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PubMed2006

[Diagnosis and gene analysis of congenital hemolytic anemia].

Congenital hemolytic anemia is relatively uncommon and tends to be left undiagnosed because unusual special tests outside health insurance adaptation are needed for the diagnosis. To diagnose properly these patients, we instituted a comprehensive examination system for hemolytic anemia in Fukuoka University Hospital in 1990. In addition to basic laboratory tests, investigation of hemoglobin, SDS-PAGE analysis of red blood cell membrane proteins, a complete panel of red cell enzyme measurements and gene analysis were included. The red cell enzyme measurements was facilitated by the automation on the COBAS MIRA instrument (NIPPON ROCHE). By such a comprehensive examination, we have identified and confirmed 382 cases of congenital hemolytic anemia which otherwise would have escaped detection during the period October 1990 to September 2005 in our institution. SDS-PAGE procedure contributed to the diagnosis of 24 cases of band 3 deficiency, 13 cases of band 4.2 deficiency and 13 cases of band 4.1 deficiency. Hemoglobin studies uncovered 20 cases of abnormal hemoglobins, 126 cases of beta thalassemia and 7 cases of alpha thalassemia. Red cell enzyme measurements were also contributory to the diagnosis of 29 cases of hemolytic anemia in which enzyme levels were reduced.

Anemia, Hemolytic, Congenital↗

PubMed1995

[Clinical pharmacology of hydroxyurea].

Hydroxyurea, an antineoplastic drug evaluated clinically more than 30 years ago, is still the principal drug in patients with myeloproliferative syndromes. It is suggested now that it should be used as initial therapy for chronic myelogenous leukemia. Recently hydroxyurea is used in the treatment of patients with sickle cell disease. It has been shown to augment production of fetal hemoglobin and decrease the propensity of abnormal hemoglobin to polymerize and from the sickle cells in this way.

Anemia, Sickle Cell↗

PubMed1988

Hyperunstable hemoglobin Koriyama anti-Hb Gun Hill insertion of five residues in the beta chain.

A new hyperunstable hemoglobin was found in a Japanese girl who had very severe, chronic hemolytic anemia. Her parents and siblings were hematologically normal. The abnormal hemoglobin comprised a very small proportion of the total hemoglobin, although it was produced almost at the same rate as normal hemoglobin. Sequencing of an abnormal peptide which was liberated from the beta chain by hydrolysis with a protease from Staphylococcus aureus V8 disclosed the tandem insertion of a five-residue segment which included the proximal histidine at beta 92(F8).

Amino Acid Sequence↗

PubMed1992

A novel beta-globin structural mutant, Hb Brescia (beta 114 Leu-Pro), causing a severe beta-thalassemia intermedia phenotype.

This study describes a patient with a thalassemia intermedia-like phenotype in whom beta-globin gene sequencing detected a novel abnormal hemoglobin (Hb) due to a T-C substitution at codon 114 of the beta-globin gene arising as a de novo mutation. The abnormal variant was designated Hb Brescia after the place of birth of the propositus. Normal sequences were detected at the in trans beta-globin locus. In addition, alpha-globin gene analysis detected a triple alpha-globin locus which was inherited from the father. The T-C change at position 114 of the beta-globin gene results in a leucine to proline substitution (Leu-Pro) in the G-helix. The resulting Hb tetramer is highly unstable and precipitates forming inclusion bodies in the peripheral red blood cells. Moreover, the Leu-Pro substitution interferes negatively with the four alpha 1 beta 1 contact points of the G-helix most likely adversely affecting the alpha beta dimer formation. The very severe phenotype presented by our patient is unusual in a heterozygote for an unstable Hb variant and may be explained by the coinheritance of the triple alpha-globin locus.

Adolescent↗

PubMed1980

Hemoglobin Legnano (alpha 2 141 (HC3) Arg leads to Leu beta2) a new high oxygen affinity variant. Functional and structural studies.

Hb Legnano (alpha 2 141 (HC3) Arg leads to Leu beta 2) is an abnormal hemoglobin, for which preliminary structural and functional studies demonstrated an amino acid substitution (Arg leads to Leu) in the alpha-C-terminus. This substitution modifies the functional properties observed in whole blood as well as in red blood cells, as reported in this paper. On the basis of its pI, previously determined by analytical isoelectric focusing (IEF), Hb Legnano was purified on a preparative IEF slab. The purified fraction was subjected to functional ultracentrifugal studies under various conditions of pH and salt concentration. The findings are compared with those for Hb Suresnes (alpha 2 141 (HC3) Arg leads His beta2) and Hb-CPB, a normal hemoglobin in which the C-terminal alpha 141 Arg has been cleaved by carboxypeptidase B. Hb Legnano, like the other hemoglobins considered, shows an increased P50, a decreased Hill's "n" values and a decreased Bohr effect that are partially restored in presence of organic phosphates. The presence of inorganic ions decreases the Bohr effect and enhances the dissociation into dimers, as observed in Hb-CPB. The dissociation of hemoglobin in carboxy form in ultracentrifugal studies and the different slope of Hill's "n" value as a function of pH are presumably due to presence of Leu, which probably modifies the stereochemistry of the variant.

