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PubMed1990

A new hemoglobin variant found during investigations of diabetes mellitus: Hb Pavie [alpha 135 (H18) Val----Glu].

Hb Pavie [alpha 135 (H18) Val----Glu], found during HbA1c measurement in a patient of Italian origin investigated for diabetes mellitus, exemplifies how the presence of an abnormal hemoglobin interferes with the measurement of glycated hemoglobin. This variant hemoglobin migrates as Hb A1c on polyacrylamide gel isoelectric focusing (IEF) and therefore hindered the estimation of glycated hemoglobin by this method. By ion-exchange high-performance liquid chromatography (IE-HPLC) Hb Pavie was eluted as a shoulder of the major component and the corresponding glycated fraction together with Hb A1b. Hb Pavie was purified in order to determine how its functional properties may modify red cell survival. The only functional abnormality observed was a slight decrease of the oxygen affinity, and therefore the total amount of glycated hemoglobin was not expected to be decreased by a shortening of the red cell survival.

Amino Acid Sequence↗
PubMed2002

[Hemoglobin anomalies at the university hospital center in Lome, Togo].

Togo is a sub-Saharan African nation with a number of public health problems including endemic tropical disease. The country is also located in the Lehmann sickle cell belt characterized by a high incidence of genetic red blood cell disorders. The purpose of this study was to identify the main hemoglobin variants, evaluate their incidence and discuss diagnostic pitfalls. Data on 5604 subjects was compiled from the 3 studies, i.e., a 405-case prospective study conducted in a rheumatology department, a 5028-case retrospective study using electrophoresis and a 171-case transversal study in newborns. Diagnosis of hemoglobinopathy was based on alkaline electrophoresis. Rare hemoglobins were identified in the Biochemistry Laboratory of the Henri Mondor Hospital in Paris, France. Diagnosis of alpha-thalassemia was checked by PCR. The main abnormal hemoglobins were the S and C variants with respective incidence ranges of 15.8 to 16.7% for the AS trait and 12.1 to 15.8% for AC trait. SS sickle cell disease was observed in 1.2 to 2% of subjects and SC sickle disease in 2.3 to 4.2%. Rare hemoglobulinopathies involved the fast hemoglobulin variant, hemoglobin D, and hereditary persistence of hemoglobin F. Alpha-thalassemia was detected in 47% of the 171 newborns studied with a predominance of the heterozygous form (36.8%), followed by the homozygous form (8%). The incidence of alpha gene triplication in the newborns was about 2.4%. Hemoglobin Barts was not a consistent finding in association with diagnosis of alpha-thalassemia since it was present in 15 newborns with normal alpha genotype (8.8%) and absent in 10 newborns with heterozygous alpha genotype (5.9%). This study demonstrates that molecular biology is the best method for the detection of the alpha-globin gene abnormalities.

Cross-Sectional Studies↗
PubMed1983

Tissue oxygenation and muscular substrate turnover in two subjects with high hemoglobin oxygen affinity.

Oxygen transport to and substrate turnover in leg muscle were studied at rest and during light and heavy upright bicycle exercise in two brothers with a hereditary hemoglobinopathy associated with high oxygen affinity (P50 = 13 mmHg). Femoral venous oxygen tension was below normal and femoral venous oxygen saturation above normal at rest and during exercise. Thus, the arterial-femoral venous oxygen saturation difference was decreased. Despite a compensatory increase in hemoglobin concentration, the arterial-femoral venous oxygen content difference tended to be below normal at heavy exercise. Approximately 25% of the oxygen was delivered via the abnormal hemoglobin at relative heavy exercise. Arterial lactate levels, lactate release, and muscle lactate concentration were not increased at any level of exercise. Glucose, alanine, pyruvate, and glycerol turnover were essentially normal, but the glycogen and creatine phosphate stores were abnormally depleted at the termination of heavy exercise. The exercise electrocardiogram (ECG) was normal, indicating that myocardial oxygenation was adequate. Muscle-surface oxygen pressure fields were normal at rest (not investigated during exercise). It is concluded that the high oxygen affinity of the hemoglobin in our two subjects did not lead to heart or skeletal muscle hypoxia during heavy exercise, as judged from the ECG and from the leg lactate turnover. Despite the lack of evidence for muscle hypoxia, the subjects experienced leg muscle fatigue and the creatine phosphate and glycogen stores were depleted more than normally.

