Cyclic Seasonal Variation of G-6-PD Deficiency in Newborn Infants from Sardinia

Glucose-6-Phosphate Dehydrogenase has been studied in 5267 consecutive newborn infants from Sardinian population during a four years period. The proportion of G-6-PD deficient female infants is much higher in those conceived in the winter-spring than among those conceived in summer-autumn, resulting in a lower sex ratio among G-6-PD deficient infants conceived in winter-spring as compared to G-6-PD deficient infants conceived in the summer-autumn. The overall frequency of the gene for G-6-PD deficiency is much lower in infants conceived in the summer period than in infants conceived in the other seasons. A greater reproductive efficiency of G-6-PD deficient males in the winter-spring season and/or some effect at post zygotic level favouring the survival of heterozygous G-6-PD deficient females conceived in the winter-spring period could contribute to the pattern described. Fresh vegetables containing oxidative substances are more abundant in the spring time. These substances may interact with seasonal reproductive cycles influencing reproduction efficiency of G-6-PD deficient males and/or the relative survival rate of heterozygous female embryos.     

Characteristics of a new abnormal variant of G-6-PD in human red cells.

Kinetic and electrophoretic properties were studied in 230--300 fold purified preparations of glucose-6-phosphate dehydrogenase (G-6-PD) from red cells of donors and patients with hemolytic anemia induced by G-6-PD deficiency. In abnormal variant of G-6-PD isolated from red cells of a patient with hemolytic anemia which had not before been described in the literature was found. The abnormal variant differs from the normal enzyme by a decreased Michaelis constant for G-6-P and NADP, by increased utilization of substrate-analogues (2-deoxy-G-6-P and deamino NADP in particular), by low heat stability, the character of pH dependence, and by the appearance of one band of G-6-PD activity during electrophoresis in polyacrylamide gel. The isolated abnormal variant of G-6-PD has been called "Kremenchug" according to the origin of the patient.     

The occurrence of G-6-PD union in Thailand

Summary Partially purified G-6-PD from 4 deficient Thai males presenting with acute hemolytic anemia showed low Km G-6-P consumption, and very high consumption of 2d G-6-P, Gal-6-P, and dTPN. DPN consumption was zero. The enzyme had very biphasic pH optimum curve and very low heat stability. Electrophoretic mobility was 103–106% of normal. These properties are very similar to those of G-6-PD Union. The enzyme of these 4 subjects is thus named G-6-PD Union (Thai).

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Zusammenfassung Teilweise gereinigtes G-6-PD von 4 Thai-Männern, die wegen einer hämolytischen Anämie zur Behandlung kamen, zeigten eine niedrige km G-6-P, dagegen hohe 2d G-6-P, Gal-6-P und dTPN-Utilisation. DPN-Utilisation was O. Das Enzym zeigte eine starke biphasische pH-Optimum-Kurve und sehr geringe Hitzestabilität. Die elektrophoretische Wanderungsgeschwindigkeit war 103–106% des Normalen. Diese Eigenschaften sind sehr ähnlich denen des G-6-PD-Union. Deshalb wird das Enzym dieser drei Personen als G-6-PD-Union (Thai) bezeichnet.

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Supported by U.S. Public Health research grant AM 09805 from the National Institute of Arthritis and Metabolic Diseases and research grant no G3/181/74 from the World Health Organization.     

A new glucose-6-phosphate dehydrogenase variant (G-6-PD Kalyan) found in a Koli family

Summary A new Indian variant of erythrocytic glucose-6-phosphate dehydrogenase (G-6-PD) has been detected in a Koli male subject during population genetic studies. The enzyme variant is characterized by mild enzyme deficiency, slow electrophoretic mobility, low K_m for G-6-P, increased utilization of substrate analogues, heat instability and a normal pH optimum curve. From these results this was considered to be a new variant and was designated G-6-PD Kalyan. The family history and routine hematological studies did not reveal any evidence that the G-6-PD Kalyan is associated with any hematological abnormalities or clinical symptoms.     

G-6-PD Jalisco and G-6-PD Morelia: Two new Mexican variants

Summary Two new G-6-PD variants designated G-6-PD Jalisco and G-6-PD Morelia were identified in two unrelated Mexican families. An additional G-6-PD variant was found in each family: G-6-PD trinacria and G-6-PD A^-. In both families compound heterozygotes were identified. G-6-PD Jalisco and G-6-PD Morelia belong to Classes 3 and 4, respectively. G-6-PD Morelia is the first variant from its class with a high Km for NADP and a low Ki for NADPH.     

