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The clinical significance of hemoglobinopathies in the Hamilton region: a twenty-year review.

Between 1970-1990, the Laboratory tested 38,391 specimens for hemoglobinopathies, of which 7,935 were positive. The major abnormalities detected were beta thalassemia trait (4,688), alpha thalassemia trait (1,248) and sickle cell trait (847). Clinically significant hemoglobinopathies detected were Hemoglobin H disease (100), sickle cell disease (67) and sickle cell Hemoglobin C disease (79). Hemoglobinopathies are therefore common in the Hamilton area as a reflection of the cultural diversity of area citizens. Of the 49 patients with thalassemia without documented iron deficiency, 8 (16%) received iron therapy for a variable period of time and 3 were investigated for gastrointestinal blood loss. Hemoglobin abnormalities cause or have the potential to cause clinical disease and they can, if not detected, result in unnecessary iron therapy or gastrointestinal investigation.

Hemoglobin C Disease↗

Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings.

We encountered an abnormal hemoglobin (Rahere), with a threonine residue replacing the beta 82 (EF6) lysine residue at the binding site of 2,3-diphosphoglycerate, which was responsible for overt erythrocytosis in two individuals of a Japanese family. Hemoglobin Rahere shows a lower oxygen affinity on the binding of 2,3-diphosphoglycerate or chloride ions than hemoglobin A. Although a decrease in the positive charge density at the binding sites of 2,3-diphosphoglycerate in hemoglobin Rahere apparently shifts the allosteric equilibrium toward the low affinity state, it greatly diminishes the cofactor effects by anions. The oxygen affinity of the patient's erythrocytes is substantially lowered by the presence of bezafibrate, which combines with sites different from those of 2,3-diphosphoglycerate in either hemoglobin Rahere or hemoglobin A.

2,3-Diphosphoglycerate↗

Hemoglobin Djelfa beta98 (FG 5) Val leads to Ala: isolation and functional properties of the heme saturated form.

Hemoglobin Djelfa beta98 (FG 5) Val leads to Ala is a neutrally substituted unstable hemoglobin, exhibiting the same gross features as hemoglobin Köln beta98 (FG 5) Val leads to Met. In addition to the presence of a deheminized fraction, a heme saturated abnormal hemoglobin was visualized and isolated by high resolution electrofocusing. By functional studies of the fully heminized form, a slightly increased oxygen affinity, an impairment of heme-heme interaction and a decreased response to organic phosphates were demonstrated. These functional perturbations point out the importance of the beta98 invariant valyl residue, in the quaternary contacts. They can account for the poor oxygen delivery of erythrocytes.

Alanine↗

Hemoglobin Sphakiá: a delta-chain variant of hemoglobin A2 from Crete.

A new variant of the normal minor component Hb A(2) has been detected in a family that lives in Sphakiá, Crete. Chemical studies of this abnormal hemoglobin, designated Hb A(2) delta Sphakiá, indicates a substitution of the histidyl residue number two of the delta-chain by an arginyl residue.

Adult↗

Hb Val de Marne [alpha 133(H16)Ser-->Arg]: a new hemoglobin variant with moderate increase in oxygen affinity.

Hb Val de Marne [alpha 133(H16)Ser-->Arg] was found in a French family during a neonatal hemoglobinopathy screening program. The abnormal hemoglobin was found, within a few months interval, in two newborn children who were first cousins. In the children as well as in the parents carrying this hemoglobin variant, the red cell parameters were normal. Hb Val de Marne, isolated by isoelectrofocusing, displayed a slightly higher auto-oxidation rate than Hb A. Its oxygen affinity was increased 1.7-fold in comparison to that of Hb A. The heterotropic effects were normal.

Adult↗

Hemoglobin variations on a small Bahamian island.