Adenosine Triphosphate↗
PubMed1991

Hemoglobin Cagliari (beta 60 [E4] Val----Glu): a novel unstable thalassemic hemoglobinopathy.

This report describes a patient with thalassemia intermedia-like phenotype born to normal parents in whom globin gene sequencing detected a novel abnormal hemoglobin (Hb) due to a T to A substitution at codon 60 of the beta-globin gene arising as a de novo mutation. Normal sequences were detected at the homologous beta-globin locus. This mutation results in the substitution of a polar (glutamic acid) for a nonpolar (valine) residue near the corner of the heme pocket of the beta-globin chain. The novel variant has been designated Hb Cagliari, from the place of birth of the propositus. Kinetics of globin synthesis performed following splenectomy suggest that this new Hb variant is synthesized at a near normal rate but undergoes rapid breakdown. The extreme lability of the variant explains the clinical and hematologic picture characterized by marked ineffective erythropoiesis, thalassemia-like bone changes, iron overload, high proportion of Hb F in the peripheral blood, reduced beta/alpha-globin chain synthesis ratio in peripheral blood reticulocytes, and absence of the abnormal Hb in peripheral blood at extensive protein structural analysis before splenectomy. This case indicates that a thalassemic hemoglobinopathy should be suspected in the presence of a patient with a thalassemia intermedia-like phenotype born to normal parents, even when protein structural analysis fails to detect an abnormal Hb. DNA sequencing may allow to define the mutation, thus making the proper diagnosis.

Anemia, Hemolytic↗
PubMed1993

Globin chain synthesis in hemolytic anemia reticulocytes. A case of hemoglobin Burke.

Peripheral red blood cells from an anemic patient were incubated with [14C]Leu and the labeled globin chains were analyzed by CM-cellulose column chromatography in 8M urea. The radioactivity almost equal to that of beta chain emerged between beta and alpha chains. The newly appeared materials were found to be derived from an abnormal hemoglobin (Hb), Hb Burke [beta 107(G9)Gly to Arg], by the sequence analyses of abnormal globin chain and beta globin mRNA from the patient.

Aged↗
PubMed1980

Hemoglobin Hasharon [alpha 247 (CD5)Asp leads to His beta 2] linked to alpha-Thalassemia in northern Italian carriers. Hematological and biosynthetic studies.

This report is concerned with the evaluation of hematological parameters and of both relative (%) and absolute (mean pg/cell) quantities of the abnormal Hemoglobin (Hb) Hasharon in 53 heterozygous carriers and 7 double heterozygotes for Hb Hasharon and beta-thalassemia from 43 apparently unrelated families living in the province of Rovigo (northern Italy). Biosynthetic studies are also reported. The data strongly suggest the presence of an alpha-thalassemia-2 determinant closely linked to the alpha Hasharon-chain locus. Selective advantage of heterozygotes carrying such alpha-haplotype would explain the relatively high frequency of Hb Hasharon (0.23%) in northeastern Italy, a past-endemic malaria region. The interaction between Hb Hasharon and beta-thalassemia results in preferential decrease of the abnormal Hb level.

Blood Protein Electrophoresis↗
PubMed1990

High-performance liquid chromatography of globin chains in the identification of human globin gene abnormalities.

This article summarizes experience and data obtained using a previously developed reverse-phase high-performance liquid chromatography method (J.B. Shelton, J.R. Shelton and W.A. Schroeder, J. Liq. Chromatogr. 7 (1984) 1969) in the study of a number of hemoglobinopathies in the Sardinian population. The occurrence and incidence of several abnormal hemoglobins are described, as well as aspects of the expression of abnormal gamma-globin gene arrangements and thalassemic genes.

Chromatography, High Pressure Liquid↗
PubMed1972

Structural and functional studies on hemoglobin Bethesda (alpha2beta2 145His), a varient associated with compensatory erythrocytosis.