Insulin secretion in patients deficient in glucose-6-phosphate dehydrogenase

Intravenous (IVGTT) and oral glucose tolerance tests (OGTT) were carried out in 12 men with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and in 11 normal men. The race, the mean age and body mass index were similar in the G-6-PD deficient and in the normal men. No significant differences were demonstrated between mean plasma glucose levels in the G-6-PD deficient subjects and those in the normal men during IVGTT and OGTT. In contrast the insulin levels were significantly lower for the G-6-PD deficient subjects as compared to the controls at 30 minutes (P less than 0.04) in the OGTT and at 1 min (P less than 0.001), 3 min (P less than 0.001), 5 min (P less than 0.001) and 10 minutes (P less than 0.002) in the IVGTT. All indexes of first phase insulin release were also significantly (P less than 0.001) lower in G-6-PD deficient men. These results emphasize the metabolic importance of G-6-PD in the process of glucose induced insulin release.     

Thalassemia and G-6-PD Deficiency in Chinese-Canadians: Admission Screening of a Hospital Population

Admission screening was performed on 684 Chinese-Canadian patients for thalassemia, abnormal hemoglobins and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Thirty-six healthy Chinese adults were also studied. The incidence of beta-thalassemia minor (hemoglobin A₂ greater than 3.5%) was 3.8%. Presumptive alpha-thalassemia minor (demonstration of occasional red cells containing hemoglobin H inclusion bodies) was found in 6.7%. Two patients had findings consistent with alpha-beta-thalassemia. The incidence of G-6-PD deficiency (abnormal methemoglobin reduction test) in adult males was 4.7%. In a parallel study the incidence of hemoglobin Bart''s in 310 Chinese newborns was 6.8%. Two mutant hemoglobins were found — hemoglobin E and hemoglobin J (Bangkok).     

Inheritance of quantitative expression of erythrocyte glucose-6-phosphate dehydrogenase activity in the Negro—a twin study

Studies have been conducted on eight sets of monozygous and nine sets of dizygous female Negro twins, both members of whom were heterozygous for G-6-PD deficiency. Twins were studied both by assay of erythrocytic G-6-PD activity and by the methemoglobin elution test (MET). The MET is a procedure which identifies histochemically cells with appreciable G-6-PD activity and permits accurate determination of the percentage of such cells in heterozygotes. Monozygous twins showed significantly less within-pair variation than dizygous twins with both the MET and G-6-PD assay.Concerning the significantly greater agreement in MET results in monozygous twins than dizygous twins, our present working hypothesis is that X-chromosomal inactivation in the Negro female is genetically controlled, rather than random. However, certain alternate hypotheses allowing for random X-inactivation have not been excluded; these include somatic cell selection after random X-inactivation, and cell exchange between identical twins in utero/it. Studies in nontwin related heterozygotes now underway should help differentiate among these various possibilities.In addition to the studies on 17 pairs of female twins heterozygous for G-6-PD deficiency, 26 pairs of nondeficient female Negro twins have been studied by G-6-PD assay. Within-pair variation in monozygous twins was significantly less than within-pair variation in dizygous twins in all cases. The genetic influences detected with the G-6-PD assay in the female twins could theoretically be due to nonrandom X-inactivation, to genetically determined quantitative differences in enzyme activity (e.g., isoalleles), or to both. By appropriate calculations, based on the MET results, we have factored out the effects of X-inactivation on overall enzyme activity in the heterozygous deficient twins. After removal of the effect of X-inactivation, monozygous twins heterozygous for enzyme deficiency continue to show significantly less within-pair variation than dizygous twins. This finding indicates significant genetic influences on quantitative G-6-PD activity other than X-inactivation and other than the deficiency allele. This conclusion has been strengthened by studies on male twins where X-inactivation is not present.Supported by USPHS research grants AM-09381, HE-17544, AM-09919, and HE-03341, by USPHS Career Development Award 1-K3-AM-7959 (Dr. Brewer) and by U.S.A.E.C. Contract (11-1)-1552.     

G-6-PD and haemoglobin variants among twelve endogamous Dhangar castes of Maharashtra, India

Incidence of haemoglobin variants and G-6-PD deficiency among 1385 males belonging to 12 endogamous Dhangar castes of Maharashtra, India, have been reported. Of the 12 castes studied 11 lacked the allele for G-6-PD deficiency; 2.7% of the Thellaris were found to be deficient. Haemoglobin Hb-D trait is found in 2 of the 12 castes; the incidence among Ahirs and Hatkars being 0.82% and 1.91%, respectively. One case of Hb-J among the Ahirs, and 2 examples of thalassaemia trait, one each among Ahirs and Gadharis, have been detected. The low incidence of observed G-6-PD deficiency and the detection of Hb-D and J traits, as well as thalassaemia have been discussed in the light of the nomadic way of life of some of the Dhangar castes and prevalence of malaria in the region they occupy. The data strongly suggest that the Dhangars arrived in Maharashtra in the recent past from northwest.     