Amino Acids↗

PubMed1990

A new alpha chain variant Hb Tonosho [alpha 110(G17)Ala----Thr]: subunit dissociation during cation exchange chromatography for Hb A1c assay.

A new alpha chain variant, alpha 110(G17)Ala----Thr, was detected because of subunit dissociation during the determination of the Hb A1c by automated cation exchange high performance liquid chromatography. The abnormal hemoglobin overlapped the cathodic edge of the band of Hb A in isoelectrofocusing. It was slightly unstable in the isopropanol test and had a slightly increased oxygen affinity. The abnormal alpha chain eluted slightly faster than the normal alpha chain in reversed phase high performance liquid chromatography. The amino acid substitution was determined by purification of S-alkylated alpha T-12,13 tryptic peptide, chymotryptic digestion, and sequencing of an octapeptide alpha 110-117. The abnormal alpha chain comprised about 14% of the total alpha chain. A biosynthetic study did not suggest selective loss of the abnormal chain in reticulocytes.

Adult↗

PubMed1988

Hemoglobin constant spring defined by specific oligonucleotide hybridization and hemoglobin D Punjab (beta 121----Gln) in a Batak Indonesian family.

A Batak Indonesian from North Sumatra with hemoglobin (Hb) D Punjab (alpha 2 beta 2 121----Gln) and hemoglobin Constant Spring (Hb CoSp) is described. The 24-year-old man did not have clinical symptoms, and his hematological indices were normal. However, he had a persistent slight elevation of fetal hemoglobin level. His mother and his brother were heterozygous for Hb D Punjab; his father had Hb CoSp trait. A sister did not have any abnormal hemoglobin. To show the exact molecular defect leading to the synthesis of Hb CoSp in this family, genomic DNA from the father was analyzed by hybridization with synthetic oligonucleotides. Genomic DNA was digested with Sst I and Hind III producing a 1.05-kb fragment from the 3' end segment of the alpha 2-globin gene, including the termination codon. Two nonadecamers were synthesized to serve as probes: one, entirely homologous to the normal 3' end of alpha 2A-globin gene sequence, including the termination codon TAA, the other different from it by a replacement of the T in the termination codon TAA with C, changing it to CAA, the codon for the amino acid glutamine. DNA from normal controls gave a positive signal with the normal alpha 2TAA oligonucleotide probe but negative with the alpha 2 CAA probe. The father of propositus who had Hb CoSp trait gave a positive signal with the normal alpha 2TAA oligonucleotide probe as well as with the alpha 2CAA oligonucleotide probe, showing him to be heterozygous for the alpha 2CAA-globin gene. This result shows that the Hb CoSp in the Batak family is indeed due to a replacement of T by C in the TAA termination codon of the alpha 2-globin gene changing it to CAA the condon for glutamine. This explains the resulting readthrough of the untranslated sequence of the mRNA.

Adult↗

PubMed2006

Two independent origins of Hb Dhonburi (Neapolis) [beta 126 (H4) Val-->Gly]: an electrophoretically silent hemoglobin variant.

BACKGROUND: A beta-hemoglobin variant (beta 126 (H4) Val-->Gly) was reported from Thailand and Naples (Southern Italy) as Hb Dhonburi (1) and Hb Neapolis (2), respectively. This abnormal hemoglobin, resulting from a valine to glycine substitution in the contact region between alpha and beta subunits, gives rise to instability at non-physiological conditions. However, it was difficult to distinguish this variant from Hb A using hemoglobin electrophoresis and cation exchange liquid chromatography. Hb Dhonburi was rarely reported, possibly due to a relatively milder phenotype in heterozygote with slightly decreased MCV. Thus several Hb Dhonburi carriers might have been under-diagnosed. METHODS: Combined molecular analyses by PCR-single strand conformation polymorphism (PCR-SSCP) and direct genomic sequencing of the beta globin genes were carried out in 2 pediatric patients with mild thalassemia intermedia. A novel amplification refractory mutation system (ARMS-PCR) was developed and performed in five individuals with microcytosis and borderline Hb A(2). RESULTS: Both patients were compound heterozygotes for Hb E and Hb Dhonburi. In addition, 5 Hb Dhonburi heterozygotes, including 3 identified through thalassemia carrier screening, were identified by ARMS-PCR. Linkage analysis of the affected families revealed that the haplotype of Hb Dhonburi in Thailand (VII) was different from that of Hb Neapolis (V) suggesting 2 independent mutational events. CONCLUSIONS: The molecular strategy described provides a robust and economical measure, alternative to the whole beta globin genes sequencing, to identify rare or unknown beta globin mutations. To overcome its 'silent' nature on electrophoresis, we proposed a novel ARMS-PCR for a rapid diagnosis of Hb Dhonburi in future cases.