Hemoglobino characteristic were investigated in 492 blood specimens collected in a small island community (1,450 inhabitants) in the Bahamas. Using two different methods, abnormal variants were detected in 20.3% of the sample, including genotypes AS, AC, AF(A/HPFH), SC, and SF. Biodemographic evidence suggests that the origin and distribution of the hemoglobinpathies in this population have been influenced by historical migrations and genetic drift. The opportunity for drift has been particularly heightened by the "founder effect," the maintenance of small population size, a relatively endogamous mating structure, and restricted immigration. Health survey results reveal a wide discrepancy between the actual prevalence of abnormal hemoglobins and that indicated by informant reports.

Bahamas↗

Hb Villaverde [beta 89 (F5) Ser-->Thr]: the structural modification of an intrasubunit contact is responsible for a high oxygen affinity.

Hb Villaverde [beta 89 (F5) Ser-->Thr], identified in a Spanish patient, is a new human hemoglobin variant, electrophoreticaly silent, responsible for a severe erythrocytosis. This abnormal hemoglobin displays a very high oxygen affinity and a markedly reduced cooperativity that is partly restored in the presence of IHP. Determination of the structural abnormality was achieved on a mixture of the normal and abnormal beta-chains. After isolation of the abnormal tryptic peptide by RP-HPLC, its sequence was determined by mass spectrometry. The structural abnormality disturbs the intrasubunit interaction between helices F and H and, thus, may weaken the C-terminal bonds of the deoxy conformation and the heme contacts of several hydrophobic residues. Hb Villaverde demonstrates that this intrasubunit contact between helices F and H is essential for the cohesion of the hemoglobin molecule.

Adult↗

Hemoglobin Mizuho or beta 68 (E 12) leucine leads to proline, a new unstable variant associated with severe hemolytic anemia.

A hitherto undescribed, unstable hemoglobin was discovered in a four-year-old Japanese girl with relatively severe hemolytic anemia requiring monthly blood transfusion. Although no abnormal hemoglobin was detectable by electrophoresis at pH 8.6 and 7.0, heat denaturation and isopropanol tests gave positive results. Chemical analyses of the heat labile hemoglobin have demonstrated an amino acid substitution of a prolyl for the leucyl residue at the beta 68th (E 12) position. Remarkable clinical improvement was observed after splenectomy.

Amino Acid Sequence↗

Hemoglobin Miyashiro (beta 23[B5] val substituting for gly) an electrophoretically silent variant discovered by the isopropanol test.

A new unstable hemoglobin was discovered in a Japanese boy without any signs of hemolytic disease during screening of patients by the isopropanol test. The abnormal hemoglobin was found in three generations. This slightly unstable hemoglobin could not be separated from Hb A by electrophoresis. All carriers showed an increased whole blood oxygen affinity. Structural studies demonstrated a previously unreported amino acid substitution, beta 23[B5] valine substituting for glycine. This new unstable variant has been named Hb Miyashiro.

Adolescent↗

[Hemoglobin O Arab in Ivory Coast and western Africa].

The authors report 44 cases of hemoglobin O Arab share out in 3 phenotypes (A O Arab, C O Arab and S O Arab). The study of this abnormal hemoglobin has allowed the following conclusions: The Hb O Arab is a rare mutant of hemoglobin. The heterozygote form A O Arab and the association Hb C--Hb O Arab do not present any clinical and hematological manifestations. The associations Hb S--Hb O Arab brings about a serious hemoglobinopathy which has clinical and hematological features like the sickle-cell disease (SSFA2).

Adolescent↗

Isoelectric focusing of human hemoglobins.

Isoelectric focusing on thin layer of acrylamide gel has been used for the characterization of 79 different variants of hemoglobin A. This method has replaced the cellulose acetate electrophoresis in clinical laboratories in Martinique, Guadeloupe and Creteil for the detection of abnormal hemoglobins in populations at risk. Up to now 15,000 samples from adults have been evaluated. In addition this method has been used for the screening of 7,000 cord blood samples and for the prenatal diagnosis of severe hemoglobinopathies.