Glucose-6-phosphate dehydrogenase in the population of northern Thailand: Evidence for two common electrophoretic variants with deficient enzyme activity

Summary Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, identified by a dye decolorization test, was found in 101 (12.5 percent) of 811 male subjects from northern Tailand. Blood samples from 169 subjects with normal G-6-PD activity and from all 101 subjects with G-6-PD deficiency were examined by electrophoresis on cellulose acetate gel with the following results: In all samples with normal G-6-PD activity the enzyme had the electrophoretic mobility of type B G-6-PD. 73 of the 101 G-6-PD deficient samples had the same mobility and are therefore probably identical with the common Mediterranean variant B-. 16 of the 101 deficient samples contained an electrophoretically fast G-6-PD, and 1 sample a slow variant. In 11 deficient samples the enzyme could not be made visible. Kinetic studies on crude hemolysates suggest that the fast variant has a higher mean activity and heat stability in comparison to the B- variant.Established and supported by Stiftung Volkswagenwerk, Hannover.     

Erythrocyte G-6-PD and 6-PGD genetic polymorphisms in South African Negroes,with a note on G-6-PD and the malaria hypothesis

Summary Sample of 981 and 998 South African Negroes belonging to seven different ethnic groups were screned for G-6-PD and 6-PGD phenotypes, respectively. The results are discussed in terms of the interethnic variability and the possible adaptive values of these genetic polymorphisms. Particular attention is paid to the geographic co-distribution and interrelationship of G-6-PD deficiency and the occurrence of malaria in South Africa.     

Detection of female heterozygous glucose-6-phosphate dehydrogenase deficiency]

Diagnostics of heterozygotes are required for population studies, for the detection and consultation of persons with G-6-PD deficiency prone to hemolysis. The diagnostics of heterozygous females with the corresponding trait are problematic in families without hemizygous patients. 1. The determination of the activity is only applicable to the differentiation between heterozygotes and homozygotes if the activities are below the reference range. Heterozygous G-6-PD deficiency with normal activity cannot be identified by this method. 2. Existence of G-6-PD defects is demonstrated by mosaicism even in case of normactivity (T?nztest). 3. Incubation with and without NADP of stroma-free hemolysates involving heat labile enzyme mutants results in a marked decrease of activity within 20 min at 46 degrees C. 4. Electrophoresis on Cellogel demonstrates changes of charge in the mutated enzyme. 5. Family examination verifies suspicion of the heterozygous trait. A combination of parameters is recommended to obtain an improvement in the detection of persons with the heterozygous trait.     

Polymorphism of erythrocyte G-6-PD in the baboon

Blood samples from several populations of baboons (genus Papio) were examined for G-6-PD variants. Several G-6-PD phenotypes were detected by starch gel electrophoresis. The so-called fast variant phenotypes of G-6-PD in baboons differ from human variant phenotypes in several physicochemical constants.     

Plasma and erythrocyte magnesium, manganese, zinc, and plasma calcium levels in G-6-PD-deficient and normal male children

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is the most common human enzymopathy in the world. Trace elements are important for normal hematopoiesis and can play a role in acute hemolytic anemia induced by G-6-PD deficiency. For this purpose, we studied two groups consisting of 10 male children who are G-6-PD-deficient and 12 age-matched normal male children to compare plasma and erythrocyte magnesium, manganese, zinc, and plasma calcium levels between G-6-PD-deficient and normal children. All assays were performed under normal conditions free of any oxidative attack that may result in hemolytic crisis in G-6-PD-deficient subjects. All parameters in each group did not differ significantly except for erythrocyte G-6-PD activities. These data show that plasma and erythrocyte trace element contents of G-6-PD-deficient subjects do not differ in normal conditions.     

G-6-PD Poznań, variant with severe enzyme deficiency.

A new variant of G-6-PD with severe enzyme dificiency without chronic hemolysis is characterized. The biochemical properties of the variant closely resemble those of the G-6-PD Ramat-Gan described in a case of chronic non-spherocytic hemolytic anemia. As the family data on linking of chronic hemolysis with Ramat-Gan variant are lacking, the differentiation of the variants on the basis of clinical manifestations is not well-founded.     

Glucose-6-phosphate dehydrogenase deficiency and sickle cell disease in Brazil.

The frequency of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency was determined in 54 male patients with sickle cell diseases: 31 sickle cell anemia (SS), 14 sickle cell hemoglobinopathy (SC) and 9 HbS/beta-thalassemia (S/B-thal) by a combination of quantitative assay, fluorescent spot test and electrophoresis. Of the 54 patients tested, 7 were found to be G-6-PD deficient (G-6-PD-) (3 SS, 3 SC and 1 S/B-thal) and 47 G-6-PD normal (G-6-PD+) (6 G-6-PD A and 41 G-6-PD B). All the deficient patients were G-6-PD A-. The frequency of G-6-PD deficiency did not differ significantly from that observed in the general population. Compared to patients who were not G-6-PD-, there were no significant differences in the hemoglobin concentration and reticulocyte count in patients with sickle cell diseases who were G-6-PD-.     

