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Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 371: 64-74

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Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 371: 64-74

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Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, being present in more than 400 million people worldwide. The global distribution of this disorder is remarkably similar to that of malaria, lending support to the so-called malaria protection hypothesis. G6PD deficiency is an X-linked, hereditary genetic defect due to mutations in the G6PD gene, which cause functional variants with many biochemical and clinical phenotypes. About 140 mutations have been described: most are single base changes, leading to aminoacid substitutions. The most frequent clinical manifestations of G6PD deficiency are neonatal jaundice, and acute haemolytic anaemia, which is usually triggered by an exogenous agent. Some G6PD variants cause chronic haemolysis, leading to congenital non-spherocytic haemolytic anaemia. The most effective management of G6PD deficiency is to prevent haemolysis by avoiding oxidative stress. Screening programmes for the disorder are undertaken, depending on the prevalence of G6PD deficiency in a particular community.

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... When exposed to oxidant stress like exposure to drugs (antimalarial), infection or some natural plant products like fava beans, hemolysis can occur in these individuals [20]. However, it can manifest with chronic non spherocytic hemolytic anemia, neonatal jaundice, favism, acute hemolytic anemia (AHA) induced either by drug or by infection in children [21,22]. ...
... These factors include erythrocyte metabolic function, characteristics of G6PD enzyme defect, genetic manipulation of pharmacokinetics and pharmacodynamics (dose, absorption, metabolism and excretion of drug). Similarly, other triggers consist of ongoing oxygen free radicle generation, hemoglobin concentration and old to new erythrocyte ratio [20,21]. Infection with Hepatitis A, and B, cytomegalovirus, other bacterial infections, can also induce AHA. ...
... Infection with Hepatitis A, and B, cytomegalovirus, other bacterial infections, can also induce AHA. Most probable reason for AHA could be generation of oxidizing species by leucocytes, transmitting oxidative stress in erythrocytes [2,21]. ...
Article
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most frequent enzyme deficiency which leading to substantial morbidity and mortality in children. Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme present in cytoplasm, coded by X-linked gene. G6PD catalyzes the initial step in hexose monophosphate shunt, which is a rate limiting reaction. This shunt helps in producing NADPH (Nicotinamide adenine dinucleotide phosphate), a reducing equivalent that helps glutathione reductase to regenerate reduced glutathione (GSH). Due to its crucial role in defence against oxidizing species, it is perceived that any mutation in G6PD encoding gene can affect enzyme's structural and functional integrity leading to malfunctioning of enzyme. G6PD deficiency is a highly prevalent genetic disorder which is transmitted as X-linked recessive pattern. Nearly 210 variants have been reported all over the world. In India, G6PD deficiency is a significant public health problem. It is an important cause for drug induced hemolysis in children. G6PD gene variants are often named as per the geographical area where they were first discovered. In India Mediterranean, Orissa, Jammu, Andhra Pradesh, Kalyan-Kerala and G6PD West Bengal are frequently seen. G6PD Mediterranean leads to severe deficiency when compared to others. Worldwide highest preponderance of g6PD deficiency is seen in African sub Saharan region and Arabian Peninsula.
... It is a housekeeping enzyme that exists in almost all human cells. The monomer of G6PD is composed of 515 amino acids with a molecular weight of about 59 kDa (Cappellini and Fiorelli, 2008). G6PD can catalyze the oxidation of glucose-6 -phosphate (G6P), convert NADP into NADPH, and provide the reduction capacity for body cells in the form of NADPH (Cappellini and Fiorelli, 2008). ...
... The monomer of G6PD is composed of 515 amino acids with a molecular weight of about 59 kDa (Cappellini and Fiorelli, 2008). G6PD can catalyze the oxidation of glucose-6 -phosphate (G6P), convert NADP into NADPH, and provide the reduction capacity for body cells in the form of NADPH (Cappellini and Fiorelli, 2008). NADPH can promote the production of reduced glutathione (GSH), thereby reducing the oxidative stress response of oxidants to body cells (Tsai et al., 1998). ...
... X linkage has an essential effect on the genetic characteristics of G6PD deficiency. There are only two genotypes in males: hemizygote normal and half zygote G6PD deficiency, while females, have three genotypes: homozygote normal, homozygous deficient, and heterozygote (Cappellini and Fiorelli, 2008). It is generally considered incorrect that the incidence of G6PD deficiency is higher in males than in females since homozygote female are less likely than hemizygote men. ...
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Pneumocystis pneumonia (PCP) is an opportunity acquired infection, which is usually easy to occur in patients with AIDS, organ transplantation, and immunosuppressive drugs. The prevention and treatment must be necessary for PCP patients with immunocompromise. And the oxidants are currently a typical regimen, including sulfanilamide, dapsone, primaquine, etc. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked gene-disease that affects about 400 million people worldwide. The lack of G6PD in this population results in a decrease in intracellular glutathione synthesis and a weakening of the detoxification ability of the oxidants. As a result, oxidants can directly damage haemoglobin in red blood cells, inducing methemoglobin and hemolysis. When patients with G6PD deficiency have low immunity, they are prone to PCP infection, so choosing drugs that do not induce hemolysis is essential. There are no clear guidelines to recommend the drug choice of this kind of population at home and abroad. This paper aims to demonstrate the drug choice for PCP patients with G6PD deficiency through theoretical research combined with clinical cases.
... The global distribution of the G6PD deficiency is strikingly similar to that of malaria. In areas where G6PD deficiency is common, Plasmodium Falciparum malaria is endemic, supporting the so-called malaria protection hypothesis [28]. Epidemiological evidence for the association between G6PD deficiency and a reduction in the risk of severe malaria [29] has been accompanied by the results of in vitro work showing that parasite growth is slowest in G6PD-deficient cells [28]. ...
... In areas where G6PD deficiency is common, Plasmodium Falciparum malaria is endemic, supporting the so-called malaria protection hypothesis [28]. Epidemiological evidence for the association between G6PD deficiency and a reduction in the risk of severe malaria [29] has been accompanied by the results of in vitro work showing that parasite growth is slowest in G6PD-deficient cells [28]. ...
... In its catalytic center, there is an amino acid sequence that binds to NADPH. The deficiency is caused by protein instability due to amino acid substitutions in different enzyme locations [28]. The diagnosis of G6PD deficiency is based on the spectrophotometric quantification of the enzyme's activity [32]. ...
Article
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Hypomorphic Glucose 6-P dehydrogenase (G6PD) alleles, which cause G6PD deficiency, affect around one in twenty people worldwide. The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in Drosophila Melanogaster and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.
... 2,3 Glucose 6 phosphate dehydrogenase (G6PD) deficiency is the commonest inherited enzyme defect, affecting an estimated 400 million people worldwide. 4 Infections, such as viral hepatitis, enteric fever, respiratory and gastrointestinal infections, or exposure to certain drugs and chemicals, may be the triggers of massive hemolysis. Hemolytic anemia may be associated with viral hepatitis but is more severe with underlying G6PD deficiency state. ...
... 6 G6PD deficiency is an X-linked recessive disorder caused by mutations in G6PD gene and as per literature, and the prevalence in India is almost double of the global prevalence rate. 4,7 This enzyme is classified into five types based on the clinical presentation and G6PD levels, and our patient belongs to type 2 of G6PD deficiency. 4 Most children with G6PD deficiency remain asymptomatic throughout their lives, but the deficiency state gets unfolded in phase of acute hemolysis triggered by an exogenous agent or oxidative stress. Glucose 6 phosphate dehydrogenase is an enzyme that produces reduced glutathione, thereby preventing oxidative damage to cells. ...
... 4,7 This enzyme is classified into five types based on the clinical presentation and G6PD levels, and our patient belongs to type 2 of G6PD deficiency. 4 Most children with G6PD deficiency remain asymptomatic throughout their lives, but the deficiency state gets unfolded in phase of acute hemolysis triggered by an exogenous agent or oxidative stress. Glucose 6 phosphate dehydrogenase is an enzyme that produces reduced glutathione, thereby preventing oxidative damage to cells. ...
Article
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Hepatitis A is the most prevalent viral hepatitis in India and rarely can lead to life-threatening complications such as acute liver failure (ALF). Glucose 6 phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency in the world, and in the setting of acute viral hepatitis, it can cause massive intravascular hemolysis, resulting in acute kidney injury. Here, we report a case of a 12-year-old male child who had hepatitis A–associated ALF, which was complicated by massive hemolysis due to underlying G6PD deficiency, manifesting as acute renal failure requiring renal replacement therapy with other supportive management. He had a prolonged, protracted stormy clinical course, which was further complicated by dialysis disequilibrium syndrome, posterior reversible encephalopathy syndrome, and nosocomial sepsis, which improved over 4 weeks. Our case highlights the importance of having high index of clinical suspicion for G6PD deficiency in a child with acute viral hepatitis with complications.
... and pyruvate kinase (PKLR; EC:2.7.1.40) deficiencies are the most common hereditary metabolic disorders affecting red blood cells [1,2]. G6PD deficiency triggers haemolytic anaemia in states of oxidative stress because deficient erythrocytes contain low levels of NADPH, which is required for maintaining cellular redox homeostasis through glutathione recycling [2]. ...
... deficiencies are the most common hereditary metabolic disorders affecting red blood cells [1,2]. G6PD deficiency triggers haemolytic anaemia in states of oxidative stress because deficient erythrocytes contain low levels of NADPH, which is required for maintaining cellular redox homeostasis through glutathione recycling [2]. Millions of people worldwide, mostly in Africa, the Mediterranean, the Middle East, and Asia, are affected by this condition. ...
... The frequency of G6PD status follows the Hardy Weinberg equilibrium. This makes heterozygous females are more common than hemizygous males and homozygous females are the least common [2]. ...
Article
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Abstract Background Glucose 6-phosphate dehydrogenase (G6PD) and pyruvate kinase (PKLR) deficiencies are common causes of erythrocyte haemolysis in the presence of antimalarial drugs such as primaquine and tafenoquine. The present study aimed to elucidate such an association by thoroughly investigating the haematological indices in malaria patients with G6PD and PKLR R41Q variants. Methods Blood samples from 255 malaria patients from Thailand, Myanmar, Laos, and Cambodia were collected to determine haematological profile, G6PD enzyme activity and G6PD deficiency variants. The multivariate analysis was performed to investigate the association between anaemia and G6PD Mahidol G487A , the most common mutation in this study. Results The prevalence of G6PD deficiency was 11.1% (27/244) in males and 9.1% (1/11) in female. The MAFs of the G6PD Mahidol G487A and PKLR R41Q variants were 7.1% and 2.6%, respectively. Compared with patients with wildtype G6PD after controlling for haemoglobinopathies, G6PD-deficient patients with hemizygous and homozygous G6PD Mahidol G487A exhibited anaemia with low levels of haemoglobin (11.16 ± 2.65 g/dl, p = 0.041). These patients also exhibited high levels of reticulocytes (3.60%). The median value of G6PD activity before treatment (Day 0) was significantly lower than that of after treatment (Day 28) (5.51 ± 2.54 U/g Hb vs. 6.68 ± 2.45 U/g Hb; p
... Glucose-6-phosphate dehydrogenase deficiency (G6PDd), an X-linked hereditary disease, is one of the most common genetic diseases amongst Asian populations (Cappellini & Fiorelli, 2008;Howes et al., 2012). G6PDd affects roughly 400 million people worldwide, mostly in Southern Europe, Africa, the Mediterranean, the Middle East, and Southeast Asia (Bancone et al., 2019;He et al., 2020;Hue et al., 2009;Liu et al., 2019;Louicharoen & Nuchprayoon, 2005;Matsuo et al., 2003;Matsuoka et al., 2004;Monteiro et al., 2014;Nuchprayoon et al., 2002;Ong et al., 2019;Phompradit et al., 2011;Sanephonasa et al., 2021;Satyagraha et al., 2015;Sulistyaningrum et al., 2020;Yusoff et al., 2003;Wang et al., 2008;Zhong et al., 2018). ...
