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Sickle cell trait and aviation.

Sickle cell trait is a benign genetic abnormality which has been wrongly projected as a health hazard in aviation. Conflicting reports on the relationship between this trait and flying exist in the literature. Limitations placed on sickle trait individuals unfairly stigmatize large numbers of people, both socially and economically. The imprecise identification of the sickle hemoglobinopathies and unrecognized interactions of other abnormal hemoglobins with hemoglobin S have perpetuated the controversy. There is a tendency to use isolated anecdotal incidents as evidence of increased morbidity in sickle cell trait; however, it has not been documented that hypoxic conditions cause in vivo sickling in pure trait carriers. An analysis of the definitions of the hemoglobinopathies, the molecular basis of hemoglobin S, the interactions of abnormal hemoglobins, and the sickling phenomenon shows both that there is no evidence that the sickle trait is a health hazard and that most of the literature contrary to this finding is invalid.

Aerospace Medicine↗

A new unstable, high oxygen affinity hemoglobin: Hb Nagoya or beta 97 (FG4) His----Pro.

An unstable hemoglobin was detected by isopropanol and heat precipitation tests in a 49-year-old Japanese man suffering from acute exacerbation of a chronic hemolytic disorder which was apparently triggered by infection of cholelithiasis. One of his two sons carried the same abnormal hemoglobin, and was jaundiced, but otherwise healthy, without anemia. The abnormal hemoglobin focused at a slightly more anodic position than Hb A in thin layer polyacrylamide gel electrofocusing. The abnormal beta chain emerged after normal beta chain in reverse phase high performance liquid chromatography of the hemolysate. It comprised 16.7% and 25.5% of the total beta chain in the propositus and his son, respectively. The partially heme-depleted abnormal beta subunit was precipitated with p-chloromercuribenzoic acid, and the abnormal beta chain was isolated by urea CM-cellulose column chromatography. Structural analysis demonstrated substitution of proline for histidine at position 97 (FG4) in the beta chain. The abnormal hemoglobin was purified by ion-exchange column chromatography. It showed a hyperbolic oxygen equilibrium curve indicating a high oxygen affinity and the absence of cooperative intersubunit interaction. Subunit dissociation seemed to be slightly enhanced. The variant was markedly susceptible to oxidation and rapidly lost heme upon oxidation.

Amino Acid Sequence↗

[Clinical, structural and functional studies of HbG Philadelphia detected in a Moroccan newborn].

Hb G Philadelphia (alpha68 Asn leads to Lys) is widely distributed in black people but is uncommon in North-Africa. Only one case has been previously described in an Arab immigrant. The latter and our propositus originated from North-East morocco. Hb G alpha Philadelphia is stable. The abnormal hemoglobin represented 28% of total hemoglobin in the hemolysate of the propositus, a 7 month old child. At birth, 4 fractions were detected on electrophoresis: Hb A, Hb F, Hb G Philadelphia, which migrated like Hb S, and a mutant alpha2Ggamma2. The oxygen affinity of Hb G Philadelphia was slightly elevated. Cooperativity and Bohr effect were normal. The abnormal hemoglobin was also detected in the father of the propositus in the heterozygote state: its clinical and hematological data were normal. No evidence of thalassemia trait was found in the family. The percentage of abnormal hemoglobin obtained in the propositus and his father is in accordance with the presence of two loci for the alpha chain on the homologous chromosome.

Electrophoresis, Cellulose Acetate↗

Hb Bart's level in cord blood and deletions of alpha-globin genes.

The white blood cell DNA of 36 cord blood samples with Hb Bart's in the red blood cells was studied for alpha-globin gene deletions by hybridization of DNA fragments digested by the restriction endonucleases Eco RI, Hpa I, Bam HI, and Bgl II. All 16 DNA samples from cord blood with Hb Bart's below 3% and no other abnormal hemoglobin had one alpha-globin gene deletion (alpha thal2), except one which had two alpha-globin gene deletions (alpha thal1). Most of the alpha thal2 were of the rightward deletion alpha thal2 genotype. Two new types of alpha thal2 variation was found, probably due to a polymorphism somewhere in an area outside the alpha-globin gene. All 14 cases with Hb Bart's between 3.5% and 8.5% and no other abnormal hemoglobin had two alpha-globin gene deletions (alpha thal1), except one that did not have any alpha-globin gene deletion and one that had one alpha-globin gene deletion. Three DNA samples of cord blood with Hb Bart's accompanied by Hb CoSp did not have any alpha-globin gene deletion. Sixty-five DNA samples from cord blood without Hb Bart's or other abnormal hemoglobin had no alpha-globin gene deletions, except one that had one alpha-globin gene deletion (alpha thal2). Two of the 65 DNA samples were found to have triplicated alpha-globin gene loci.

