients with sickle-cell anemia (SS) and coexisting homozygous alpha thalassemia-2 (alpha thal-2). Results were compared with 18 sickle cell patients with normal alpha globin genes, who were matched to the study group by age, gender, and size, and to published normal values. SS alpha thal-2 patients were less anemic: 9.9 +/- 1.0 vs 8.2 +/- 1.2 gm/dl for SS alone (P<.05). Left ventricular dimensions were normal in SS alpha thal-2 (4.9 +/- 0.7 cm), but increased in SS (5.4 +/- 0.7, cm P=.05) (normal range, 3.7-5.6 cm). Left ventricular wall thickness was, however, dramatically increased in the SS alpha thal-2 patients (free wall, 1.8 +/- 0.6 cm; septum, 1.6 +/- 0.4 cm), though SS controls had normal wall thickness (free wall, 1.0 +/- 0.2 cm; septum, 1.0 +/- 0.2 cm, P<.001) (normal range, 0.6-1.1 cm). At rest, Doppler indices of systolic function were not significantly different between sickle groups and normal values. SS alpha thal-2 patients did have abnormal diastolic filling at rest, as evidenced by a reduced ratio of early/late diastolic filling, 1.4 +/- 0.3 vs. 2.0 +/- 0.5 for SS controls (P<.01), and 1.8 +/- 0.4 for normals. An analysis of covariance suggested that this abnormality persisted after taking into account the previously demonstrated hypertrophy. During exercise, SS alpha thal-2 patients had higher heart rates and blood pressures than SS controls in spite of performing the same or less work. This resulted in a higher double product (an estimate of oxygen consumption) in SS alpha thal-2 patients (37,470 +/- 2,310 mm Hg-BPM) than in SS controls (33,310 +/- 1,490 mm Hg-BPM, P<.01). Work capacity, peak heart rate, and blood pressure were all abnormally decreased in both sickle-cell groups when compared to normal. Cardiac abnormalities noted at rest and during exercise in SS alpha thal-2 patients suggest a role of microvascular occlusion and a protective effect of decreased hemoglobin.
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PMID:Cardiovascular function during rest and exercise in patients with sickle-cell anemia and coexisting alpha thalassemia-2. 863 48

A 3-year-old Filipino-American child with recurrent fever, splenomegaly, anemia, and thrombocytopenia, was found to have a hemoglobin F level of 76.9%. His reticulocyte count was elevated (4.3%), and erythroblasts were present in his peripheral blood. The child's erythrocytes were microcytic (MCV 66.9 fl) but his serum ferritin level was normal. His bone marrow at initial presentation demonstrated normal cellularity without an increase in blast cells. The disease progressed with worsening anemia, leukocytosis, and thrombocytopenia, with increased blasts in his marrow and the appearance of a mediastinal mass. His liver, spleen, and lymph nodes were found to be infiltrated with myeloblasts, supporting a diagnosis of juvenile myelomonocytic leukemia (JMML). Analysis of the child's Hb F showed a Ggamma/Agamma ratio of 2.2, which was within the characteristic range for JMML. A globin synthesis study using blood reticulocytes showed an alpha/non-alpha globin synthesis ratio of 2.24, typical of severe homozygous beta thalassemia. Southern blot analysis of blood-leukocyte DNA from the patient and his parents demonstrated no apparent abnormality in the beta-globin gene promoter or coding regions. The elevated level of Hb F in this child with JMML appeared to be part of an acquired Cooley's anemia-like hematologic phenotype.
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PMID:Juvenile myelomonocytic leukemia (JMML) with the hematologic phenotype of severe beta thalassemia. 959 Jan 52

Hemoglobin E (HbE; alpha2beta226glu-lys), globally the commonest hemoglobin variant, is synthesized at a slightly reduced rate and has a homozygous phenotype similar to heterozygous beta thalassemia. Yet, when it is inherited together with a beta thalassemia allele, the resulting condition, HbE/beta thalassemia, is sometimes characterized by a severe, transfusion-dependent thalassemia major. The severity of this interaction has not been explained. We have explored the possibility that it may reflect the instability of HbE consequent upon globin chain imbalance imposed by the beta thalassemia allele. Time-course and pulse-chase globin chain synthesis studies at 37 degrees C on peripheral blood and bone marrow suggest that hemoglobin instability is not significant in steady-state HbE/beta thalassemia; this is confirmed by density-gradient centrifugation studies that show no decrease in HbE levels relative to HbA as HbE/beta+ thalassemia red blood cells age. Globin binding to membranes was assessed and only alpha globin chains were found, in contrast to other unstable hemoglobins in which both alpha and beta chains were present. However, in experiments performed on blood from HbE/beta thalassemics in the temperature range 39 degrees C to 41 degrees C, there was evidence of instability of HbE, a finding that was also observed in homozygous HbE. These findings suggest that the phenotype of HbE/beta thalassemia is primarily the result of the interaction of two beta thalassemia alleles; however, hemoglobin instability may be important during febrile episodes, contributing to worsening anemia.
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PMID:Is hemoglobin instability important in the interaction between hemoglobin E and beta thalassemia? 973 Oct 73