... G6PDd is caused by a deficiency in the enzyme glucose-6-phosphate dehydrogenase encoded by the G6PD (OMIM: 305900) gene on chromosome Xq28 (Cappellini & Fiorelli, 2008). Clinically, patients with G6PDd present with either the early onset of neonatal hyperbilirubinemia or the late onset of fulminant episodes of hemolysis by specific oxidative agents (such as primaquine and chloroquine, which are prescribed in malarial prophylaxis) or by the intake of fava beans (Cappellini & Fiorelli, 2008;Ong et al., 2017;Tarhani et al., 2021). ...
... G6PDd is caused by a deficiency in the enzyme glucose-6-phosphate dehydrogenase encoded by the G6PD (OMIM: 305900) gene on chromosome Xq28 (Cappellini & Fiorelli, 2008). Clinically, patients with G6PDd present with either the early onset of neonatal hyperbilirubinemia or the late onset of fulminant episodes of hemolysis by specific oxidative agents (such as primaquine and chloroquine, which are prescribed in malarial prophylaxis) or by the intake of fava beans (Cappellini & Fiorelli, 2008;Ong et al., 2017;Tarhani et al., 2021). There is no treatment; thus, the most effective therapy is knowing the disease's presence and preventing exogenously oxidative agents. ...
Article
Full-text available
Background Several inherited metabolic diseases are underreported in Vietnam, namely glucose-6-phosphate dehydrogenase deficiency (G6PDd), phenylketonuria (PKU) and galactosemia (GAL). Whilst massively parallel sequencing (MPS) allows researchers to screen several loci simultaneously for pathogenic variants, no screening programme uses MPS to uncover the variant spectra of these diseases in the Vietnamese population. Methods Pregnant women (mean age of 32) from across Vietnam attending routine prenatal health checks agreed to participate and had their blood drawn. MPS was used to detect variants in their G6PD, PAH and GALT genes. Results Of 3259 women screened across Vietnam, 450 (13.8%) carried disease-associated variants for G6PD, PAH and GALT. The prevalence of carriers was 8.9% (291 of 3259) in G6PD and 4.6% (152 of 3259) in PKU, whilst GAL was low at 0.2% (7 of 3259). Two GALT variants, c.593 T > C and c.1034C > A, have rarely been reported. Conclusion This study highlights the need for routine carrier screening, where women give blood whilst receiving routine prenatal care, in Vietnam. The use of MPS is suitable for screening multiple variants, allowing for identifying rare pathogenic variants. The data from our study will inform policymakers in constructing cost-effective genetic metabolic carrier screening programmes.
... G6PD is an essential enzyme in the pentose phosphate pathway, the only pathway for red blood cells (RBCs) to maintain their redox potential by reducing nicotinamide adenine dinucleotide phosphate (NADP+) to NADPH [7]. The G6PD gene is located on the X-chromosome, hence males are hemizygous and can be either G6PD deficient or normal, whereas females can be homozygous deficient, homozygous normal, or heterozygous for the gene [7]. ...
... G6PD is an essential enzyme in the pentose phosphate pathway, the only pathway for red blood cells (RBCs) to maintain their redox potential by reducing nicotinamide adenine dinucleotide phosphate (NADP+) to NADPH [7]. The G6PD gene is located on the X-chromosome, hence males are hemizygous and can be either G6PD deficient or normal, whereas females can be homozygous deficient, homozygous normal, or heterozygous for the gene [7]. The latter results in intermediate enzyme activity determined by the embryonic process of Xchromosome inactivation (lyonization) [5]. ...
... The latter results in intermediate enzyme activity determined by the embryonic process of Xchromosome inactivation (lyonization) [5]. Mature RBCs do not have a nucleus and depend on the G6PD generated during erythropoiesis, hence reticulocytes and young RBCs have the greatest G6PD activity which decreases with the age of the RBC [7]. The risk of drug induced haemolysis is determined by the patients G6PD variant, the degree of enzyme activity, the degree of lyonization in females, the age of the red cell population, and the degree of exposure [8,9]. ...
Article
Full-text available
Primaquine and tafenoquine are the only licensed drugs with activity against Plasmodium vivax hypnozoites but cause haemolysis in patients with glucose–6–phosphate dehydrogenase (G6PD) deficiency. Malaria also causes haemolysis, leading to the replacement of older erythrocytes with low G6PD activity by reticulocytes and young erythrocytes with higher activity. Aim of this study was to assess the impact of acute malaria on G6PD activity. Selected patients with uncomplicated malaria were recruited in Bangladesh (n = 87), Indonesia (n = 75), and Ethiopia (n = 173); G6PD activity was measured at the initial presentation with malaria and a median of 176 days later (range 140 to 998) in the absence of malaria. Among selected participants (deficient participants preferentially enrolled in Bangladesh but not at other sites) G6PD activity fell between malaria and follow up by 79.1% (95%CI: 40.4 to 117.8) in 6 participants classified as deficient (
... Glucose-6-phosphate dehydrogenase (G6PD) is a housekeeping enzyme for all cells and particularly important for the integrity and functioning of red blood cells (RBCs). It catalyzes the production of nicotinamide adenine dinucleotide phosphate (NADPH) and provides the cell reduced form of glutathione, thus glutathione helps the erythrocytes to survive oxidative stress [1][2][3][4]. Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is an X-linked genetic disorder caused by mutations in the G6PD gene on X-chromosome (Xq28) [2]. The X-linkage results in G6PDd of hemizygous males and homozygous females, while heterozygous females acquire two groups of RBCs with either normal or deficient G6PD activities [5,6]. ...
... It catalyzes the production of nicotinamide adenine dinucleotide phosphate (NADPH) and provides the cell reduced form of glutathione, thus glutathione helps the erythrocytes to survive oxidative stress [1][2][3][4]. Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is an X-linked genetic disorder caused by mutations in the G6PD gene on X-chromosome (Xq28) [2]. The X-linkage results in G6PDd of hemizygous males and homozygous females, while heterozygous females acquire two groups of RBCs with either normal or deficient G6PD activities [5,6]. ...
... Males are hemizygous with only one copy of G6PD gene on X-chromosome, and thus can be either normal or G6PD deficient. By contrast, females have two copies of the G6PD gene on each X-chromosome, which can result in either homozygous normal, heterozygous intermediate, or homozygous deficient enzyme level [2]. Nguetse et al. [36] showed that 22% of males' children are G6PDAdeficient while only 3% of females are G6PDA-deficient. ...
Article
Full-text available
Background Glucose-6-phosphate dehydrogenase (G6PD) is cytosolic enzyme, which has a vital role for the integrity and functioning of red blood cells. Lower activity of this enzyme leads to the occurrence of acute haemolytic anaemia after exposure to oxidative stressors like primaquine. Primaquine is an important drug for the radical cure of Plasmodium vivax and blocking transmission of Plasmodium falciparum , and thereby enhancing malaria elimination. However, there is a need to identify G6PD deficient individuals and administer the drug with caution due to its haemolytic side effects. The main objective of this study is to determine the prevalence of G6PD deficiency among malaria-suspected individuals. Methods A facility-based cross-sectional study was conducted from September 2020 to September 2021 in Metehara Health Centre, Eastern Ethiopia. A structured questionnaire was used to collect the socio-demographic and clinical information of the study participants. Capillary and venous blood samples were collected based on standard procedures for onsite screening, dried blood spot preparation, and malaria microscopy. The G6PD enzyme activity was measured by careSTART™ G6PD biosensor analyzer. Data was entered and analysed by SPSS. Results A total of 498 study participants were included in the study, of which 62% (309) were males. The overall prevalence of G6PD deficiency based on the biosensor screening was 3.6% (18/498), of which 2.9% and 4.8% were males and females, respectively. Eleven of the G6PD deficient samples had mutations confirmed by G6PD gene sequencing analysis. Mutations were detected in G267 + 119C/T, A376T, and ChrX:154535443. A significant association was found in sex and history of previous malaria infection with G6PD deficiency. Conclusions The study showed that the G6PD deficient phenotype exists in Metehara even if the prevalence is not very high. G267 + 119C/T mutation is the predominant G6PD variant in this area. Therefore, malaria patient treatment using primaquine should be monitored closely for any adverse effects.
... Once consumed, v-c are enzymatically degraded by the β-glucosidase enzyme in the small intestine to the reactive aglycone divicine (2,6-diamino-4,5-dihydroxypyrimidine) and isouramil (6-Amino-2,4,5-trihydroxypyrimidine) [1,2,[4][5][6][11][12][13]. Accumulation of the aglycones can potentially be toxic to individuals with a genetic deficiency of glucose-6phophate dehydrogenase, leading to haemolytic anaemia or favism [1,[3][4][5]10,11,14]. ...
... Once consumed, v-c are enzymatically degraded by the β-glucosidase enzyme in the small intestine to the reactive aglycone divicine (2,6-diamino-4,5-dihydroxypyrimidine) and isouramil (6-Amino-2,4,5-trihydroxypyrimidine) [1,2,[4][5][6][11][12][13]. Accumulation of the aglycones can potentially be toxic to individuals with a genetic deficiency of glucose-6phophate dehydrogenase, leading to haemolytic anaemia or favism [1,[3][4][5]10,11,14]. Favism affects approximately 400 million people globally [1,4,11], with the highest prevalence in Asia, the Mediterranean and Africa [6,11]. ...
... Accumulation of the aglycones can potentially be toxic to individuals with a genetic deficiency of glucose-6phophate dehydrogenase, leading to haemolytic anaemia or favism [1,[3][4][5]10,11,14]. Favism affects approximately 400 million people globally [1,4,11], with the highest prevalence in Asia, the Mediterranean and Africa [6,11]. ...
Article
Full-text available
The faba bean is one of the earliest domesticated crops, with both economic and environmental benefits. Like most legumes, faba beans are high in protein, and can be used to contribute to a balanced diet, or as a meat substitute. However, they also produce the anti-nutritional compounds, vicine and convicine (v-c), that when enzymatically degraded into reactive aglycones can potentially lead to hemolytic anemia or favism. Current methods of analysis use LC-UV, but are only suitable at high concentrations, and thus lack the selectivity and sensitivity to accurately quantitate the low-v-c genotypes currently being developed. We have developed and fully validated a rapid high-throughput LC-MS method for the analysis of v-c in faba beans by optimizing the extraction protocol and assessing the method of linearity, limit of detection, limit of quantitation, accuracy, precision and matrix effects. This method uses 10-times less starting material; removes the use of buffers, acids and organic chemicals; and improves precision and accuracy when compared to current methods.