DNA↗

Hemoglobin Pyrgos (beta83 Gly replaced by Asp) in a Japanese family.

A screening survey for abnormal hemoglobins at a hospital in Mizunami city, Gifu prefecture, Japan detected a fast-moving variant of hemoglobin in a family of Japanese origin. The abnormal hemoglobin constitutes about 45 percent of the total hemoglobin from the propositus and another carrier in the family, but neither of these persons had anemia, jaundice, cyanosis or splenomegaly. Structural analysis of this hemoglobin revealed that the amino acid substitution was at residue 83 in the beta chain, where a glycine was replaced by an aspartic acid. This hemoglobin variant has been previously reported in a Greek child (hemoglobin Pyrgos) (1). Oxygen affinity of hemoglobin Pyrgos was found to be normal.

Aged↗

Role of height and glycosylated hemoglobin in abnormal nerve conduction in pediatric patients with type I diabetes mellitus after 4-9 yr of disease.

OBJECTIVE: To determine the role of height and glycosylated hemoglobin in abnormal nerve conduction in pediatric patients with insulin-dependent (type I) diabetes mellitus. RESEARCH DESIGN AND METHODS: Sixty-six pediatric patients (aged 6.3-18.2 yr) with a duration of diabetes from 4 to 8.5 yr but free of clinical neuropathy were evaluated for abnormal nerve conduction. RESULTS: Mean HbA1 values for 1 and 2 yr before study were available. Electroneurographic findings were significantly different from control subjects in upper and lower extremities and included all five measured velocities, three sensory latencies, and one amplitude. Stepwise regression analysis identified an adverse effect of height on latency (5 of 6) and of mean HbA1 concentration on decreasing velocity (4 of 5). The data analysis from 52 patients who were restudied and who had a duration of diabetes from 5.3 to 9.6 yr confirmed that all velocity values slowed; one of five values did so significantly. The coefficients associated with mean HbA1 concentration usually increased in both upper- and lower-extremity velocity analyses at the follow-up examination. The change in peroneal motor velocity between the first and last examinations was significantly related to the increasing time interval between examinations. CONCLUSIONS: Prospective evaluation of nerve conduction parameters in pediatric patients with diabetes should include both height (the most significant independent variable in latency analysis) and mean glycemic control (the most consistent variable in velocity analyses) as variables in the assessment of the natural history of evolving peripheral neuropathy.

Body Height↗

Gamma chain variants in Jamaican newborns.

15,661 cord bloods from Jamaican infants were examined for abnormal hemoglobins using alkaline cellulose acetate electrophoresis for the initial screening, supplemented by acid agar gel electrophoresis for samples exhibiting abnormal hemoglobin bands. Of the 16 electrophoretic variants which were detected, six were fully characterized and found to be: four Hb F Port Royal (alpha2 Ggamma2 125 Glu replaced by Ala) and two Hb F Victoria Jubilee (alpha2Agamma2 80 Asp replaced by Tyr). The Hb F Port Royal samples each constituted about one eighth of the total Hb F as did seven additional samples presumed to be Hb F Port Royal. The infants with this variant exhibited no special hematological characteristics or other consistent associations. Both Hb F Victoria Jubilee samples occurred in somewhat lower proportions of the total Hb F compared with Hb F Port Royal and exhibited an apparent increase of free alpha chains in the whole hemolysate. The data available on detectable gamma chain variants suggest that a specific point mutation may occur in either a HbGgamma or a HbAgamma locus.

Chromatography, Gel↗

Structure of the EF corner favors deamidation of asparaginyl residues in hemoglobin: the example of Hb La Roche-sur-Yon [beta 81 (EF5) Leu----His].