Hb H disease is generally associated with moderate to severe anemia but rarely requires regular blood transfusion. We recently studied two apparently unrelated patients with transfusion-dependent Hb H disease. Hemoglobin studies demonstrated Hb H and Hb Bart's without other detectable abnormal globin species. Extensive molecular analyses of the alpha globin genes and their regulatory sequence (HS-40) revealed that both patients are compound heterozygotes for alpha0 thalassemia (--(SEA)) and a novel point mutation, a thymidine insertion after codon 131 of the alpha1 gene. The resulting frameshift gives rise to a highly unstable alpha globin chain, which we refer to as "Hb Pak Num Po," containing an additional 34 amino acids. This unusual alpha1 globin variant clearly causes alpha thalassemia, but the unexpectedly severe phenotype suggests that this mutation may have additional effects on red cell physiology. A PCR-based (ARMS) assay was developed for rapid detection of this novel mutation, and this might be useful to study the prevalence of this novel mutation which poses potentially significant clinical consequences in populations of Southeast Asia. Detecting carriers of this mutation using the molecular diagnostic procedures described will provide the means to screen and prevent a potentially severe form of alpha thalassemia in Thailand.
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PMID:Co-inheritance of Hb Pak Num Po, a novel alpha1 gene mutation, and alpha0 thalassemia associated with transfusion-dependent Hb H disease. 1497 97

The coinheritance of beta-thalassemia major with the genotype of Hb H disease is extremely rare, with few reported cases. We investigated the hematological, biochemical, biosynthetic, molecular and pathophysiological parameters to evaluate a rare male patient with this compound syndrome. The patient was studied at first diagnosis during hospitalization at 50 years of age and subsequently followed up for more than a year. Examinations included full hematological, biochemical, biosynthetic, molecular, pathophysiological and clinical parameters. Besides standard parameters, we additionally measured reticulocyte hemoglobin content (CHr), erythropoietin (Epo), soluble transferrin receptors (sTfR), oxygen pressure at 50% hemoglobin saturation (P50), 2,3-bisphosphoglycerate (2,3-BPG), total glutathione (GSHt), oxidized glutathione (GSSG), malonyldialdehyde (MDA), nontransferrin-bound iron (NTBI), vitamins A and E. The male patient was first hospitalized for a 2-day period at 50 years of age, following the finding of marked anemia (hematocrit 20%) during a blood test to investigate the cause of fatigue in the absence of weight-loss or other notable symptomatology. He had never been transfused, maintaining Hb 85-95 g/l. Definitive diagnosis was achieved through DNA studies, which showed coexistence of beta-thalassemia major (IVSI-6 T > C/IVSI-I G > A) with Hb H disease (-alpha(3.7)/-(Med)). Alpha/non-alpha globin chain biosynthesis was completely balanced. Parameters demonstrated a well-compensated anemia with ineffective erythropoiesis and oxidative stress, which was ameliorated following splenectomy. In conclusion, this case is a remarkable example that the coinheritance of severe forms of beta-thalassemia and alpha-thalassemia interact in a "synergistic" manner to almost complete balance the symptoms of classic thalassemia syndromes.
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PMID:A rare example that coinheritance of a severe form of beta-thalassemia and alpha-thalassemia interact in a "synergistic" manner to balance the phenotype of classic thalassemic syndromes. 1500 25

The beta thalassemias are one of a few medical conditions in which reactivation of a gene product that is expressed during fetal life can functionally replace a deficiency of essential proteins expressed at a later developmental stage. The fetal globin genes are present and normally integrated in hematopoietic stem cells, and at least one fetal gene appears accessible for reactivation, particularly in beta degrees thalassemia. However, rapid cellular apoptosis from alpha globin chain precipitation, and relatively low levels of endogenous erythropoietin (EPO) in some beta(+) thalassemia patients contribute to the anemia in beta thalassemia syndromes. In clinical trials, three classes of therapeutics have demonstrated proof-of-principle of this approach by raising total hemoglobin levels by 1-4 g/dL above baseline in thalassemia patients: EPO preparations, short chain fatty acid derivatives (SCFADs), and chemotherapeutic agents. Although thalassemic erythrocytes survive only for a few days, the magnitude of these responses is similar to those induced by rhu-EPO in anemic conditions of normal erythrocyte survival. New oral therapeutic candidates, which stimulate both fetal globin gene expression and erythropoiesis, and combinations of therapeutics with complementary molecular actions now make this gene-reactivation approach feasible to produce transfusion independence in many patients. Development of the candidate therapeutics is hindered largely by costs of drug development for an orphan patient population.
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PMID:Fetal globin induction--can it cure beta thalassemia? 1630 57


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