PubMed Health⌕ Search

Biomedical subjects

M H Steinberg

Publications and source records attributed to M H Steinberg.

At least 19 recordsLinked to original sources
PubMed1992

Beta-thalassemia intermedia with exceptionally high hemoglobin A2: relationship to mutations in the beta-gene promoter.

Small deletions of the 5' portion of the beta-globin gene that remove the promoters but stop 3' to the delta-globin gene are recognized as the sole cause of beta-thalassemia with exceptionally high hemoglobin A2 (HbA2) levels. Two patients with beta-thalassemia intermedia and exceptionally high levels of HbA2 (10.4 and 12.0%) were examined. One patient was a combined heterozygote for the -88 C----T and a novel -87 C----A mutation, while the other was homozygous for the -29 A----G beta(+)-thalassemia mutation. The remainder of the beta genes were normal. There was no evidence for deletions involving the 5' portion of the beta gene or the region between the beta and delta genes. Gene mapping studies excluded the possibility of a beta delta-anti-Lepore hemoglobin gene with beta promoters and delta coding sequences. There were no mutations in the promoters of the G gamma or A gamma-globin genes that have been associated with the hereditary persistence of HbF phenotype. The delta-globin gene promoters were normal from codon 17 to position -145 relative to the mRNA capping site. There appears to be considerable heterogeneity of HbA2 and HbF levels in patients who are homozygous or mixed heterozygotes for mutations in the TATA box and other promoter elements of the beta-globin gene. The capacity for proteolysis within the erythrocyte may vary among individuals. The authors hypothesize that in the exceptionally high HbA2 beta-thalassemia intermedia phenotype, proteolysis of superfluous alpha-globin chains is less efficient than in patients with customary levels of HbA2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Hemoglobin Terre Haute arginine beta 106. A posthumous correction to the original structure of hemoglobin Indianapolis.

The initial report of Hb Indianapolis described two affected individuals with the phenotype of severe beta-thalassemia that was dominantly inherited. The structure of this variant could not be deduced by standard techniques because of its extreme instability. Because of this limitation, the structure was ascertained by analysis of the abnormal globin chain, which had been radioactively labeled. These studies strongly suggested that the structure of this variant was cysteine beta 112 to arginine. Subsequent to this report, two additional families with Hb Indianapolis were found. The carriers were minimally affected and the abnormal hemoglobin was only mildly unstable. This major difference in phenotypic expression suggested that further investigation of the original family should be carried out. Unfortunately, both of the original carriers of the variant succumbed to their severe anemia prior to the subsequent reports. However, by the use of the polymerase chain reaction, enough DNA was obtained to sequence the third exon of the beta-globin gene in the original family from the DNA scraped off a 10-year-old bone marrow microscope slide. These studies revealed a substitution of leucine to arginine at position 106 of the beta-globin chain. The polymerase chain reaction results may be consistent with the original protein structural data, if incomplete tryptic cleavage of this arginine residue occurred in the original sample. We have renamed this variant Hb Terre Haute in an attempt to avoid confusion with the Cys beta 112----Arg substitution.

Arginine↗
PubMed1991

High hemoglobin A2 beta 0-thalassemia due to a 532-basepair deletion of the 5' beta-globin gene region.

We identify and characterize a novel beta 0-thalassemia mutation that is associated with an unusually high level of hemoglobin (Hb) A2 in the heterozygote. This newly discovered mutation is caused by a 532-basepair deletion that extends from positions -454 to + 78 relative to the mRNA cap site of the beta-globin gene. The propositi are 9-month-old fraternal twins. One of the twins is a compound heterozygote for the deletion and Hb S, the other is a compound heterozygote for the deletion and Hb C.

Base Sequence↗
PubMed1991

Effect of beta-globin gene cluster haplotype on the hematological and clinical features of sickle cell anemia.