... Glucose-6-phosphate dehydrogenase deficiency (G6PDd), an X-linked hereditary disease, is one of the most common genetic diseases amongst Asian populations (Cappellini & Fiorelli, 2008;Howes et al., 2012). G6PDd affects roughly 400 million people worldwide, mostly in Southern Europe, Africa, the Mediterranean, the Middle East, and Southeast Asia (Bancone et al., 2019;He et al., 2020;Hue et al., 2009;Liu et al., 2019;Louicharoen & Nuchprayoon, 2005;Matsuo et al., 2003;Matsuoka et al., 2004;Monteiro et al., 2014;Nuchprayoon et al., 2002;Ong et al., 2019;Phompradit et al., 2011;Sanephonasa et al., 2021;Satyagraha et al., 2015;Sulistyaningrum et al., 2020;Yusoff et al., 2003;Wang et al., 2008;Zhong et al., 2018). ...
... G6PDd is caused by a deficiency in the enzyme glucose-6-phosphate dehydrogenase encoded by the G6PD (OMIM: 305900) gene on chromosome Xq28 (Cappellini & Fiorelli, 2008). Clinically, patients with G6PDd present with either the early onset of neonatal hyperbilirubinemia or the late onset of fulminant episodes of hemolysis by specific oxidative agents (such as primaquine and chloroquine, which are prescribed in malarial prophylaxis) or by the intake of fava beans (Cappellini & Fiorelli, 2008;Ong et al., 2017;Tarhani et al., 2021). ...
... G6PDd is caused by a deficiency in the enzyme glucose-6-phosphate dehydrogenase encoded by the G6PD (OMIM: 305900) gene on chromosome Xq28 (Cappellini & Fiorelli, 2008). Clinically, patients with G6PDd present with either the early onset of neonatal hyperbilirubinemia or the late onset of fulminant episodes of hemolysis by specific oxidative agents (such as primaquine and chloroquine, which are prescribed in malarial prophylaxis) or by the intake of fava beans (Cappellini & Fiorelli, 2008;Ong et al., 2017;Tarhani et al., 2021). There is no treatment; thus, the most effective therapy is knowing the disease's presence and preventing exogenously oxidative agents. ...
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Background: Several inherited metabolic diseases are underreported in Vietnam, namely glucose-6-phosphate dehydrogenase deficiency (G6PDd), phenylketonuria (PKU) and galactosemia (GAL). Whilst massively parallel sequencing (MPS) allows researchers to screen several loci simultaneously for pathogenic variants, no screening programme uses MPS to uncover the variant spectra of these diseases in the Vietnamese population. Methods: Pregnant women (mean age of 32) from across Vietnam attending routine prenatal health checks agreed to participate and had their blood drawn. MPS was used to detect variants in their G6PD, PAH and GALT genes. Results: Of 3259 women screened across Vietnam, 450 (13.8%) carried disease-associated variants for G6PD, PAH and GALT. The prevalence of carriers was 8.9% (291 of 3259) in G6PD and 4.6% (152 of 3259) in PKU, whilst GAL was low at 0.2% (7 of 3259). Two GALT variants, c.593 T > C and c.1034C > A, have rarely been reported. Conclusion: This study highlights the need for routine carrier screening, where women give blood whilst receiving routine prenatal care, in Vietnam. The use of MPS is suitable for screening multiple variants, allowing for identifying rare pathogenic variants. The data from our study will inform policymakers in constructing cost-effective genetic metabolic carrier screening programmes.
... It is not intended as a comprehensive review, but rather as an overview, with emphases on lesions that are more common or relatively more common and on diagnoses that may be suggested by bone scintigraphy and radiologic imaging. G-6PD deficiency is one of the most common human enzyme defects that causes many biochemical and clinical phenotypes, including neonatal jaundice, chronic haemolysis and acute haemolytic anaemia [1]. However, 99m Tc-MDP bone scan and radiological patterns of G-6PD deficiency have rarely been reported [2]. ...
... Hematologic abnormalities of G-6PD deficiency are exceedingly common. Besides ingestion of fava beans, drugs and infection affecting oxidative stress of red blood cells can also trigger manifestations of G-6PD deficiency [1]. This patient subsequently presented with anemia, thrombocytopenia and fatigue. ...
Article
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Here, we reported a panel of rare diseases involving bilateral lower extremities with similar imaging patterns on 99mTc-MDP bone scans. Glucose-6-phosphate dehydrogenase deficiency (G-6PD deficiency), Gaucher disease (GD), steroid-induced osteonecrosis, progressive diaphyseal dysplasia (PDD), Erdheim–Chester disease (ECD) and Langerhans cell sarcoma (LCS) were included and imaging characteristics were analyzed. The rare properties of these diseases and mimicking features on 99mTc-MDP bone scans rendered differential diagnosis difficult but necessary. We believe that the rarely known imaging features of the reported diseases will undoubtedly help nuclear medicine physicians make differential diagnoses in clinical practice.
... In our study, most patients that underwent ET had G6PD deficiency, which is common in malaria-endemic areas, such as tropical Africa and tropical and subtropical Asia (19). G6PD deficiency has been observed in the Myanmar population (20), with a prevalence rate of 6.1% (21). ...
... According to the AAP guidelines adopted in Myanmar, where screening for G6PD is not performed on a routine basis, neonatal assessment including the Beutler fluorescent spot test should be performed when neonates develop hyperbilirubinemia {bilirubin concentrations greater than the 95th percentile [150 µmol/L (8.8mg/dL)]} within the first 24 h of life (6). However, hyperbilirubinemia caused by G6PD deficiency is evident at 1-4 days of age, and its manifestation is similar to that of physiological jaundice (19), which is present in approximately 60% of the term newborns in the first week of life (22). This makes it difficult to suspect neonates with G6PD deficiency on day 0, thereby leaving them uncared for until hyperbilirubinemia is so obvious that they need ET. ...
Article
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Background Neonatal hyperbilirubinemia is a significant health problem in Myanmar. We introduced transcutaneous bilirubin (TcB) measurements in 2017 and developed an hour-specific TcB nomogram for early detection and treatment of hyperbilirubinemia in Myanmar neonates. This study aimed to evaluate whether our screening method for hyperbilirubinemia decreased the requirement of blood exchange therapy (ET). Methods This retrospective cohort study was conducted at the Central Women’s Hospital, Yangon. Two groups were included as follows: group 1 (control group; comprising infants born in 2016 and screened on the basis of Kramer’s rule), and group 2 (intervention group; comprising infants born in 2019 and screened by TcB measurement using a nomogram). The number of ETs was analyzed based on causes of hyperbilirubinemia and number of days after birth. Results Groups 1 and 2 comprised 12,968 and 10,090 infants, respectively. Forty-six and two infants in Groups 1 and 2, respectively, required an ET. The odds ratio for ET was 18.0 (Group 1 to Group 2; 95% confidence interval [CI]: 4.8–67.1; p = 0.000). Serum bilirubin values at the time ET was administered were significantly higher in Group 1 than those in Group 2 (median: 23.0 and 16.8, respectively). Conclusion The management of hyperbilirubinemia using our screening method (TcB Nomogram) can effectively reduce the need for ET in neonates in Myanmar.
... 12−15 A better understanding of the relative frequency of G6PD gene variants would support evaluations towards safe administration strategies and radical cure. 16,17 Therefore, this work aims to provide an accurate and comprehensive mapping of G6PD deficiency in malaria endemic areas in the Brazilian Amazon. ...
... The World Health Organization (WHO) recommends the fluorescent spot test to be used for population screenings. 2,16,22,23 Field workers were trained for sample collection at a reference institution in Manaus, Brazil. Samples were collected through domicile visits (only one individual per household, the oldest if more than one present) and in places of great circulation within the peri urban areas of the municipalities. ...
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Background Difficulties associated with the assessment of glucose-6-phosphate dehydrogenase deficiency (G6PDd), particularly in remote areas, hinders the safe use of 8-aminoquinolines such as primaquine (PQ) and tafenoquine against Plasmodium vivax malaria due to the risk of haemolysis. Methods This cross-sectional study was conducted in 41 malaria-endemic municipalities of six states in the Brazilian Amazon, between 2014 and 2018. Male individuals were screened for G6PDd using the qualitative Fluorescent Spot Test using fingerpick-collected whole blood samples. Point and interval estimates of the G6PDd prevalence were calculated for each state. Deficient samples were genotyped for the most prevalent variants in the Amazon. Frequencies of P. vivax malaria recurrences were estimated for G6PDd and non-G6PDd patients. Interpretation This is one of the largest surveys ever conducted in Latin America, covering the entire malaria endemic area in the Brazilian Amazon. These results indicate that an important proportion of the population is at risk of hemolysis if exposed to PQ and its congener drug tafenoquine. The adoption of G6PDd screening protocols is essential to ensure the safety of individuals treated with those drugs and should also be considered when implementing malaria elimination strategies. Findings A total of 14,847 individuals were included, of which 5.6% presented G6PDd. The state of Acre had the highest G6PDd prevalence (8.3%), followed by Amapá (5.8%), Pará (5.7%), Rondônia (5.4%), Roraima (4.2%) and Amazonas (4.0%). From 828 genotyped samples, African A⁺ (6.2%), African A⁻ (39.3%) and wild-type (non-African non-Mediterranean; 54.2%) variants were found. A greater proportion of malaria recurrences was found among G6PD deficient individuals [16.7% vs 4.1%, Risk ratio 3.52 (2.16–5.74) p < 0.01]. Funding Brazilian Ministry of Health; Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM).
... Primaquine and Pamaquine are antimalarial drugs known to induce hemolysis in G6PDdeficient patients. Other drugs that exert similar effects include Nitrofurantoin, Sulfones, and Sulfonamides such as Sulfanilamide and Sulfacetamide (54,55). These drugs are either oxidative in nature or can generate oxidant compounds in the body, inducing oxidative stress to the RBCs leading to hemolysis. ...
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a prevalent condition worldwide and is caused by loss-of-function mutations in the G6PD gene. Individuals with deficiency are more susceptible to oxidative stress which leads to the classical, acute hemolytic anemia (favism). However, G6PD deficiency in newborn infants presents with an increased risk of hyperbilirubinemia, that may rapidly escalate to result in bilirubin induced neurologic dysfunction (BIND). Often with no overt signs of hemolysis, G6PD deficiency in the neonatal period appears to be different in the pathophysiology from favism. This review discusses and compares the mechanistic pathways involved in these two clinical presentations of this enzyme disorder. In contrast to the membrane disruption of red blood cells and Heinz bodies formation in favism, G6PD deficiency causing jaundice is perhaps attributed to the disruption of oxidant-antioxidant balance, impaired recycling of peroxiredoxin 2, thus affecting bilirubin clearance. Screening for G6PD deficiency and close monitoring of affected infants are important aspects in neonatal care to prevent kernicterus, a permanent and devastating neurological damage. WHO recommends screening for G6PD activity of all infants in countries with high prevalence of this deficiency. The traditional fluorescent spot test as a screening tool, although low in cost, misses a significant proportion of cases with moderate deficiency or the partially deficient, heterozygote females. Some newer and emerging laboratory tests and diagnostic methods will be discussed while developments in genomics and proteomics contribute to increasing studies that spatially profile genetic mutations within the protein structure that could predict their functional and structural effects. In this review, several known variants of G6PD are highlighted based on the location of the mutation and amino acid replacement. These could provide insights on why some variants may cause a higher degree of phenotypic severity compared to others. Further studies are needed to elucidate the predisposition of some variants toward certain clinical manifestations, particularly neonatal hyperbilirubinemia, and how some variants increase in severity when co-inherited with other blood- or bilirubin-related genetic disorders.