Some abnormal hemoglobins constitute models which allow one to evaluate the structural requirements for post-translational modifications in proteins, such as deamidation. Hb La Roche-sur-Yon [beta 81 (EF5) Leu----His] is an unstable hemoglobin variant displaying a moderately increased oxygen affinity. About half of the abnormal hemoglobin, in addition to the substitution at position beta 81, carries a deamidation of the neighboring asparagine residue, beta 80 (EF4). The histidine at position beta 81 cannot fit into the small hydrophobic pocket which normally accomodates the leucine residue. This structural change opens the heme pocket and modifies the general conformation of the EF segment, thus explaining the increase in oxygen affinity and the achievement of a three-dimensional structure favoring asparagine deamidation. Histidine beta 81 could also act as a catalyst in the deamidation reaction. Deamidation has already been reported for two other variants of the EF corner, Hb Providence [beta 82 (EF6) Lys----Asn] and Hb J Singapore [alpha 79 (EF8) Ala----Gly]. In all these cases it seems that a histidine may catalyze the deamidation of the asparagine residues and that disturbing the folding of the EF corner will provide an extra flexibility favoring the reaction.

Adolescent↗

Hemoglobin Nigeria (alpha-81 Ser replaced by Cys):a new variant associated with alpha-thalassemia.

Hematologic evaluation of a Nigerian obstetrical patient disclosed the presence of sickle-cell trait as well as evidence of a hemoglobin alpha-chain abnormality. Hemoglobins containing the variant alpha-chain were isolated by DEAE-cellulose column chromatography, and analysis of the purified alpha-chain demonstrated a ser replaced by cys substitution at alpha-81. The abnormal alpha-chain represented approximately 45% of the total, and hemoglobins containing this alpha-chain appeared to have normal stability and functional properties. In addition to the abnormal hemoglobins that were identified in this patient, she also was found to have persistent microcytosis in the absence of iron deficiency, and the percentage of HbS in her erythrocytes was less than that usually present in individuals with sickle cell trait. These findings, together with a reduced alpha/beta globin synthesis ratio from her peripheral blood reticulocytes, indicated that the presence of alpha-thalassemia trait. Hematologic findings from members of the patients's family suggest that an alpha-thalassemia gene may be linked to that of the structurally abnormal alpha-chain.

Absorption↗

Low proportions of glycosylated hemoglobin associated with hemoglobin S and hemoglobin C.

Using a cation-exchange chromatographic method, we found normal or subnormal values for glycosylated hemoglobin in a few diabetic patients with persistent hyperglycemia. Subsequent investigations revealed that these unexpected results had originated from black patients with diabetes. In view of common occurrence of abnormal hemoglobins in the Negro population, we subjected blood preparations to electrophoresis on cellulose acetate and acrylamide gel. The results have shown the presence of hemoglobin S or hemoglobin C in each patient. When allowance was made for the percentage of the abnormal hemoglobin, the "corrected values" of glycosylated hemoglobin increased to the diabetic range. Furthermore, the corrected values agreed well with the "expected values" calculated from a regression line correlating fasting blood glucose concentrations and proportions of glycosylated hemoglobin in more than 300 diabetics with no evidence of hemoglobinopathy. We conclude that in diabetic patients presenting with hemoglobin S or hemoglobin C, there is a considerable decrease in the values for glycosylated hemoglobin as measured by cation-exchange chromatographic methods, and that this decrease is proportional to the percentage of the abnormal hemoglobin.

Blood Glucose↗

Hemoglobin Beth Israel. A mutant causing clinically apparent cyanosis.

We found that an abnormal hemoglobin with a very low oxygen affinity was responsible for overt cyanosis in an otherwise healthy adolescent. Hemoglobin Beth Israel, in which serine replaces the asparagine residue normally present at position 102 (G4) of the beta-polypeptide chain, was associated with normal blood counts and no apparent exercise intolerance in the heterozygous carrier. Cyanosis resulted from a drastically right-shifted oxygen dissociation curve, whose position and shape could account for the absence of "physiologic" anemia. The whole-blood oxygen tension at 50 per cent oxygen saturation was 88 mm Hg (normally 26 +/- 1 mm Hg), and the arterial blood was only 63 per cent saturated with oxygen despite a normal oxygen tension of 97 mm Hg. The hemolysate showed a low oxygen affinity but normal Bohr effect. Unexplained cyanosis, particularly in association with normal arterial oxygen tension should prompt a search for an abnormal hemoglobin, which may obviate the need for invasive diagnostic procedures.

Adolescent↗

Hemoglobin E disease in pregnancy.

Abnormal hemoglobin patterns such as hemoglobin-E are rarely found in Western populations. The condition is fairly common in Southeast Asian countries such as Thailand, however. It is not commonly found in West Asian countries such as Saudi Arabia. A case report of hemoglobin E disease in pregnancy is made; its impact on pregnancy and labor is discussed.