Adult↗

[Clinicohematologic effects of hemoglobin Altdorf (alpha 2 beta 2 135 Ala replaced by Pro)].

Hb Altdorf alpha 2 beta 2 135 Ala leads to Pro is an unstable variant occurring near Lecce in Italy. The abnormal hemoglobin does not separate from Hb A in the electrophoresis. In vitro a marked Heinz body formation is produced with phenylhydrazin. In heterozygous individuals an almost compensated hemolysis and a slight splenomegaly are found. Hemolysis can be aggravated by exogenous factors. A rather severe hemolysis was induced by a viral infection in a 3 years old girl.

Adolescent↗

Globin chain analysis by reversed phase high performance liquid chromatography: recent developments.

Reversed phase high performance liquid chromatography of globin chains is an important additional tool in the study of hemoglobin abnormalities. Using a technique modified from that of Leone et al.,[1] we report here the relative chromatographic behavior of about 200 different hemoglobin variants. This method provides an additional dimension in the presumptive characterization of hemoglobin variants. It was also found to be of special value for measuring the expression of neutral variants, such as thalassemic or unstable hemoglobins, and to identify neutral mutations associated with another variant, resulting in unusual hematological presentations.

Chromatography, High Pressure Liquid↗

Ontogenetic expression of larval and adult hemoglobin phenotypes in the intergeneric salmonid hybrids.

Ontogeny of the hemoglobins of Honmasu (Oncorhynchus rhodurus, HXH),brook trout (Salvelinus fontinalis, BXB) and their reciprocal hybrids (HXB and BXH) was examined electrophoretically as well as spectrophotometrically. All of these fish have electrophoretically distinct larval and adult type hemoglobins and the transition from one type to the other occurred early during post-hatching development. In the case of larval hemoglobins, the electrophoretic pattern of a hybrid, BXH, resembled that of the maternal parent, brook trout (BXB), while the hemoglobin of the reciprocal hybrid, HXB, differed markedly from that of the maternal parent, Honmasu (HXH), in that it possesses a diffuse pattern. Spectrophotometric examinations indicated that this was mostly methemoglobin. Adult type hemoglobins at more advanced stages of both hybrids were electrophoretically resolved into the parental hemoglobins. However, no "hybrid" hemoglobins were detected. Because there was abnormal hemoglobin formation in the larval erythrocytes (erythrocytes L) of the HXB hybrid, and then normal hemoglobin synthesis in the adult erythrocytes (erythrocytes A) of the same fish at later developmental stages, it appears that the paternal effects upon the hemoglobin differed in these two erythroid cell lines of the developing trout.

Animals↗

[Salmonella meningitis in children in Libreville. Retrospective study of 9 cases].

BACKGROUND: Salmonella meningitis is a rare entity, even in tropical area where salmonellosis is common. Its prognosis is poor and the choice of adequate antibiotic therapy is difficult. PATIENTS AND METHODS: The files of nine children (three boys, six girls) admitted to the pediatric unit of the Owendo Pediatric Hospital in Libreville for salmonella meningitis between January 1, 1989, and December 31, 1993 were retrospectively studied. Diagnosis was established by a positive culture of cerebrospinal fluid. RESULTS: Salmonella was the third cause (8.65%) of purulent meningitis observed during this period. Eight children were less than 1-year old, seven were from low socioeconomic standard families. The main clinical manifestations were fever (seven cases), pallor (six cases), diarrhea (four cases), nuchal rigidity (four cases), convulsions (three cases) and bulging fontanel (three cases). Five children (55.5%) were severely anemic (hemoglobin < 5 g/dL) but none had abnormal hemoglobin. Serotyping could not be performed in any case. Salmonella isolates were resistant to chloramphenicol in six cases and to ampicillin in five. Cefotaxime (200 mg/kg/24 h intravenously in three divided doses) was given to seven patients. The duration of therapy was at least 3 weeks in four patients. There were five deaths at ages ranging from 1 to 12 months, ie, a case fatality rate of 55.5%. Three patients (33.3%) recovered with neurological sequels. CONCLUSION: The prognosis of salmonella meningitis is poor, even in the case of prompt diagnosis and adequate therapy. Preventive measures only can decrease the risk of illness in children.