... The G6PD gene, on the X chromosome, shows extensive polymorphism with nearly 200 genetic variants described usually resulting in enzymatic instability. G6PD deficiency is the most prevalent enzyme deficiency worldwide, with an estimated 500 million people affected (reviewed in [22][23][24][25]. G6PD is the first enzyme in the pentose phosphate pathway, which generates NADPH (from NADP), required for the production of reduced glutathione in RBCs, and it is essential for the function of catalase. ...
Article
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Nitrofurantoin, a broad-spectrum antibiotic available since 1953, is used widely for the treatment of urinary tract infections as it often retains activity against drug-resistant uropathogens. It is contraindicated in pregnant women at term, and in neonates. Like trimethoprim/sulfamethoxazole, nitrofurantoin carries a warning for patients with known sensitivity to oxidant drugs, notably glucose-6-phosphate dehydrogenase (G6PD) deficiency, in whom it may cause haemolytic anaemia. This is a barrier to uptake in tropical regions where there is a high burden of antimicrobial resistance and where G6PD deficiency is common. Early studies of erythrocyte survival following nitrofurantoin suggest it is less likely to cause oxidant haemolysis in individuals with G6PD deficiency than primaquine. Here we review reports of haemolysis associated with nitrofurantoin from the published literature and from USA (FDA Adverse Event Reporting System; FAERS) and European (VigiBase) pharmacovigilance databases. In total, 318 episodes of haemolytic anaemia were reported and 10 deaths, with 42 (13%) in individuals with confirmed or highly probable G6PD deficiency, out of at least 245 million exposures. A causal link between death and exposure was not reported and a precise risk estimation in G6PD-deficient individuals was not possible as there are few reports from regions where this enzymopathy is most prevalent. The evidence suggests a total daily dose of 200 mg nitrofurantoin may be used for short (3–5 day) course urinary tract infection treatment without G6PD screening when accompanied by appropriate advice. Pharmacovigilance in countries with high prevalence of G6PD-deficiency is recommended to monitor for serious adverse events.
... This is an X-chromosome-linked genetic disorder where red blood cells are prone to oxidized stress leading to haemolysis when exposed to oxidizing agents such as PMQ [6,7]. G6PD deficiency is estimated to be present in a population of 400 million across the globe [8]. In Laos, its prevalence among males is estimated at 8.1% based on G6PD genotypic data [9]. ...
Article
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Background: Plasmodium vivax (Pv) infections were 68% of the total malaria burden in Laos in 2019. The parasite causes frequent relapses, which can be prevented by primaquine (PMQ). Testing for glucose-6-phosphate-dehydrogenase (G6PD) deficiency is recommended before giving PMQ to avoid haemolysis. Because of the risk of haemolysis in G6PD intermediate deficiencies among females, Laos uses the PMQ 14-days regimen only in G6PD normal females. Among G6PD point-of-care tests, qualitative tests cannot differentiate between G6PD normal and intermediate females. Quantitative tests are required to differentiate between G6PD normal and intermediate deficiencies. However, the quantitative test lacks the cost-effectiveness evidence necessary for decision-making for large-scale adoption. This study examined the cost-effectiveness of quantitative G6PD test, with either supervised PMQ treatment or unsupervised PMQ treatment, against the usual unsupervised PMQ 8-weeks strategy. Supervised PMQ 8-weeks strategy without G6PD testing was also compared against the unsupervised PMQ 8-weeks strategy since the former had recently been adopted in malaria high burden villages that had village malaria volunteers. A budget impact analysis was conducted to understand the incremental cost and effect needed for a nationwide scale-up of the chosen strategy. Methods: A decision tree model compared the cost-effectiveness of implementing four strategies at one health facility with an average of 14 Pv cases in one year. The strategies were unsupervised PMQ strategy, supervised PMQ strategy, G6PD test with unsupervised PMQ strategy, and G6PD test with supervised PMQ strategy. Disability Adjusted Life Years (DALYs) was the effect measure. Costs were calculated from a payer perspective, and sensitivity analyses were conducted. One Gross Domestic Product (GDP) per capita of Laos was set as the cost-effectiveness threshold. Budget impact analysis was conducted using the health facility wise Pv data in Laos in 2020. Findings: Supervised PMQ strategy was extendedly dominated by G6PD test strategies. When compared against the unsupervised PMQ strategy, both G6PD test strategies were more costly but more effective. Their Incremental Cost-Effectiveness Ratios (ICER) were 96.72US$ for the G6PD test with unsupervised PMQ strategy and 184.86US$ for the G6PD test with supervised PMQ strategy. Both ICERs were lower than one GDP per capita in Laos. Following the sensitivity analysis, low adherence for PMQ 14 days made both G6PD test strategies less cost-effective. The lower the Pv case number reported in a health facility, the higher the ICER was. In the budget impact analysis, the expected budget need was only half a million US$ when the G6PD test rollout was discriminately done depending on the Pv case number reported at the health facilities. Indiscriminate roll out of G6PD test to all health facilities was most expensive with least effect impact.
... Many studies show the G6PD c.202G > A and c.376A > G variants and Duffy-negative blood group are two RBC variants that confer protection against malaria [19,31,32]. Many authors postulate that this is a result of the increased sensitivity of P. vivax to oxidative stress in G6PD deficiency, with negative influence on the parasite, as well as the association of different phenotypes of the Duffy blood group in the invasion of RBCs [33][34][35]. Furthermore, the mechanism of action between G6PD and Duffy group is not fully known. Based on these facts, this study aimed to determine the prevalence of Duffy alleles and G6PD c.202G > A and c.376A > G variants in uncomplicated and severe malaria patients, in order to answer if these erythrocyte variants deserve to be better investigated with clinical signs, susceptibility, protection and parasitaemia against of P. vivax infections. ...
Article
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Background Over a third of the world’s population is at risk of Plasmodium vivax -induced malaria. The unique aspect of the parasite’s biology and interactions with the human host make it harder to control and eliminate the disease. Glucose-6-phosphate dehydrogenase (G6PD) deficiency and Duffy-negative blood groups are two red blood cell (RBC) variations that can confer protection against malaria. Methods Molecular genotyping of G6PD and Duffy variants was performed in 225 unrelated patients (97 with uncomplicated and 128 with severe vivax malaria) recruited at a Reference Centre for Infectious Diseases in Manaus. G6PD and Duffy variants characterizations were performed using Real Time PCR (qPCR) and PCR–RFLP, respectively. Results The Duffy blood group system showed a phenotypic distribution Fy(a + b−) of 70 (31.1%), Fy(a + b +) 96 (42.7%), Fy(a−b +) 56 (24.9%) and Fy(a−b−) 1 (0.44%.) The genotype FY*A/FY*B was predominant in both uncomplicated (45.3%) and severe malaria (39.2%). Only one Duffy phenotype Fy(a-b) was found and this involved uncomplicated vivax malaria. The G6PD c.202G > A variant was found in 11 (4.88%) females and 18 (8.0%) males, while c.376A > G was found in 20 females (8.88%) and 23 (10.22%) male patients. When combined GATA mutated and c.202G > A and c.376A > G mutated, was observed at a lower frequency in uncomplicated (3.7%) in comparison to severe malaria (37.9%). The phenotype Fy(a−b +) (p = 0.022) with FY*B/FY*B (p = 0.015) genotype correlated with higher parasitaemia. Conclusions A high prevalence of G6PD c202G > A and c.376A > G and Duffy variants is observed in Manaus, an endemic area for vivax malaria. In addition, this study reports for the first time the Duffy null phenotype Fy(a-b-) in the population of the Amazonas state. Moreover, it is understood that the relationship between G6PD and Duffy variants can modify clinical symptoms in malaria caused by P . vivax and this deserves to be further investigated and explored among this population.
... Deficiency of G6PDH, the first enzyme in the PPP, is relatively common and is considered to provide resistance against malaria. Drugs that cause oxidative stress can trigger acute hemolysis in people with deficiency of G6PDH because of the compromised antioxidant system [68]. After this brief introduction to RBC's redox biochemistry, we will discuss each component separately. ...
Chapter
We have centered our discussion on the role of blood thiols on the general homeostasis of oxygen- and nitrogen-derived oxidants. The central thiol participation in redox homeostasis is supported by the high relative concentration of thiol antioxidants both in plasma and blood cells together with their preferential reaction with oxidants of diverse nature. Blood accomplishes multiple and important physiological functions, including the regulation of the redox homeostasis of the entire body. Blood components actively participate as targets and scavengers, but also as a source of oxidants. Thiols, both in plasma and in blood cells, participate in the redox crosstalk between blood and the surrounding tissues. In fact, because of their quantitative predominance in blood, the intracellular abundance of highly reactive thiols, and the continuous exchange with the surroundings, RBCs play a paramount role in blood and tissue redox homeostasis, regulating uncontrolled molecular oxidative modifications that lead to disease.
... Glucose-6-phosphate dehydrogenase deficiency (G6PDd) affects up to 500 million people worldwide and is considered the most common human hemoglobinopathy. [1][2][3] Typically asymptomatic, a key clinical feature of G6PDd is haemolytic anaemia, which results from infection, exposure to certain medications and the consumption of fava beans. 1,4 Carriers of G6PDd variants are found predominantly in Africa, the Mediterranean, Middle East and Southeast Asia, with the highest allelic frequencies reported at up to ~30% in regions of sub-Saharan Africa and the Arabian Peninsula. ...
Article
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Primaquine (PQ) and Tafenoquine (TQ) are clinically important 8‐aminoquinolines (8‐AQ) used for radical cure treatment of P. vivax infection, known to target hepatic hypnozoites. 8‐AQs can trigger haemolytic anaemia in individuals with glucose‐6‐phosphate dehydrogenase deficiency (G6PDd), yet the mechanisms of haemolytic toxicity remain unknown. To address this issue, we used a humanized mouse model known to predict haemolytic toxicity responses in G6PDd human red blood cells (huRBCs). To evaluate the markers of eryptosis, huRBCs were isolated from mice 24–48 h post‐treatment and analysed for effects on phosphatidylserine (PS), intracellular reactive oxygen species (ROS) and autofluorescence. Urinalysis was performed to evaluate the occurrence of intravascular and extravascular haemolysis. Spleen and liver tissue harvested at 24 h and 5–7 days post‐treatment were stained for the presence of CD169+ macrophages, F4/80+ macrophages, Ter119+ mouse RBCs, glycophorin A+ huRBCs and murine reticulocytes (muRetics). G6PDd‐huRBCs from PQ/TQ treated mice showed increased markers for eryptosis as early as 24 h post‐treatment. This coincided with an early rise in levels of muRetics. Urinalysis revealed concurrent intravascular and extravascular haemolysis in response to PQ/TQ. Splenic CD169+ macrophages, present in all groups at day 1 post‐dosing were eliminated by days 5–7 in PQ/TQ treated mice only, while liver F4/80 macrophages and iron deposits increased. Collectively, our data suggest 8‐AQ treated G6PDd‐huRBCs have early physiological responses to treatment, including increased markers for eryptosis indicative of oxidative stress, resulting in extramedullary haematopoiesis and loss of splenic CD169+ macrophages, prompting the liver to act as the primary site of clearance.