Amino Acid Sequence↗

PubMed1966

Ocular manifestations of hemoglobin S-C disease.

Three patients with hemoglobin S-C disease, all with ocular lesions, were studied and contrasted with four other patients who had predominantly either hemoglobin S or C but no ocular lesions. Attention is drawn to the diagnostic value of hemoglobin electrophoresis in such cases. With this technique a diagnosis of hemoglobin S-C disease was made in a patient previously thought to the "Eales' disease"; one sister was found to have asymptomatic hemoglobin S-C disease and unsuspected early ocular lesions. The number of persons in Canada with hemoglobinopathies is increasing. Awareness of an association between abnormal hemoglobins and ocular disease may lead to the recognition of an unsuspected blood disorder or of an unsuspected retinopathy.

Adrenal Cortex Hormones↗

PubMed1985

The interaction of hemoglobin O Arab with Hb S and beta+ thalassemia among Israeli Arabs.

We have studied 105 individuals in the village of Jasser El Zarka in the Northern Coast of Israel of whom 59% had at least one abnormal hemoglobin. Of the individuals studied 41% were AA, 13.3% AS, 28.6% AOArab, 10.5% SOArab, 0.9% SS, 38% OArab-beta + Thal, and 1.9% beta Thal trait. The SOArab double heterozygotes were characterized by a normal mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC), and an increase of Hb F (11.7 +/- 4.3%) and 2,3-diphosphoglycerate levels (27.8 microns/g Hb). The increase of Hb F is higher than the one seen among OArabs of other ethnic backgrounds. Their clinical course was moderately severe and osteoporosis was quite frequent. The interactions of Hb OArab and Hb S were studied in vitro and it was confirmed the Hb OArab lowers the minimal gelling concentration of mixtures with Hb S (as compared to mixtures of Hb S and Hb A), but that this effect is ionic-strength dependent. Our data are in conflict with previous claims that Hb OArab mixtures with Hb S polymerized almost as much as pure S. Oxygen association curves show a significant displacement of the p50 to the right, but the effect of oxygen dissociation is less apparent. The displacement was not nearly as significant as with SS cells, confirming our gelation data. Blood group determinations establish that these Arab populations had black African admixture. The Hb OArab/beta + Thal double heterozygotes exhibit moderate anemia (10.3 g% of Hb) and the percentage of Hb A was 17.2 +/- 1.8%. The fetal Hb was 5.4 +/- 2.1% and the 2,3-diphosphoglycerate level in two cases was 17.4 mumol/g Hb. The only case of a homozygote SS had moderate anemia (10.3g Hb%), 25.7% of Hb F, and a very benign course.

Adolescent↗

PubMed2002

Allele related mutation specific-polymerase chain reaction for rapid diagnosis of Hb New York (beta 113 (G15) Val-->Glu, beta(CD113 GTG-->GAG)).

Hemoglobin New York (beta 113 (G15) Val-->Glu), a beta-globin variant, was first reported in a Chinese family living in New York. Subsequently, this abnormal hemoglobin was reported in many Chinese descendants from several groups and it was also known as Hb Kaohsiung. The subtle change in alpha1beta1 contact region apart from the heme group connecting area by Val-->Glu substitution has minor changes in both the electrophoretic mobility and stability making this hemoglobin variant difficult to distinguish from Hb A using routine hemoglobin analysis. The authors described a case of heterozygosity of Hb New York diagnosed by a molecular technique and revealed a mutation in beta(CD113 GTG-->GAG). A novel Allele Related Mutation Specific-Polymerase Chain Reaction (ARMS-PCR) for rapid diagnosis of this mutation has been proposed.

Adult↗

PubMed1977

Sulfonamide-induced hemolytic anemia and hemoglobin Hasharon.

A patient with Hb Hasharon had severe hemolytic anemia after several days of daily ingestion of 2 gm of sulfisoxazole. After recovery, her erythrocytes were incubated with the drug, leading to preferential oxidation and precipitation of the abnormal hemoglobin. Since carboxyhemoglobin and cyanmethemoglobin Hasharon were as stable in the heat stability test as identically liganded Hb A, we conclude that the substitution of the hydrophilic aspartate residue by histidine on the surface of the molecule at alpha47 has led by a still unknown mechanism to an interaction of hemoglobin with the drug that labilized the heme-globin bond. Since Hb Hasharon has been found in several unrelated families, the risk of drug-induced hemolytic anemia in such carriers deserves emphasis.