Studies have been performed on a 12-yr-old Chinese girl with compensatory erythrocytosis due to the presence of hemoglobin Bethesda comprising about 45% of the red cell hemoglobin. Her parents and three siblings were normal. The oxygen affinity of her blood was markedly increased: under physiological conditions (pH 7.40, 37 degrees C). P(50) was 12.8 mm Hg (normal = 26.5 mm Hg). The red cell 2,3-diphosphoglycerate (2.3-DPG) level was normal. The abnormal hemoglobin could not be separated from hemoglobin A by zone electrophoresis at pH 8.6 or isoelectric focusing on polyacrylamide gel. However, after the hemoglobin was split into free alpha and beta chains by treatment with p-hydroxymercuribenzoate (PMB) or 6 M urea, an abnormal beta chain was readily demonstrated having a higher isoelectric point (more positive net charge) than normal beta(A). Structural analysis of the variant beta chain demonstrated the substitution of histidine for tyrosine at position 145: hemoglobin Bethesda (alpha(2)beta(2) (145His)). From earlier chemical and crystallographic studies, it has been postulated that this residue is a critical determinant of hemoglobin function. Hemoglobin Bethesda was separated from hemoglobin A by column chromatography. Oxygen equilibria of purified hemoglobin Bethesda revealed an extremely high oxygen affinity (exceeding that of isolated alpha and beta chains), and markedly reduced cooperativity. The Bohr effect of hemoglobin Bethesda was 1/3 that of hemoglobin A. However, hemoglobin Bethesda showed a significant interaction with 2.3-DPG and inositol hexaphosphate.

Adenosine Triphosphate↗
PubMedDate not supplied

Molecular characterization and functional studies on Hb Kempsey, beta 99 (G-1) Asp----Asn, a high-oxygen affinity variant.

BACKGROUND: Hb Kempsey (beta 99 Asp----Asn) is a high-oxygen affinity hemoglobin, never before reported in Italy, associated with secondary erythrocytosis. It has been found in the heterozygous state in two subjects from the same family originating from the Verona area in Northern Italy. METHODS: The abnormal hemoglobin was studied both at the protein and at the DNA level. The amino acid substitution was identified by fingerprinting and amino acid analysis. The nucleotide replacement was investigated by means of polymerase chain reaction (PCR) of the beta gene and direct sequencing. Oxygen affinity and other functional parameters were assessed on whole blood and on the separate hemoglobin fractions. RESULTS: These studies allowed us to establish the molecular substitution GAT (Asp)----AAT (Asn) at codon 99. Functional studies revealed a left-shifted and biphasic dissociation curve of the proposita, with a very low p50. The two carriers of this hemoglobinopathy have different degrees of polyglobulia, since iron deficiency in one of them reduces total and abnormal Hb. CONCLUSIONS: The compensatory mechanisms for tissue hypoxia are discussed with the conclusion that erythrocytosis has to be preserved in these patients to maintain adequate tissue oxygenation.

Aged↗
PubMed1984

Hemoglobin constitution of double heterozygotes for alpha or beta-thalassemia and Hb J Sardegna.

In this study, we carried out alpha-globin gene mapping in 12 heterozygotes for Hb J Sardegna and in 5 double heterozygotes for this variant and beta-thalassemia. Then, we correlated the Hb pattern with the alpha and beta-globin genotype. In heterozygotes for Hb J Sardegna with a deletion of a single alpha-globin gene (alpha alpha/-alpha) the amount of the abnormal Hb was significantly (p much less than 0.001) higher than in heterozygotes for this variant with a full complement of 4 alpha-globin structural genes (27.5% versus 20.4%). Double heterozygotes for the abnormal hemoglobin and beta-thalassemia with a full complement of 4 alpha-globin structural genes tended to have lower amount of the abnormal Hb than heterozygotes for this variant who do not have beta-thalassemia.

Chromosome Mapping↗
PubMed2003

Hemoglobin variant HbG-coushatta (beta-22 Glu --> Ala) found by dissociation of blood glucose from values of HbA1C measured by HPLC.