... G6PD deficiency is the most common enzyme deficiency in humans affecting over 400 million people worldwide [13] . Recent evidences have revealed the role of G6PD and PPP in regulating endothelial cells [14][15][16][17] . ...
Article
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Hypoxia‐induced endothelial dysfunction is known to be involved in the pathogenesis of several vascular diseases. However, it remains unclear whether the pentose phosphate pathway (PPP) is involved in regulating the response of endothelial cells to hypoxia. Here, we established an in vitro model by treating EA.hy926 (a hybrid human umbilical vein cell line) with cobalt chloride (CoCl2; a chemical mimic that stabilizes HIF‐1α, thereby leading to the development of hypoxia), and used this to investigate the involvement of PPP by examining expression of its key enzyme, glucose‐6‐phosphate dehydrogenase (G6PD). We report that CoCl2 induces the accumulation of HIF‐1α, leading to endothelial cell dysfunction characterized by reduced cell viability, proliferation, tube formation and activation of cytokine production, accompanied with a significant decrease in G6PD expression and activity. The addition of 6‐aminonicotinamide (6‐AN) to inhibit PPP directly causes endothelial dysfunction. Additionally, N‐Acetylcysteine (NAC), a precursor of glutathione, was further evaluated for its protective effects; NAC displayed a protective effect against CoCl2‐induced cell damage by enhancing G6PD activity, and this was abrogated by 6‐AN. The effects of CoCl2 and the involvement of G6PD in endothelial dysfunction have been confirmed in primary human aortic endothelial cells. In summary, G6PD was identified as a novel target of CoCl2‐induced damage, which highlights the involvement of PPP in regulating the response of endothelial cell CoCl2. Treatment with NAC may be a potential strategy to treat hypoxia or ischemia, which are widely observed in vascular diseases.
... Patients can develop hemolytic anemia due to some infectious agents and drugs, even if they are asymptomatic. There is evidence to imply an association between G6PD deficiency and greater susceptibility to SARS-CoV-2 infection, as well as the severity of the illness [50]. G6PD deficiency might increase the susceptibility to coronavirus infection. ...
Article
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Since December 2019, the COVID-19 pandemic, which originated in Wuhan, China, has resulted in over six million deaths worldwide. Millions of people who survived this SARS-CoV-2 infection show a number of post-COVID complications. Although, the comorbid conditions and post-COVID complexities are to some extent well reviewed and known, the impact of COVID-19 on pre-existing congenital anomalies and genetic diseases are only documented in isolated case reports and case series, so far. In the present review, we analyzed the PubMed indexed literature published between December 2019 and January 2022 to understand this relationship from various points of view, such as susceptibility, severity and heritability. Based on our knowledge, this is the first comprehensive review on COVID-19 and its associations with various congenital anomalies and genetic diseases. According to reported studies, some congenital disorders present high-risk for developing severe COVID-19 since these disorders already include some comorbidities related to the structure and function of the respiratory and cardiovascular systems, leading to severe pneumonia. Other congenital disorders rather cause psychological burdens to patients and are not considered high-risk for the development of severe COVID-19 infection.
... Genetic factors predisposing to haemolysis or reduced bilirubin conjugation predispose to NH [4]. X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy, with an allelic frequencies averaging 8-10% in tropical areas, but in some populations reaching over 30% [5]. G6PD deficiency is expressed completely in the red cells of hemizygote males and homozygote females but, because of Lyonisation, heterozygotes have a range of phenotypic expression between deficient and normal. ...
Article
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Very high unconjugated bilirubin plasma concentrations in neonates (neonatal hyperbilirubinaemia; NH) may cause neurologic damage (kernicterus). Both increased red blood cell turn-over and immaturity of hepatic glucuronidation contribute to neonatal hyperbilirubinaemia. The incidence of NH requiring phototherapy during the first week of life on the Thailand-Myanmar border is high (approximately 25%). On the Thailand-Myanmar border we investigated the contribution of genetic risk factors to high bilirubin levels in the first month of life in 1596 neonates enrolled in a prospective observational birth cohort study. Lower gestational age (<38 weeks), mutations in the genes encoding glucose-6-phosphate dehydrogenase (G6PD) and uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1 were identified as the main independent risk factors for NH in the first week, and for prolonged jaundice in the first month of life. Population attributable risks (PAR%) were 61.7% for lower gestational age, 22.9% for hemi or homozygous and 9.9% for heterozygous G6PD deficiency respectively, and 6.3% for UGT1A1*6 homozygosity. In neonates with an estimated gestational age ≥ 38 weeks, G6PD mutations contributed PARs of 38.1% and 23.6% for “early” (≤ 48 hours) and “late” (49–168 hours) NH respectively. For late NH, the PAR for UGT1A1*6 homozygosity was 7.7%. Maternal excess weight was also a significant risk factor for “early” NH while maternal mutations on the beta-globin gene, prolonged rupture of membranes, large haematomas and neonatal sepsis were risk factors for “late” NH. For prolonged jaundice during the first month of life, G6PD mutations and UGT1A1*6 mutation, together with lower gestational age at birth and presence of haematoma were significant risk factors. In this population, genetic factors contribute considerably to the high risk of NH. Diagnostic tools to identify G6PD deficiency at birth would facilitate early recognition of high risk cases.
... Mutations in the G6PD gene result in an x-linked hereditary disease known as G6PD deficiency, which is associated with the protein variants having different levels of enzyme activity leading to a wide variety of biochemical and clinical phenotypes (Desnick et al., 2001). G6PD deficiency is the most common RBC enzyme deficiency which affects more than 400 million individuals worldwide (Cappellini & Fiorelli, 2008). More than 300 G6PD mutations have been reported to date, and most amongst them are the result of a single base pair change in the amino acid sequence of G6PD protein. ...
Article
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Several natural mutants of the human G6PD enzyme exist and have been reported. Because the enzymatic activities of many mutants are different from that of the wildtype, the genetic polymorphism of G6PD plays an important role in the synthesis of nucleic acids via ribulose-5-phosphate and formation of reduced NADP in response to oxidative stress. G6PD mutations leading to its deficiency result in the neonatal jaundice and acute hemolytic anemia in human. Herein, we demonstrate the molecular dynamics simulations of the wildtype G6PD and its three mutants to monitor the effect of mutations on dynamics and stability of the protein. These mutants are Chatham (A335T), Nashville (R393H), Alhambra (V394L), among which R393H and V394L lie closer to binding site of structural NADP ⁺ . MD analysis including RMSD, RMSF and protein secondary structure revealed that decrease in the stability of mutants is key factor for loss of their activity. The results demonstrated that mutations in the G6PD sequence resulted in altered structural stability and hence functional changes in enzymes. Also, the binding site, of structural NADP ⁺ , which is far away from the catalytic site plays an important role in protein stability and folding. Mutation at this site causes changes in structural stability and hence functional deviations in enzyme structure reflecting the importance of structural NADP ⁺ binding site. The calculation of binding free energy by post processing end state method of Molecular Mechanics Poisson Boltzmann SurfaceArea (MM-PBSA) has inferred that ligand binding in wildtype is favorable as compared to mutants which represent destabilised protein structure due to mutation that in turn may hinder the normal physiological function. Exploring individual components of free energy revealed that the van der Waals energy component representing non-polar/hydrophobic energy contribution act as a dominant factor in case of ligand binding. Our study also provides an insight in identifying the key inhibitory site in G6PD and its mutants which can be exploited to use them as a target for developing new inhibitors in rational drug design.
... Class I (less than 1% of normal activity) has been considered the most serious among classes and is speci cally associated with chronic nonspherocytic hemolytic anemia (CNSHA). Class II (1 to 10% of normal) is highly associated with acute hemolytic anemia, while Class III (10 to 60% of normal) is normally associated with occasional acute hemolytic anemia, and Class IV (60 to 150% of normal) and Class V (>150% of normal) are mostly asymptomatic [8]. ...
Article
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme disorder and is caused by G6PD gene mutations. To date, more than 400 variants in the G6PD gene have been discovered, and about 160 identified variants are associated with a significant decrease in the G6PD enzyme activity. However, the molecular characterization and epidemiological study of G6PD deficiency are still limited in Vietnam. Therefore, we conducted this study to determine the G6PD variants among the Vietnamese populations and evaluate their correlation to G6PD enzyme activity. A total of 339 patients (302 males and 37 females) were enrolled in this study. The G6PD variants were identified by Sanger sequencing. Our results indicate that males are more severely deficient in G6PD than females. This enzyme activity in males (1.27 ± 1.06 IU/g·Hb) is significantly lower than in females (2.98 ± 1.57 IU/g·Hb) (p<0.0001). The enzyme activity of the heterozygous-homozygous females and heterozygous females-hemizygous males was found to be significantly different (p<0.05), which is interpreted due to random X-inactivation. For G6PD molecular characteristics, Viangchan (c.871G>A), Canton (c.1376G>T) and Kaiping (c.1388G>A) variants were the most dominant, accounting for 24.48%, 17.70%, and 22.42%, respectively, whereas the highest frequency of complex variants was observed in Viangchan/Silent with 20.35%. In terms of G6PD activity, the Union variant presented the lowest mean value (1.03 IU/g·Hb) compared to the other variants (p<0.05). Computational analysis using Polyphen-2 tool investigated that all variants were relative to G6PD deficiency and separated the levels as benign and damaged. The result will establish effective methods to screen G6PD variants in Vietnam.
... Genetic abnormalities causing deficiency of the G6PD enzyme lead to uncontrolled premature hemolysis of RBCs triggered by viral or bacterial infections, sulpha-containing drugs, and certain types of food, manifested mainly as fatigue, pallidness, jaundice, shortness of breath, tachycardia, dark urine, and splenomegaly [3]. Clinical symptom severity in G6PD-deficient patients corresponds to the level of G6PD activity in the affected cells. ...
Article
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G6PD deficiency is a genetic disease that weakens the immune system and renders affected individuals susceptible to infections. In the Sultanate of Oman resides a high number of recorded G6PD cases due to widespread consanguineous marriage, which may reach 25% of the population. We studied the infection patterns and risk factors for mortality to provide antimicrobial stewardship recommendations for these patients. After obtaining ethical approval, a registry of recorded cases was consulted retrospectively to include G6PD-deficient adult patients admitted to Suhar hospital over 5 years with microbiologically confirmed infections. Patient demographics, health-related information, infection causes, treatment, and clinical outcomes were studied. Data were analyzed to describe infection patterns and risk factors. Several variables, including underlying comorbidities and hospitalization details, such as length of stay, admission to critical care unit, blood transfusion, or exposure to an invasive procedure, were statistically associated with the acquisition of multidrug-resistant and hospital-acquired infections. Meanwhile, these infections were associated with a high mortality rate (28%), significantly associated with the patient’s health status and earlier exposure to antimicrobial treatment due to previous bacterial infection. The high prevalence of G6PD deficiency among the Omani population should alert practitioners to take early action when dealing with such cases during infection that requires hospitalization. Strict infection control measures, Gram-negative empiric coverage, hospital discharge as early as possible, and potent targeted antimicrobial therapy in this patient population can ameliorate the treatment outcomes and should be emphasized by the antimicrobial stewardship team.
... Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is the most common human enzyme deficiency affecting 10% of the world population which accounts for 400 million people worldwide (Cappellini & Fiorelli, 2008). In erythrocytes G6PD is the only Nicotinamide Adenine Dinucleotide Phosphate (NADPH) generating enzyme and the most important function of this enzyme is detoxification of oxidative agents, so erythrocytes are much more sensitive to the lack or deficiency of this enzyme rather than other tissues (Gaetani, et al 1989). ...
Article
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited human enzymopathy, characterized by clinical, biochemical, and molecular heterogeneity. More than 400 million people have been affected worldwide. In this study two mutations Mediterranean (563 C→T) and Chatham (1003 G→A) G6PD are studied at molecular bases. A54 G6PD deficient patients and 10 normal Kurdish male samples are selected, and the DNA extracted from each peripheral blood samples using phenol-chloroform based method. The quality and quantity of each DNA samples measured by Nanodrop 1000. For identification of Mediterranean and Chathem mutation PCR/RFLP Technique was used in this study. 46 (85%) of 54 samples had G6PD Mediterranean (563 C→T) and 3 (5.5%) samples had G6PD Chathem (1003 G→A) mutation. No mutations have been detected in normal samples in this study. According to this study G6PD Mediterranean is the most frequent mutation in Erbil city like other provinces in Kurdistan and neighboring country among G6PD deficient individuals and the G6PD Chatham present in low frequency.
... G6PD deficiency is the most common human enzymatic deficiency disorder, found primarily in males due to G6PD being found on the X-chromosome. G6PD deficiency primarily manifests with hemolytic anemia triggered by exposure of red blood cells (RBCs) to oxidizing agents (including anti-malarial drugs, other medications, or consumption of fava beans) (5)(6)(7)(8). RBCs are particularly susceptible to the effects of G6PD deficiency since they lack mitochondria and therefore rely on G6PD as their sole source of NADPH. The persistence of G6PD deficiency in humans can be explained by the fact that the increased oxidative stress resulting from these mutations confer some resistance to the malaria parasite, and G6PD deficiency is primarily found in humans originating from areas in which malaria is endemic (9)(10)(11). ...
Article
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Human glucose-6-phosphate dehydrogenase (G6PD) is the main cellular source of NADPH, and thus plays a key role in maintaining reduced glutathione to protect cells from oxidative stress disorders such as hemolytic anemia. G6PD is a multimeric enzyme that uses the cofactors β-D-glucose 6-phosphate (G6P) and “catalytic” NADP ⁺ (NADP ⁺ c), as well as a “structural” NADP ⁺ (NADP ⁺ s) located ∼25 Å from the active site, to generate NADPH. While X-ray crystallographic and biochemical studies have revealed a role for NADP ⁺ s in maintaining the catalytic activity by stabilizing the multimeric G6PD conformation, other potential roles for NADP ⁺ s have not been evaluated. Here, we determined the high resolution cryo-electron microscopy structures of human wild-type G6PD in the absence of bound ligands and a catalytic G6PD-D200N mutant bound to NADP ⁺ c and NADP ⁺ s in the absence or presence of G6P. A comparison of these structures, together with previously reported structures, reveals that the unliganded human G6PD forms a mixture of dimers and tetramers with similar overall folds, and binding of NADP ⁺ s induces a structural ordering of a C-terminal extension region and allosterically regulates G6P binding and catalysis. These studies have implications for understanding G6PD deficiencies and for therapy of G6PD-mediated disorders.
... Red blood cells mainly depend on G6PD-derived NADPH for maintaining redox equilibrium compared with other cells. Therefore, a deficiency of G6PD causes oxidative stress, and subsequent hemolysis leads to hemolytic anemia [58][59][60]. Similarly, the role of G6PD deficiency has been linked with oxidative stress and neuroinflammation in neurodegenerative and neurodevelopmental disorders [11]. ...
Article
Human COVID-19 has affected more than 491 million people worldwide. It has caused over 6.1 million deaths and has especially perpetrated a high number of casualties among the elderly and those with comorbid illnesses. COVID-19 triggers a pro-oxidant response, leading to the production of reactive oxygen species (ROS) as a common innate defense mechanism. However, ROS are regulated by a key enzyme called G6PD via the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which controls the generation and removal of ROS in a tissue-specific manner. Therefore, a deficiency of G6PD can lead to the dysregulation of ROS, which causes a severe inflammatory response in COVID-19 patients. This report highlights the G6PD dichotomy in the regulation of ROS and inflammatory responses, as well as its deficiency in severity among COVID-19 patients.
... Neutrophil interactions with platelets during chronic inflammation and produce chemokines that activate neutrophils and promote Neutrophil Extracellular Traps NET formation. In addition to promoting neutrophil adhesion to the endothelium [25]. ...
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Background: Tramadol hydrochloride (TH) is an opioid centrally acting analgesic used to treat moderate to severe acute and chronic pains. Non-medical use of tramadol induced various health risks. Objective: We investigated the neurodegenerative disorders of tramadol in brain tissues and the protective role of royal jelly. Methods: We used 20 male albino rats allocated into four groups: Group 1, served as a control group, and Group 2, rats administrated with tramadol at a dose of 20 mg/kg/b. W for 60 days. Group 3: rats administrated tramadol at a dose of 20 mg/kg/b. W for 60 days and treated with royal jelly (RJ) in a 100 mg/kg dose. b.w. Group 4: Rats inoculated with royal jelly (RJ) at a dose of 100 mg/kg. b.w. Blood samples were collected for hematological and biochemical analysis. Brain tissues were harvested for Biochemicals and histopathological examinations. Results: Administration of tramadol revealed a significant decrease in Hb concentration, RBCs count, PCV % and Lymphocytes %, while WBCS and platelets count, Neutrophiles, and monocytes % were increased. Also, Tramadol decreased glucose-6-phosphate dehydrogenase (G6PD) level while creatine kinase-BB (CK-BB) and neuron-specific enolase enzymes (NSE) were increased. Furthermore, tramadol increased the lipid peroxidation MDA, while total antioxidants capacity (TAC) and glutathione reductase (GSH) concentrations were decreased. Histopathologically, tramadol-induced neurodegenerative changes in brain neurons manifested by acute necrosed neurons with gliosis and vascular congestions. Royal Jelly improved the previous deleterious effects by decreasing brain tissue oxidative stress. Conclusion: Tramadol misuse caused neurodegenerative effects and were relieved by RJ administration. Keywords: Tramadol, Royal Jelly, Oxidative Stress, Brain, Neurodegeneration, Misuse.
... It is an established fact that the generated free radicals are decimated by the glutathione system, catalase, and the non-thiol and thiol proteins, including peroxiredoxins and GPx [63], which makes them the target for ROS. Available data in the literature have shown that upregulation of these enzymatic and non-enzymatic antioxidants protect cells from ROS-induced apoptosis [5,45,64]. ...
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Ethnopharmacological relevance: Oxidative stress is a key player in intestinal ischemia/reperfusion (I/R) injury (IIRI) with a tendency to trigger systemic inflammatory response, resulting in progressive distal organ injury. To date, the role of Bax/caspase 3 signaling in IIRI has not been reported. Furthermore, the discovery of a safe and effective drug remains pertinent in improving the outcome of IIRI. Therefore, this study investigated the role of Bax/caspase 3 signaling in intestinal I/R-induced intestinal and hepatic injury. In addition, the protective effect and possible associated mechanism of action of methanolic Phyllanthus amarus leaf extract (PA) against intestinal I/R-induced intestinal and hepatic injury were evaluated. Materials and methods: Fifty male Wistar rats were randomized into five groups (n = 10). The sham-operated group was received 0.5 mL of distilled water for seven days prior to the sham surgery, while the IIRI, febuxostat (FEB) + IIRI, low-dose PA (LDPA) + IIRI, and high-dose PA (HDPA) + IIRI groups underwent the I/R procedure. In addition to the procedure, IIRI, FEB + IIRI, LDPA + IIRI, and HDPA + IIRI received 0.5 mL of distilled water, 10 mg/kg of febuxostat, 200 mg/kg of PA, and 400 mg/kg of PA, respectively, for seven days prior to the I/R procedure. Results: Administration of methanolic Phyllanthus amarus leaf extracts attenuated the intestinal I/R-induced rise in intestinal and hepatic injury markers, malondialdehyde, nitric oxide, TNF-α, IL-6, and myeloperoxidase activities. In addition, Phyllanthus amarus ameliorated I/R-induced suppression of reduced glutathione, thiol and non-thiol proteins, and superoxide dismutase, catalase, and glutathione peroxidase activities in intestinal and hepatic tissues. These were coupled with the suppression of I/R-induced bacterial translocation, downregulation of I/R-induced activation of Bax/caspase 3 signaling, and improvement of I/R-induced distortion of intestinal and hepatic histoarchitecture by Phyllanthus amarus. Conclusion: Methanolic Phyllanthus amarus leaf extract protects against intestinal and hepatic injuries associated with intestinal I/R by suppressing oxidative-stress-mediated activation of Bax/caspase 3 signaling. The beneficial effects of Phyllanthus amarus may be ascribed to its constituent bioactive molecules, especially tannins, anthocyanin, alkaloids, and phenolics.
... G6PD deficiency is an inherited enzymatic disorder causing hemolytic anemia and follows an X-linked recessive inheri-tance pattern in humans by loss-of-function, which affects over 400 million people globally and is one of the most polymorphic proteins with at least 140 mutations identified [2,3]. The study of G6PD deficiency in relation to the use of drugs is a classic example of pharmacogenetics [4]. ...
Article
Malaria continues to be one of the most crucial infectious burdens in endemic areas worldwide, as well as for travelers visiting malaria transmission regions. It has been reported that 8-aminoquinolines are effective against the Plasmodium species, particularly primaquine, for anti-hypnozoite therapy in P. vivax malaria. However, primaquine causes acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Therefore, G6PD deficiency testing should precede hypnozoite elimination with 8-aminoquinoline. Several point-of-care devices have been developed to detect G6PD deficiency. The aim of the present study was to evaluate the performance of a novel, quantitative G6PD diagnostics based on a metagenomic blue fluorescent protein (mBFP). We comparatively evaluated the sensitivity and specificity of the G6PD diagnostic modality with standard methods using 120 human whole blood samples. The G6PD deficiency was spectrophotometrically confirmed. The performance of the G6PD quantitative test kit was compared with that of a licensed control medical device, the G6PD strip. The G6PD quantitative test kit had a sensitivity of 95% (95% confidence interval (CI): 89.3-100%) and a specificity of 100% (95% CI: 94.3-100%). This study shows that the novel diagnostic G6PD quantitative test kit could be a cost-effective and time-efficient, and universally mandated screening tool for G6PD deficiency.