In 113 black American adults with sickle cell anemia (HbSS), we examined nine polymorphic restriction sites, including the Xmnl site 5' to the G gamma gene, to see whether haplotype is related to the level of HbF and the proportion of G gamma chains or if it influences the hematological and clinical features of the disease. Seventy-five percent of the patients were homozygous or heterozygous for the Benin (no. 19) or Central African Republic (Bantu, no. 20) haplotypes; 13.3% were homozygous or heterozygous for the Senegal (no. 3) haplotype, while 11.5% had other genotypes. Of the subjects, 14.2% were either homozygous or heterozygous for the Xmnl restriction site 5' to the G gamma gene. We found no effect of haplotype on HbF levels. The level of G gamma chains was 60.5% +/- 17.0% in individuals heterozygous or homozygous for haplotype no. 3 and was 46.9% +/- 11.6% in individuals with other haplotypes. Subjects with the Xmnl site 5' to the G gamma gene had G gamma globin levels of 59.5% +/- 16.7% while those lacking that site had an average of 47.2% +/- 12.1%. There were no significant differences among these groups in hemoglobin concentration, packed cell volume, mean cell volume, or clinical indicators of vaso-occlusive severity, including crises, hospitalizations per year, aseptic bone necrosis, acute chest syndrome, or leg ulcers. While the presence of haplotype 3 and the 5' G gamma Xmnl site were associated with increased G gamma chains, there was no effect on HbF level or other hematological and clinical features that might reflect disease severity. It is likely that determinants unrelated to haplotype, linked or unlinked to the beta-globin gene cluster, are the major effectors of differences in the levels of HbF in American patients with sickle cell anemia.

Adult↗
PubMed1991

Hb S/beta zero-thalassemia due to the approximately 1.4-kb deletion is associated with a relatively mild phenotype.

We report a relatively mild phenotype associated with two siblings who are compound heterozygotes for Hb S and a beta zero-thalassemia mutation due to a approximately 1.4-kb deletion of the 5' region of the beta-globin gene. Each is found to have unusually high levels of Hb A2 and Hb F, accounting for more than 20% of the total hemoglobin. These may interfere with intracellular Hb S polymerization, thus leading to a mild clinical course.

Adult↗
PubMed1991

Sickle cell anemia: pathophysiology, management, and prospects for the future.

Sickle cell anemia is present in about 1 in 600 Black Americans at birth. It claims the life of many infants, causes pain and suffering in adults, and usually culminates in premature death. We currently understand a great deal about this disease on a molecular, cellular, and clinical basis. The results of years of research are slowly being translated to innovative therapies and improvements in patient care. In this paper I review the pathophysiology of this disorder, highlight the currently available treatment, and discuss new forms of therapy that promise a more direct approach to avoiding the many complications of sickle cell anemia.

Anemia, Sickle Cell↗
PubMed1991

Neonatal screening for sickle cell disease: a cost-effectiveness analysis.

PURPOSE: To determine the cost-effectiveness of screening newborn infants for sickle cell disease. DESIGN: We developed a decision model that examined two strategies: (1) screening neonates and administering penicillin to infants found to have sickle cell disease in the hope of preventing pneumococcal sepsis, and (2) not screening but administering penicillin to infants after symptoms of sickle cell disease develop. The model calculates the cost-effectiveness of these strategies during the first 3 years of life. We applied the model to three prototypic populations of neonates--black, nonblack with a relatively high prevalence of hemoglobin S genes, and nonblack with a low prevalence of hemoglobin S genes. DATA IDENTIFICATION: We obtained from the published literature the effectiveness and risk of penicillin prophylaxis, the risk of pneumococcal sepsis, and the probability that in infants not screened the development of symptoms would lead to the discovery of sickle cell disease within the first 3 years of life; we used the published literature and the Hardy-Weinberg law to determine the prevalence of sickle cell disease. We used actual variable costs of screening, antibiotic prophylaxis, and hospitalization for pneumococcal sepsis or anaphylaxis. RESULTS: Screening and then treating affected black infants costs only $3100 more per life saved than not screening. Screening nonblack populations with a high prevalence of hemoglobin S genes would cost $1.4 million per life saved, and screening low prevalence populations would cost $450 billion per life saved. CONCLUSIONS: Screening black infants is very worthwhile, but screening populations in which the hemoglobin S gene is rare is unjustified.

Anaphylaxis↗
PubMed1991

Prospects of gene therapy for hemoglobinopathies.

Gene therapy offers the promise of a definitive cure of the hemoglobinopathies and thalassemias. The background of gene therapy for these disorders is discussed along with the obstacles that must be overcome before this promise becomes reality.

Forecasting↗
PubMed1991

Disappearance of the protein of a somatic mutation: a possible example of stem cell inactivation.