OBJECTIVE: Unexpectedly low values of HbA1C, measured by HPLC compared with their blood glucose levels were found in three related persons. We investigated whether this discrepancy was due to abnormal hemoglobin. PATIENTS AND METHODS: HbA1C was measured by latex agglutination and ordinary HPLC. For further examination, a hemoglobin specimen from the 82-year-old female case was prepared and analyzed by PolyCAT A chromatography, ESI/MS and MS/MS. The HbA1C levels of the three cases measured by HPLC were lower than those measured by latex agglutination. The elution profiles on HPLC of the three gave an unusual peak between HbA1C and HbA0. RESULTS: PolyCAT A chromatography revealed two additional peaks which were not present in normal hemolysates. These peaks were revealed to correspond to abnormalities of HbA0 and HbA1C. The amounts of HbA0 and HbX were almost the same (1:0.85) and their glycation ratios were almost equal (5.2% and 5.9%). ESI/MS showed that the woman's intact globin contained an abnormal beta(X)-chain in addition to the normal alpha(A)- and beta(A)-chains. The molecular weight of this abnormal beta(X)-chain was 58 Da lower than that of the normal beta(A)-chain. Glutamate at the 22nd amino acid residue of the beta(A)-chain was replaced by alanine in the abnormal beta(X)-chain. This variant of Hb was revealed to be the same as HbG-Coushatta (beta-22 Glu --> Ala) from the library of variant Hb. Family studies showed that the variant was inherited as a dominant trait. CONCLUSION: The dissociation was due to underestimation of HbA1C in the measurement by HPLC which excluded glycated variant Hb.

Aged↗
PubMed1989

[The Japanese family of congenital high red cell membrane phosphatidylcholine hemolytic anemia].

A Japanese family of congenital high red cell membrane phosphatidylcholine hemolytic anemia (HPCHA) is reported. The propositus was a 48-year-old woman, who had been followed up as hemolytic anemia of unknown origin and undergone splenectomy. She showed no improvement after splenectomy. She also had primary biliary cirrhosis, of which a diagnosis was made based on laboratory data and liver biopsy. Red cell morphology demonstrated stomatocytosis with erythroid hyperplasia in the bone marrow. Abnormal hemoglobins and the red cell enzyme activities were not demonstrated. A marked abnormality was noted in red cell membrane lipids, specifically the elevation of phosphatidylcholine (PC) and free cholesterol (FC), despite of normal plasma lipids and lecithin cholesterol acyltransferase activity. Sodium transport, both influx and efflux, was increased. Therefore, the diagnosis of HPCHA was confirmed. The three additional cases were found in her pedigree. The data on the red cells of her mother and elder sister were similar to hers with respect to the red cell lipids and sodium transport. The propositus and her mother showed no improvement of anemia or icterus after splenectomy. There are only three reports of the family with HPCHA in the world.

Anemia, Hemolytic, Congenital↗
PubMed1990

Hemoglobin Calais [beta 76 (E20) Ala----Pro]: a hemoglobin variant with decreased intrinsic oxygen affinity.

Hb Calais [beta 76 (E20) Ala----Pro] is a new human hemoglobin variant displaying a decreased oxygen affinity. The only electrophoretical difference with Hb A was a slightly more acidic isoelectric point. A 2-fold decrease in the oxygen affinity was found by equilibrium measurements performed in a suspension of intact red blood cells and in the lysate. It was confirmed by kinetic studies of the purified abnormal hemoglobin. The rate of methemoglobin formation at 37 degrees C of Hb Calais was also increased relative to Hb A. The mechanism by which the Pro for Ala substitution of an external residue in the beta-chains results in these profound functional abnormalities is unclear. Subtle changes at the heme pocket, at a distance from the mutation, may be a plausible explanation for the effects observed.

Adult↗
PubMed2001

Laboratory screening for electrolyte abnormalities and anemia in bulimia nervosa: a controlled study.

OBJECTIVE: Abnormal eating patterns and recurrent purging behaviors can result in significant medical complications. The purpose of this study was to assess the frequency of abnormalities in clinical laboratory tests in patients with bulimia nervosa who reported being otherwise in good health. METHODS: Subjects included nonhospitalized women (N = 74) who met criteria for bulimia nervosa outlined in the 3rd Rev. ed. of the Diagnostic and Statistical Manual of Mental Disorders. They also reported use of self-induced vomiting and/or laxatives as compensatory behaviors (purging subtype). The control group (N = 110) included female volunteers with no history of a psychiatric disorder. All subjects reported being in good medical health, were medication free, and were in a normal weight range. Blood samples were analyzed in the hospital clinical laboratory. RESULTS: Compared with controls, patients showed more frequent occurrence of low values for serum potassium (6.8% vs. 0.9%; p <.05) and chloride (8.1% vs. 0.9%; p <.02). Electrolyte abnormalities occurred most often in patients with frequent bulimic episodes. Study groups did not differ significantly in frequency of abnormal hemoglobin concentrations. DISCUSSION: These results help to clarify the expected frequency of electrolyte abnormalities in individuals with bulimia nervosa who report otherwise good medical health. The substantial frequency of hypokalemia and hypochloremia underscores the importance of an appropriate medical assessment for individuals with this disorder.