Cefotaxime↗

Methemoglobinemia induced by an over-the-counter medication.

OBJECTIVE: To report a case of methemoglobinemia induced by benzocaine and resorcinol (Vagisil) cream, an over-the-counter medication that was used to treat diaper rash in a neonate. CASE REPORT: A 6-day-old, 3350-g white boy was found to be cyanotic with blue mucous membranes on presentation. He had a diaper rash that was red and irritated, which his mother had treated with Vagisil cream. Methemoglobinemia secondary to absorption of benzocaine and resorcinol (1,3-benzenediol) from the Vagisil was diagnosed, with a methemoglobin level of 35% on admission (normal 0.4-1.5). Intravenous methylene blue 3 mg (1 mg/kg) was given; the neonate's skin color returned to normal 45 minutes after the dose. DISCUSSION: Methemoglobinemia is a condition in which hemoglobin is oxidized to the ferric form. Oxidized hemoglobin, methemoglobin, is incapable of reversibly binding oxygen at the physiologic partial oxygen pressure. Main causes of methemoglobin formation are exposure to certain oxidizing agents and drugs, deficiency of one of the enzymes necessary for reduction of methemoglobin to hemoglobin, or the presence of an abnormal hemoglobin resistant to reduction. Clinical manifestations of methemoglobinemia include diffuse slate-gray cyanosis with low oxygen saturation in the absence of respiratory distress. A single intravenous dose of methylene blue 1-2 mg/kg is the treatment of choice. CONCLUSIONS: Newborn infants are at increased risk for methemoglobinemia due to diminished enzyme systems required to reduce ferrihemoglobin to ferrohemoglobin, as well as because fetal hemoglobin is more easily oxidized than is adult hemoglobin. It is important to recognize possible drug reactions and educate parents on the potential risks of treatment with over-the-counter medications, especially in neonates.

Adult↗

Hb Footscray or alpha 133(H16) Ser-->Arg: a new hemoglobin variant.

Hb Footscray, alpha 133(H16) Ser-->Arg, is a newly described hemoglobin variant found in an adult male of Polish-Hungarian descent. Hematological data and stability by the isopropanol stability test were normal. The abnormal hemoglobin comprised 15% of total hemoglobin and migrated as a split band in the Hb F position on cellulose acetate at pH 8.6. Like Hb Manitoba, which is also a Ser-->Arg mutation and occurs in a very similar spatial position, the split bands presumably arise from the formation of asymmetric hybrids between Hb Footscray and Hb A.

Adult↗

Hemoglobinopathies, Iron Overload and Chronic Viral Hepatitis in Patients with Hepatocellular Carcinoma in Myanmar.

To assess the relevance of altered iron metabolism, hemoglobin electrophoresis by isoelectric focusing was performed for 16 cases of hepatocellular carcinoma (HCC) from the Liver Unit, Yangon General Hospital. Serum iron, total iron binding capacity, serum ferritin and free iron were also determined. Hemoglobin A (HbA) was found in all of the cases. Four cases had one extra band, hemoglobin A(2) in three cases, and hemoglobin F in one case. No abnormal hemoglobin was detected. Anemias due to chronic disorders or associated with liver disease were observed in all of the cases. Iron overload was documented in 83% and free iron was detected in all cases. Viral markers like HBsAg, AntiHBc, and AntiHCV singly or in combination were found in all cases. HCC occurring at young age was seen in this study; the youngest patient was 23 years old and four cases (25%) were under 40 years, with a mean age of 49 years. The findings support the hypothesis that free iron and iron overload is a potential promoter of the development of HCC, especially if underlying chronic viral infection is present.

Journal Article↗