... 2 Because of its Xlinked inheritance pattern, male hemi zygotes and female homozygotes show more severe clinical phenotypes, whereas female heterozygotes show phenotypic variability due to random X inactivation. 3 life-threatening haemolysis in case of G6PD deficient individuals. Interestingly, at one HIV clinic the prevalence of G6PD deficiency was around 10%; and among those receiving oxidative stress-inducing drugs, 10% developed severe haemolysis, indicating the potential danger of these drugs and need of G6PD screening in HIV infected patients 5. HIV infected, G6PD deficient individuals may also have inherently worse outcomes i.e., oxidative stress, acute haemolysis, exacerbate HIV infection. ...
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Background: The prevalence of Glucose-6-phosphate dehydrogenase (G6PD) deficiency is 8.5% in India. G6PD deficient individual have different outcomes with certain drugs and result in unexpected events that could be even fatal. HIV affected individuals with G6PD deficient have inherently worse outcomes when they start on those drugs that precipitate the condition. We aimed to study the level of G6PD and its deficiency status among the newly diagnosed HIV patients.Methods: A cross-sectional study among the newly diagnosed HIV patients was conducted at a tertiary hospital, Kolkata. All the eligible participants (n=100) were recruited consecutively after obtaining the consent. The details on socio-demography, clinical history and investigations were extracted from them. The data were analysed using the appropriate statistical methods.Results: Out of 100 newly HIV diagnosed participants, the prevalence of G6PD deficiency was 12% (95% CI: 5.6- 18.3%). Participants belonging to tribal population, with familial history of haemolytic disease, history of haemolysis, and increased LDH levels were significantly associated with the deficient G6PD levels among the study participants. Conclusions: The prevalence of G6PD deficiency was high among the newly diagnosed HIV study population. Tribal population and familial history of haemolytic disorders had high number of deficiency and need to be screened for better clinical care.
... For example, decreased-function HMGCR variants may be associated with new-onset diabetes mellitus [78,79], illustrating another translational model to explore in zebrafish (Hmgcra; 78% amino acid . Additionally, mutations in glucose-6-phosphate dehydrogenase (G6PD; G6pd; 76% amino acid conservation) are responsible for the most prevalent enzyme deficiency worldwide [80][81][82][83]. The FDA has cautioned against the use of several drugs -from anticancer to antimalarial -by G6PD-deficient individuals [84], and targeted modeling in zebrafish could be used to evaluate the safety of alternative treatments for such patients. ...
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The number of adverse drug events in the United States is critically high, with annual rates exceeding 1 million cases over the last nine years. One cause of adverse drug events is the underlying genetic variation that can alter drug responses. Pharmacogenomics is a growing field that seeks to better understand the relationship between a patient’s genetics and drug efficacy. Currently, pharmacogenomics relies largely on human trials, as there is not a well-developed animal model for studying preventative measures and alternative treatments. Here, we analyzed pharmacogene expression at two developmental time points in zebrafish to demonstrate the potential of using this model organism for high-throughput pharmacogenomics research. We found that 76% of tiered human pharmacogenes have a zebrafish ortholog, and of these, many have highly conserved amino acid sequences. Additional gene ontology analysis was used to classify pharmacogenes and identify candidate pathways for future modeling in zebrafish. As precision medicine burgeons, adopting a high-throughput in vivo model such as the zebrafish could greatly increase our understanding of the molecular pathology underlying adverse drug events.
... 6 In addition to this, G6PD works with reduced glutathione; GSH to scavenge the free radicals within the cells. 7 Therefore, antioxidants are essential for healthy erythrocytes. ...
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Introduction: In the Mahachotarata scripture, there was a blood tonic remedy known as Bhamrung-Lohit remedy in Thai which has been used in female adult to treat menstrual irregularities, abnormal menstruation, and for nourishing blood and body. The aims of this study were to determine the amount of total phenolics and antioxidant activities of Bhamrung-Lohit remedy and its plant components. Methods: All tested extracts were prepared by decoction as practiced in traditional medicine. All extracts were analyzed for their phenolic content by Folin-Ciocalteu assay and their antioxidant activities by using DPPH radical scavenging assay, ABTS radical scavenging and ferric reducing antioxidant power assay (FRAP). The correlation analysis was evaluated by curve fitting regression model. Results: The results showed that the extract of Caesalpinia sappan, a Bhamrung-Lohit plant ingredient, contained the highest total phenolic contents of 781.72 ± 21.19, 269.38 ± 12.88 mg GAE/g. The aqueous extract of Terminalia citrina and Bixa Orellana demonstrated stronger antioxidant activity than positive control (BHT) by DPPH radical scavenging assay (EC 50 = 4.51 ± 0.21 µg/ml, 4.92 ± 0.08 µg/ml, and 13.78 ± 0.23 µg/ml, respectively). In ABTS •+ assay, the extract of Terminalia citrina and Caesalpinia sappan showed stronger activity than positive control (BHT) with (EC 50 = 4.16 ± 0.11 µg/ml, 5.19 ± 0.38, and 5.55 ± 0.23 µg/ml, respectively). The extract of Caesalpinia sappan and Bhamrung-Lohit remedy gave the highest TEAC and FRAP value of 1,223.14 ± 25.26 mg Trolox/g, 2,885.64 ± 57.27 mg Fe(II)/g, 338.28 ± 9.13 mg Trolox/g, and 795.06 ± 20.69 mg Fe(II)/g, respectively, it also showed stronger activities than positive control (BHT). DPPH and ABTS •+ scavenging activity relate to total phenolic content by negative exponential model. Both FRAP assay showed the linear correlation with the total phenolic content. Conclusion: This study demonstrated that Bhamrung-Lohit remedy and its plant components showed good antioxidant activities. These results support the indication of this preparation as blood tonic.
... ,47 Katz and Schall 47 developed a biocultural evolutionary explanation for this surprising pattern, suggesting that fava bean consumption may be beneficial for non-G6PD-deficient individuals because it produces moderate oxidative stress in red blood cells, ...
Article
Parallel evolution—where different populations evolve similar traits in response to similar environments—has been a topic of growing interest to biologists and biological anthropologists for decades. Parallel evolution occurs in human populations thanks to myriad biological and cultural mechanisms that permit humans to survive and thrive in diverse environments worldwide. Because humans shape and are shaped by their environments, biocultural approaches that emphasize the interconnections between biology and culture are key to understanding parallel evolution in human populations as well as the nuances of human biological variation and adaptation. In this review, we discuss how biocultural theory has been and can be applied to studies of parallel evolution and adaptation more broadly. We illustrate this through four examples of parallel evolution in humans: malaria resistance, lactase persistence, cold tolerance, and high‐altitude adaptation.
... G6PD deficiency is not a disease but an inherited condition where only gene therapy can rectify this. However, unless the individual having the deficiency is with CNSHA, it is pretty much asymptomatic until he/she is exposed to external oxidants such as anti-malarial primaquine or sulfa-based drug (Frank, 2005;Cappellini and Fiorelli, 2008). ...
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common X-linked enzymopathies caused by G6PD gene variant. The aim of this study was to investigate the molecular epidemiological characteristic of the G6PD deficiency among newborn screening population in Wuhan region. A total of 430,806 healthy neonates in Wuhan area of China were screened for G6PD deficiency from November 2016 to December 2021. The positive samples were further detected with gene analysis. Among the 957 neonates with abnormal G6PD enzyme activity, the prevalence of G6PD deficiency in Wuhan was calculated as 0.22%. 38 genotypes were found and the top 5 frequencies of G6PD gene variants were c.1388G > A, c.1376G > T, c.95A > G, c.1024C > T and c.871G > A. Seven rare single variants (c.25C > T, c.152C > T, c.406C > T, c.497G > A, c.679C > T, c.854G > A and c.1057C > T) and two rare multiple variants (IVS-5 637/638T del/c.1311C > T/1365-13T > C and c.406C > T/c.1311C > T/1365-13T > C) were discovered in this study. In addition, four novel variants (c.49C > T, c.691G > A, c.857A > T and c.982G > A) were detected out in our cohort, which have never been reported before. The result indicated that a rich diversity of G6PD genetic variants in Wuhan region, also had its own regional characteristic. Our data provided the basic knowledge for future prevention and research of G6PD deficiency and the findings will be useful for genetic counseling and prenatal diagnosis of G6PD deficiency in the Wuhan region.
... is responsible for the first step of the pentose phosphate pathway, in which NADPH, the reducing power required to protect red blood cell against oxidative stress, is produced. [3][4][5] Most of G6PD deficient individuals are asymptomatic, only experiencing episodic acute haemolytic anaemia (AHA) in the contexts of oxidative stress when exposed to infection, certain drugs or fava beans ingestion (classes II, III and to IV of G6PD variants). 5,6 Only a few rare class I variants, cause chronic non-spherocytic hemolytic anemia (CNSHA). ...
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Introduction: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme defect in the world, affecting more than 500 million people. In Portugal, the average frequency of G6PD deficiency in males was estimated at about 0.5% and since the year 2000 several G6PD-deficient alleles have been identified. The main goal of this study was to improve the knowledge on the molecular heterogeneity of G6PD deficiency in the Portuguese population. Material and methods: A retrospective analysis of the mutational profile of 138 unrelated Portuguese individuals (101 males; 37 females), with no known sub-Saharan ancestry, who had been diagnosed with G6PD deficiency between 1994 and 2020 at the Molecular Hematology Unit of Centro Hospitalar e Universitário de Coimbra. The molecular study was done by direct Sanger sequencing or PCR-RFLP analysis. Results: Twenty-one different pathogenic mutations were found. Among them, 20 were missense, causing the amino acid change, and one was an in-frame deletion in exon 10. The three most frequent mutations belong to the G6PD c.376A>G African background haplotype, namely the G6PD variants: A- (c.202G>A; p.68Val>Met) (58.6%), Betica (c.968T>C; p.323Leu>Pro) (12.1%) and Santamaria (c.542A>T; p.181Asp>Val) (4.3%). Conclusion: There is a wide molecular heterogeneity of G6PD deficiency in the Portuguese population.
... However, no Heinz bodies were detected. Although basophilic stippling is not a feature of glucose-6-phosphate dehydrogenase deficiency (G6PD), this diagnostic possibility was investigated and excluded [4], leading us to suspect an unstable hemoglobinopathy. Hb analysis was initiated by cellulose acetate electrophoresis (Helena) and high-performance liquid chromatography (HPLC) (VARIANT II, Bio-Rad Laboratories, Hercules), and confirmed by automated capillary electrophoresis (CapillaryS2 Flex Piercing, Sebia). ...