Adult↗
PubMed1979

Studies on a family with Hb J Calabria (alpha 2 beta 2 64 (E8) Gly replaced by Asp).

Hb J Calabria is a fast moving hemoglobin variant which was found in an Italian family by Vecchio et al (1), and in a French family by Blouquit et al. who studied its functional properties (2). The original family described by Vecchio et al. in which both Hb J Calabria and beta-thalassemia were present has been reexamined and is the subject of the present study. Hematological and clinical features of the carriers are described. The heterozygous carriers of Hb J Calabria showed only mild variable subclinical anemia and levels of the abnormal hemoglobin ranging from about 33 to 42%. The Hb J Calabria/beta-thalassemia double heterozygote showed a moderate chronic hemolytic anemia with alterations of the RBC indices and morphology in addition to splenomegaly. The relationship between structural abnormality, functional properties and clinical expression of Hb J Calabria is discussed.

Aged↗
PubMed1991

Electrospray mass spectrometry in the clinical diagnosis of variant hemoglobins.

A combination of mass spectrometric (MS) techniques [electrospray MS, liquid secondary ion MS (LSIMS) and MS-MS] has been used for variant hemoglobin (Hb) detection and characterization. Electrospray MS allowed analysis of mixtures of intact globins giving simultaneously the molecular weights (accuracy 1-2 Da) and information about relative amounts of globins present. Currently, 14 Da is the minimum molecular weight difference required experimentally to accurately measure different species present in a mixture of 15-16 kDa proteins. Thus 80 and 79% of the known variants of alpha and beta chains, respectively, can be detected in mixtures with their normal counterparts, including Hb S (molecular weight difference = 30 Da). Abnormal hemoglobins detected were fractionated by C4 reversed-phase high-performance liquid chromatography (HPLC), and the separated globin chains (or the mixture of whole precipitated globin) were digested by trypsin. The tryptic peptides were separated by C18 reversed-phase HPLC and analyzed by LSIMS to narrow down the mutation site to a single peptide. The mass measured in LSIMS frequently corresponded to a unique structure, thus giving the unequivocal identification of the mutation and its site. Where there was ambiguity, tandem MS on a Kratos Concept four-sector instrument was used for sequencing the abnormal peptide. The practical use of the methodologies presented is illustrated through analysis and identification of Hb G-San Jose, Hb Stanleyville II, Hb S and Hb Willamette.

Amino Acid Sequence↗
PubMed1999

[Molecular and cellular pathophysiology of sickle cell anemia].

The beta S mutation responsible for sickle cell disease (SCD) was identified in 1949. This mutation always consists in a T for A substitution at codon 6 of the beta-globin chain. Deoxygenated HbS becomes polymerized, producing erythrocyte shape changes and vasoocclusion. Still unexplained is the wide variability in clinical expression of SCD, whose spectrum ranges from severely incapacitating forms to virtually silent forms. Recent research has focused on genetic or environmental factors that may interfere with one or more steps of the basic pathophysiologic mechanisms. These factors can be roughly classified in three groups: i) factors that modify HbS levels within erythrocytes, thereby impacting the propensity of HbS for polymerization; ii) other normal or abnormal hemoglobins present in the erythrocyte that may modify side contacts of the hemoglobin molecule within the polymer, thus either stopping or enhancing polymerization; iii) molecules other than hemoglobin expressed at the surface of the SCD reticulocytes that may adhere to the vascular endothelium, thus slowing flow in the microcirculation and delaying HbS reoxygenation. Whatever the starting point, the same vicious circle is set in motion. These mechanisms have generally been studied separately, in vitro, under artificial conditions. An important goal is to understand how they interact in vivo in a given patient.

Anemia, Sickle Cell↗