Anemia, Hemolytic↗

PubMed1972

Hemoglobin Malmö Beta-97 (FG-4) histidine--glutamine: a cause of polycythemia.

A striking history of familial polycythemia led to a search for an abnormal hemoglobin. None could be demonstrated by routine electrophoretic methods, but the propositus' hemolysate had increased oxygen affinity. Manipulation of the conditions of electrophoresis, and chromatographic methods, permitted identification of hemoglobin Malmö. Studies of hemolysates demonstrated a normal Bohr effect, decreased heme-heme interaction (n=1.58), and a p50 of 1.3 mm Hg at 10 degrees C and pH 7.2. The amino acid substitution occurs in the same position (FG-4) as that of hemoglobin Chesapeake, but in the beta-chain rather than the alpha-chain. The two types of hemolysate have different pathophysiologic properties, and carriers of hemoglobin Malmö exhibit more striking hematologic abnormalities.

Amino Acid Sequence↗

PubMed1986

Hemoglobin Woodville: alpha (2)6(A4) aspartic acid----tyrosine.

Hemoglobin Woodville was detected in a Vietnamese woman during antenatal and cord blood screening programs for families of South East Asian origin. The variant constitutes 9% of total hemoglobin and structural analysis demonstrated the substitution alpha 6 Asp----Tyr. Hematological data on the proposita were normal. No apparent clinical or pathological findings were associated with this abnormal hemoglobin.

Adult↗

PubMed1990

Hb south Milwaukee [beta 105 (G7) Leu----Phe]: a newly-identified hemoglobin variant with high oxygen affinity.

Fifteen individuals among four generations of a family of English ancestry demonstrated elevated hemoglobin levels accompanied by leftward-shifted whole blood oxygen equilibrium curves. Five of the affected family members have required phlebotomies for relief of symptoms attributable to erythrocytosis. An abnormal hemoglobin or globin chain could not be isolated, but 43% of the beta chains of the affected individuals contained a Leu----Phe substitution at position 105 (G7). Oxygen equilibrium curves demonstrated a normal Bohr effect but decreased cooperativity.

Adult↗

PubMed1975

Hemoglobin Atlanta or alpha 2 beta 2 75 Leu-Pro (E19): an unstable variant found in several members of a Caucasian family.

Hemoglobin Atlanta, alpha 2 beta 2 75 Leu-Pro (E19), has been found in several members of three generations of a Caucasian family living in metropolitan Atlanta. The abnormal hemoglobin is one of the nine unstable variants in which either a leucyl or an alanyl residue is replaced by a prolyl residue. These substitutions have been observed in the B, E, F, and G helixes of the beta chain and in the H helix of the alpha-chain. Hemoglobin Atlanta heterozygotes are mildly affected by the presence of this unstable hemoglobin.

Alanine↗

PubMed1998

HB Les Andelys [alpha83(F4)LEU-->PRO]: a new moderately unstable variant.

Hb Les Andelys [alpha83(F4)Leu-->Pro] is a mildly unstable variant that was found during glycated hemoglobin measurement in a French family. In this hemoglobin molecule the affected site, in the alpha chain, and the amino acid substitution are identical to those of Hb Santa Ana, an unstable beta chain variant. The structural abnormality was demonstrated by protein chemistry methods, involving, in addition to the classical techniques, a selective precipitation of the abnormal hemoglobin by isopropanol and a mass spectrometry analysis of the alphaT-9 peptide following carboxypeptidase digestion. DNA sequencing demonstrated that the mutation was CTG-->CCG at codon 83 of the alpha2 gene.

Amino Acid Sequence↗

PubMed1980

Carboxymethyl-cellulose microchromatography for the quantitation of hemoglobin Bart's (gamma 4) and its use in the detection of the alpha-thalassemia conditions.

A modification of an existing (micro) CM-cellulose chromatographic procedure is introduced for the quantitation of hemoglobin Bart's (or gamma 4) in blood samples of newborn babies. Normal newborn with four active alpha chain genes (alpha alpha/alpha alpha) have small amounts (average 0.55%) of this abnormal hemoglobin while increased percentages are present in newborn with an alpha-thalassemia-2 heterozygosity (alpha 0 alpha/alpha alpha; average 1.55%) or an alpha-thalassemia-2 homozygosity (alpha 0 alpha/alpha 0 alpha; average 4.65%). The identification of hemoglobin Bart's in normal newborn was made by high-performance liquid chromatography, and the absence of contaminating non-hemoglobin proteins was confirmed by electrophoresis and additional chromatographic experiments. This rapid procedure is useful for the detection and differentiation at time of birth of the different alpha chain deficiencies which are common among various populations in the world.

Chromatography↗