About a rare case of intolerance toVicia faba in a non G-6-PD deficient subject

Summary The history of a non G-6-PD deficient woman, who developed a hard intolerance reaction to theVicia fiba ingestion is described.     

Frequency of glucose-6-phosphate dehydrogenase deficiency in sickle-cell disease. A study in Saudi Arabia

The frequency of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in 50 Hb S homozygotes (SS) and 98 Hb S heterozygotes (AS) was determined and compared with the frequency obtained in individuals with normal haemoglobin (AA). The observed number of SS patients with G-6-PD deficiency was significantly greater than the expected value (p less than 0.05). The frequency of G-6-PD deficiency in AA, AS and SS was found to be 0.172, 0.214 and 0.420, respectively. A statistically significant increase of G-6-PD deficiency was apparent in the Saudi sicklers. The possibility that G-6-PD deficiency and Hb S gene interact, influencing the survival of the carriers of these genetic abnormalities, is discussed.     

Studies of enzymes connected with erythrocyte glutathione metabolism in a rural tropical population

Summary The activities of the erythrocyte enzymes hexokinase (HK), glucose-6-phosphate dehydrogenase (G-6-PD), 6-phosphogluconate dehydrogenase (6-PGD), glutathione reductase (GR) and glutathione peroxidase (GSH-PO) were determined in a group of 12 Europeans and in a group of 103 male Thai subjects in northern Thailand. In the Thai group there were 16 subjects with G-6-PD deficiency and 28 subjects with abnormally low levels of GR activity. A comparison of the enzyme activities in the different subgroups indicated that HK and 6-PGD are not influenced by G-6-PD deficiency whereas GR and GSH-PO activities are significantly higher in G-6-PD deficient subjects. In the group with low GR activity G-6-PD and GSH-PO showed a tendency to an elevation of activity when compared with the normal control group. Significant positive correlations exist between G-6-PD and 6-PGD in the normal group and between GR and GSH-PO in the G-6-PD deficient group. A negative correlation between GR and GSH-PO was present in the group with low GR activities. A study of the families of subjects with low activity of GR did not yield evidence for the existence of a deficiency polymorphism.

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Zusammenfassung Bei 12 Europäern und einer Gruppe von 103 männlichen thailändischen Versuchspersonen wurden die Aktivitäten der Erythrocytenenzyme Hexokinase (HK), Glucose-6-Phosphat-Dehydrogenase (G-6-PD), 6-Phosphogluconat-Dehydrogenase (6-PGD), Glutathion-Reduktase (GR) und Glutathion-Peroxidase (GSH-PO) bestimmt. In der Thai-Gruppe waren 16 Personen mit G-6-PD-Mangel und 28 Personen mit abnormal niedrigen Aktivitäten der GR. Ein Vergleich der Enzymaktivitäten in verschiedenen Untergruppen zeigte, daß HK und 6-PGD durch G-6-PD-Mangel nicht beeinflußt werden. Im Gegensatz hierzu sind die Aktivitäten der GR und der GSH-PO bei G-6-PD-Mangel signifikant erhöht. In der Gruppe mit erniedrigter GR-Aktivität bestand eine Tendenz zu erhöhten Werten für G-6-PD und GSH-PO. Die Korrelationen zwischen G-6-PD und 6-PGD in der Gruppe mit normaler G-6-PD und die zwischen GR und GSH-PO in der Gruppe mit G-6-PD-Mangel waren signifikant. In der Gruppe mit erniedrigter GR-Aktivität fand sich eine negative Korrelation zwischen GR und GSH-PO. Die Untersuchungen in Familien von Personen mit niedriger GR-Aktivität ergaben keinen sicheren Hinweis auf das Vorliegen eines GR-Mangel-Polymorphismus in der untersuchten Bevölkerung.

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Established and supported by Stiftung Volkswagenwerk, Hannover.     

Population study in Assam: ABO blood groups, haemoglobin E and G-6-PD deficiency

An attempt has been made to give a comprehensive picture of occurrence of ABO blood groups, haemoglobin E and G-6-PD deficiency among certain representative populations of the two major racial groups--Mongoloids and Caucasoids--of Assam, India. The qualitative pattern of distribution of ABO gene frequencies shows a clear demarcation between these two major groups. The same is true in respect of HbE gene, too. The Mongoloids present high frequencies of this gene, while among the Caucasoids its frequency is comparatively much lower. With regard to G-6-PD deficiency the distinction between the two groups is not so clear cut, yet some Mongoloid populations show relatively higher incidence of the trait in comparison to that in the Caucasoid populations.