Adult↗

Hb Isehara (or Hb Redondo) [beta 92 (F8) His----Asn]: an unstable variant with a proximal histidine substitution at the heme contact.

A 50-year-old Japanese female patient was found to have hemolytic anemia. Isoelectrofocusing of her hemolysate revealed two abnormal hemoglobin bands, one of which was very close to the Hb A2 band, and the other between the Hb A2 and Hb F bands. CM-cellulose column chromatography of the globin prepared from the abnormal hemoglobin showed that the abnormal chain eluted faster than the normal beta and delta chains; the beta X chain, however, did not separate from the normal beta chain in urea cellulose acetate electrophoresis. An instability test of the patient's hemolysate revealed the presence of an unstable component. Structural analysis of the abnormal beta chain indicated that the histidine residue at beta 92(F8) was replaced by an asparagine or aspartic acid residue. DNA amplified by polymerase chain reaction was sequenced by the dideoxy method. The nucleotide sequence of the beta 92 codon was AAC instead of CAC, suggesting that the amino acid substitution corresponded to His----Asn, which is the same as is found in Hb Redondo or beta 92(F8)His----Asn----Asp.

Amino Acid Sequence↗

Hb Miyano or alpha 41(C6)Thr----Ser: a new high oxygen affinity alpha chain variant found in an erythremic blood donor.

An abnormal hemoglobin found in an erythremic blood donor was separable only by isoelectrofocusing, where it was located at the cathodic edge of Hb A. Cation exchange high performance liquid chromatography of a tryptic digest from the total alpha chain revealed splitting of the alpha T-6 peak, although our routine procedures failed to uncover the abnormality. This enabled the chemical characterization and quantitation of the abnormal hemoglobin as alpha 41(C6)Thr----Ser comprising about 30% of the total hemoglobin. The purified hemoglobin showed increased oxygen affinity, decreased subunit cooperativity and effect of organic phosphates, and normal Bohr effect.

Amino Acid Sequence↗

Functional abnormalities of hemoglobin Toyoake (142 (H20)beta, Ala leads to Pro).

Oxygen equilibrium of Hb Toyoake (142 (H20)beta, Ala leads to Pro) is characterized by an oxygen affinity 6-times higher than that of Hb A, a slightly decreased alkaline Bohr effect, diminished cooperativity, with Hill's coefficient decreased by 1.2, and reduced response to 2,3-diphosphoglycerate and inositol hexaphosphate. These properties are in qualitative agreement with those shown previously from oxygen equilibrium data for hemolysate containing Hb Toyoake. The heat of oxygenation was -13.5 kcal/mol for Hb Toyoake and -12.9 kcal/mol for Hb A at pH 7.4 in 0.1 M Cl- and they became equal when corrected for the heat of oxygen-linked proton and Cl- release. OxyHb Toyoake autooxidized faster than oxyHb A. The visible absorption spectrum and electron paramagnetic resonance spectrum of oxidized Hb Toyake indicated that oxidation of this hemoglobin, either by autooxidation or by K3Fe(CN)6, is followed by gradual conversion into hemichrome derivatives. The soret peak of deoxyHb Toyoake was lowered compared to that of deoxyHb A and the magnitude of narrow-banded oxy-minus-deoxy difference spectrum around 290 nm was smaller for Hb Toyoake than for Hb A, indicating that the former remains predominantly in the R state upon deoxygenation. The functional abnormalities, including tendency to lose heme groups previously reported, were interpreted in terms of structural disturbance by proline at 142beta of 141 leucine, 143 histidine, 145 tyrosine, and 146 histidine residues of the same beta chain.

Diphosphoglyceric Acids↗

Reproductive profile of mothers in relation to hemoglobin E genotypes.

The reproductive profile of 190 Ahom-Kachari mothers belonging to Mongoloid ethnic stock of Assam has been studied in relation to hemoglobin (Hb) E genotypes. No significant variations have been observed in the reproductive performance between the normal population and abnormal hemoglobin homozygote (HbEE) and heterozygote (HbAE) mothers. However, the reproductive wastage among the hemoglobin homozygote (HbEE) mothers has been observed to be double than the normal hemoglobin (HbAA) and abnormal hemoglobin heterozygote (HbAE) mothers. The reproductive performance parameters have also been compared with the other available studies.

Child, Preschool↗