The low concentration of the hemoglobin variant, Hb Vicksburg (leucine-beta-75 deleted), and a profound deficit of its mRNA led us to postulate that a beta(+)-thalassemia mutation existed in cis to the coding region mutation, suppressing its synthesis. We examined blood from this patient 6, 8, and 10 yr after our initial studies, using methods of analysis unavailable initially. We found 1) mutations causing beta(+)-(-88 C----T) and beta 0-(849 A----G) thalassemia; 2) that the proportion of Hb Vicksburg in erythrocytes fell over time, from 8 to 4%, and ultimately disappeared; and 3) that the mutation causing Hb Vicksburg was not detectable in genomic DNA isolated from blood leukocytes when this variant was present in hemolysate. We postulate that Hb Vicksburg arose from a somatic mutation of a beta(+)-thalassemia gene in an erythroid-committed stem cell. Its gradual disappearance suggests the cycling of stem cells, with inactivation of different clones over time.

Adolescent↗
PubMed1991

Effects of alpha-thalassemia and sickle polymerization tendency on the urine-concentrating defect of individuals with sickle cell trait.

A defect in urine concentrating ability occurs in individuals with sickle cell trait (HbAS). This may result from intracellular polymerization of sickle hemoglobin (HbS) in erythrocytes, leading to microvascular occlusion, in the vasa recta of the renal medulla. To test the hypothesis that the severity of the concentrating defect is related to the percentage of sickle hemoglobin present in erythrocytes, urinary concentrating ability was examined after overnight water deprivation, and intranasal desmopressin acetate (dDAVP) in 27 individuals with HbAS. The HbAS individuals were separated into those who had a normal alpha-globin genotype (alpha alpha/alpha alpha), and those who were either heterozygous (-alpha/alpha alpha) or homozygous (-alpha/-alpha) for gene-deletion alpha-thalassemia, because alpha-thalassemia modulates the HbS concentration in HbAS. The urinary concentrating ability was less in the alpha alpha/alpha alpha genotype than in the -alpha/alpha alpha or -alpha/-alpha genotypes (P less than 0.05). After dDAVP, the urine osmolality was greater in patients with the -alpha/-alpha genotype than with the -alpha/alpha alpha genotype (882 +/- 37 vs. 672 +/- 38 mOsm/kg H2O) (P less than 0.05); patients with the -alpha/alpha alpha genotype had greater concentrating ability than individuals with a normal alpha-globin gene arrangement. There was an inverse linear correlation between urinary osmolality after dDAVP and the percentage HbS in all patients studied (r = -0.654; P less than 0.05). A linear correlation also existed for urine concentrating ability and the calculated polymerization tendencies for an oxygen saturation of 0.4 and O (r = -0.62 and 0.69, respectively). We conclude that the severity of hyposthenuria in HbAS is heterogeneous. It is determined by the amount of HbS polymer, that in turn is dependent upon the percentage HbS, which is itself related to the alpha-globin genotype.

Adult↗
PubMed1991

The interactions of alpha-thalassemia with hemoglobinopathies.

Because of their high prevalence throughout the world, alpha-thalassemia and hemoglobinopathies often occur in the same individual. Southern blot hybridization analysis of the alpha-globin gene cluster permits the detection of the common deletion alpha-thalassemias and the definition of the phenotypes affiliated with the interactions of alpha-thalassemia and hemoglobinopathies. Important insights into the pathophysiology of Hb SS have been gained, and the nature of the perturbation of heterozygous hemoglobinopathies by alpha-thalassemia has been established.

Anemia, Sickle Cell↗
PubMed1990

Molecular basis for alpha-thalassemia associated with the structural mutant hemoglobin Suan-Dok (alpha 2 109leu----arg)

Hemoglobin (Hb) Suan-Dok (alpha 109Arg) is a rare alpha-globin structural mutation that is linked to an alpha-thalassemia (alpha-thal) determinant. When inherited in trans to an alpha-thal-1 mutation (-), it results in Hb H disease associated with low levels (9%) of the Suan-Dok Hb. The nature of the thalassemic defect associated with the alpha SD mutation has been investigated by structural and functional studies. Sequence analysis of the cloned Suan-Dok allele showed a missense mutation (T----G) at codon 109 in an otherwise normal alpha 2-globin gene. When the alpha 2SD-globin gene was introduced into mouse erythroleukemia cells, the steady state alpha-globin messenger RNA (mRNA) level was equivalent to the alpha A-globin gene control. Although in vitro translation of a synthetic alpha 2SD-globin mRNA generated levels of alpha globin equivalent to alpha 2A-globin mRNA at early time points, the ratio of alpha SD to alpha A globin decreased markedly at later time points. These data suggest that the thalassemic defect associated with the Suan-Dok mutation results from a significant instability of the alpha SD globin.

Amino Acid Sequence↗