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Background Unstable hemoglobinopathies are rare inherited disorders of hemoglobin causing a reduction of hemoglobin molecule solubility. This results in an unstable hemoglobin tetramer/globin polypeptide, which precipitates within the red blood cell. Affected red blood cells have a reduced lifespan due to oxidative stress and cellular rigidity, and tend to be phagocytized by spleen macrophages more rapidly. Unstable hemoglobin is frequently under- or misdiagnosed, because its clinical presentation varies broadly. Therefore, testing for unstable hemoglobinopathies is indicated in cases of unexplained hemolytic anemia. However, this approach is not systematically followed in clinical practice. Case report A 25-year-old Caucasian man with a recent history of a presumed viral upper respiratory infection was referred to the hematology outpatient clinic because of hemolytic anemia. The patient had scleral icterus, moderate splenomegaly, and mild macrocytic anemia with high reticulocyte count. Unconjugated bilirubin and lactate dehydrogenase were elevated. Haptoglobin was undetectable. Direct antiglobulin test was negative. Blood smear examination revealed anisopoikilocytosis, polychromasia, bite cells, and basophilic stippling, but no Heinz bodies. High-performance liquid chromatography and capillary electrophoresis showed slightly increased hemoglobin A2, normal fetal hemoglobin, and a variant hemoglobin. Deoxyribonucleic Acid sequencing revealed the heterozygous mutation c430delC in the beta-globin gene hallmark of hemoglobin Montreal II and the heterozygous mutation c287C>T in the alpha-globin gene corresponding to hemoglobin G-Georgia, indicative of the not yet described combination of double-heterozygous hemoglobin Montreal II and hemoglobin G-Georgia variants. Hemoglobinopathy Montreal II was here not associated with β-thalassemia syndrome, and carriers did not show ineffective erythropoiesis. In addition to the case report, we provide information about the largest pedigree with hemoglobinopathy Montreal II identified to date. Conclusion We emphasize that a transitory acute condition may uncover an underlying inherited red blood cell disorder. In this regard, awareness should be raised among hematologists caring for adult patients that unstable hemoglobinopathies should be considered in the differential diagnosis of unexplained hemolytic anemias.
Chapter
The conception that several infectious diseases were linked to an inherited disorder has been discussed, and every day, substantial evidence now is supported by the human genetic contribution to susceptibility to infectious diseases. Despite being a forerunner, personalized medicine (PM) is not yet routinely applied in infectious patient care. For this scope, education is a crucial step for the successful implementation of PM in the clinic, and with this part, we would like to encourage learning about PM in the communicable disease field. The information in this section will drive you through the concept of personalized infectious diseases and a piece of basic knowledge about the possibility of identifying determinants of clinical outcomes, looking at the host face through selected infectious diseases which are considered a global health issue such as HIV (human immunodeficiency virus) infection and related AIDS (acquired immunodeficiency syndrome), infections caused by Mycobacterium tuberculosis, malaria, and COVID-19 infection. It is especially important, as it can enable the development of one’s own thoughts and ideas to be able to understand and implement this rapidly developing field of science. A brief overview of the genetic identification of more vulnerable individuals is expected to inform personalized treatment and perhaps vaccination strategies. Additionally, new technologies are supporting the rapid identification of infective agents and targeted approaches based on the genetic resistance of pathogens to antibiotics. This information can lead to revising the data that can be used for personalized predicting diseases, improving personalized treatment, and also personalized prevention strategies specific to infectious pathogens. The last subchapter is dedicated to a deeper revision of the COVID-19 infection from a personalized medicine perspective.
Article
Background: Recent studies revealed the glucose-6-phosphate dehydrogenase (G-6-PD) deficiency prevalence of 7.7-10% among Thai blood donors. Transfusion of red blood cells (RBCs) from these subjects potentially causes haemolysis in recipients. Methods: RBC units from the National Blood Centre were sampled to assess G-6-PD levels using spectrophotometry. Patients with pure underproduction anaemia requiring blood transfusion were randomised to receive G-6-PD-deficient versus normal ABO-matched RBCs. Pre- and 48-h post-transfusion indirect bilirubin, haemoglobin, haematocrit, lactate dehydrogenase (LDH) and haptoglobin were measured. Results: From April 2020 to March 2021, 374 RBC units were tested for G-6-PD, and that 25 were found to be G-6-PD deficient. Twelve units of G-6-PD-deficient RBCs and 14 units of normal RBCs were given to patients who met the inclusion criteria. The median (interquartile range) increases of indirect bilirubin in G-6-PD-deficient (N = 11) versus normal RBCs (N = 13) were + 0.12 (0.27) versus + 0.01 (1.3) mg/dl, p = 0.030), respectively. The median increases of haemoglobin were 1.00 (0.50) versus + 0.80 (0.95), p = 0.910, respectively. The increases in haematocrit were 2.59 (1.9) versus 2.29 (2.1), p = 0.733, respectively. There were no significant differences in changes of LDH and haptoglobin levels and no transfusion reactions. Discussion: G-6-PD-deficient packed red cells were associated with mildly elevated indirect bilirubin after transfusion, but there was no observed clinical symptoms.
Article
With the development of sequencing technology, more and more rare thalassemia types have been found. In this article, we found a novel Hb H disease combined with glucose-6-phosphate dehydrogenase (G6PD) deficiency through whole genome sequencing (WGS), which was verified by Sanger sequencing and polymerase chain reaction (PCR)-reverse dot-blot hybridization, respectively.
Article
Background: Intracranial atherosclerotic stenosis (ICAS) is a major stroke cause in Asian countries. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a hereditary enzyme defect prevalent in Asian countries, has been associated with atherosclerotic cardiovascular disease and worse post-stroke outcomes. However, the impact of G6PD deficiency on ICAS remains unclear. We aimed to compare the risk of ICAS in stroke patients with and without G6PD deficiency in a Chinese cohort. Methods: We prospectively and consecutively recruited stroke patients from four centres in China. All patients received intracranial artery assessment by magnetic resonance/computed tomography angiography or digital subtraction angiography, as well as G6PD enzyme evaluation. The prevalence, burden, and characteristics of ICAS were compared between patients with and without G6PD deficiency using a multivariate regression analysis. Results: Among 1593 patients, 116 (63.7%) of 182 patient with G6PD deficiency and 714 (50.6%) of 1411 patients with normal G6PD level were identified as ICAS. Age, hypertension, diabetes, and G6PD deficiency were independent predictors of ICAS. Among patients with ICAS, G6PD-deficient individuals were more likely to have multiple (≥ 2 segments) intracranial stenosis [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.25-2.81, p=0.002]. G6PD deficiency respectively increased the risk of ICAS in patients who were male (OR 1.82, 95% CI 1.24-2.66, p=0.002), aged ≥ 70 years (OR 2.40, 95% CI 1.33-4.31, p=0.004), or hypertensive (OR 1.88, 95% CI 1.28-2.77, p=0.001). Conclusion: Stroke patients with G6PD deficiency have a higher prevalence and ICAS burden than those with normal G6PD, particularly those who are male, older, and hypertensive.
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Hepatitis E virus (HEV) is an RNA virus that is transmitted faeco-orally. Due to unhygienic living conditions and unsatisfactory treatment of drinking water, it is a major cause of acute viral hepatitis in Pakistan. Hepatitis E infection in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may cause prolonged jaundice resulting in serious complications like, severe haemolysis, acute renal failure, encephalopathy and even demise. Although both these diseases occur frequently in our country there is a dearth of literature on the effect of Hepatitis E infection in G6PD deficient patients, leading to higher rate of complications in such patients. We report the case of a 37 years old male who was referred to our hospital with worsening jaundice. Patient had HEV infection with concomitant G6PD deficiency. This case had a different prospect, since it resulted in prolonged jaundice and severe haemolysis. However the patient's condition improved with conservative management.
Article
Severe neonatal jaundice (SNNJ) is a leading cause of neonatal morbidity and mortality in low- and middle-income countries (LMICs). Risk mitigation and management modalities for SNNJ have led to a marked reduction in complications in high-income countries but not in LMICs likely in part due to knowledge gaps among healthcare providers. This study, a cross-sectional study conducted in Ogbomosho, Nigeria, aimed to identify SNNJ knowledge and practices among Nigerian healthcare providers/trainees. Healthcare providers/trainees completed a structured questionnaire. Healthcare providers/trainees included are nurse midwives (33.4%), nurses (18.6%), nursing students (15.2%), traditional birth attendants (TBAs) (12.7%), physicians (10.2%), and medical students (9.9%). Most physicians were aware of the common causes of SNNJ; however, knowledge deficits in other groups were notable. Despite most providers endorsing that glucose-6-phosphate dehydrogenase deficiency can cause SNNJ (91% of physicians, 60% of nurses, 71% of midwives, 81% of medical students, 43% of nursing students, 7% of TBAs), very few providers recognized that it is common, ranging from 3% in nurses up to a high of 47% among medical students. Gaps in provider knowledge regarding preventative measures and sequela were also noted. These data identified significant knowledge gaps regarding the etiology of SNNJ among healthcare providers/trainees, which can lead to missed opportunities in effective prevention and treatment. These deficits must be addressed if we are to eliminate tragic and preventable complications from SNNJ in Nigeria and other LMICs.
Preprint
Introduction New point-of-care (POC) quantitative G6PD testing devices developed to provide safe radical cure for P. vivax malaria may be used to diagnose G6PD deficiency in newborns at risk of severe neonatal hyperbilirubinaemia, improving clinical care, and preventing related morbidity and mortality. Methods We conducted a mixed-methods study analyzing technical performance and usability of the “STANDARD G6PD” Biosensor when used by trained midwives on cord blood samples at two rural clinics on the Thailand-Myanmar border. Results In 307 cord blood samples, the Biosensor had a sensitivity of 1.000 (95%CI 0.859-1.000) and a specificity of 0.993 (95% CI 0.971-0.999) as compared to gold standard spectrophotometry to diagnose G6PD deficient newborns using a receiving operator characteristic (ROC) analysis-derived threshold of ≤4.8IU/gHb. The Biosensor had a sensitivity of 0.640 (95%CI 0.426-0.813) and specificity of 0.954 (95%CI: 0.819-0.981) for 30-70% activity range in females using ROC analysis-derived range of 4.9 to 9.9IU/gHb. These thresholds allowed identification of all G6PD deficient neonates and 80% of female neonates with intermediate phenotypes. Need of phototherapy treatment for neonatal hyperbilirubinaemia was higher in neonates with deficient and intermediate phenotypes as diagnosed by either reference spectrophotometry or Biosensor. Focus group discussions found high levels of learnability, willingness, satisfaction, and suitability for the Biosensor in this setting. The staff valued the capacity of the Biosensor to identify newborns with G6PD deficiency early (“We can know that early, we can counsel the parents about the chances of their children getting jaundice”) and at the POC, including in more rural settings (“Because we can know the right result of the G6PD deficiency in a short time. Especially for the clinic which does not have a lab”). Conclusions: The Biosensor is a suitable tool in this resource-constrained setting to identify newborns with abnormal G6PD phenotypes at increased risk of neonatal hyperbilirubinaemia. SUMMARY BOX WHAT IS ALREADY KNOWN ON THIS TOPIC G6PD deficiency is one of the major risk factors for severe neonatal hyperbilirubinaemia and kernicterus. Accurate diagnosis of newborns with G6PD deficient and intermediate phenotypes is currently possible only in tertiary hospitals with laboratory facilities. WHAT THIS STUDY ADDS The G6PD quantitative point-of-care diagnostic device tested can be used in cord blood to provide a highly accurate identification of G6PD deficient newborns; it can also identify intermediate phenotypes in female newborns with good accuracy. The device showed good usability characteristics in a resource-constrained setting when used by clinical staff. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY Use of quantitative point-of-care G6PD diagnostics at birth can provide a timely diagnosis of G6PD status to support better perinatal care and avert morbidity and mortality in resource-constrained settings. Reliable point-of-care G6PD diagnostics can become a useful tool for universal newborn screening.
Article
Glucose 6 Phosphate Dehydrogenase (G6PD) enzyme activity estimation in a freshly collected blood sample is the most widely used diagnostic method for the diagnosis of G6PD deficiency. The objective is to evaluate the need for newborn screening for G6PD deficiency over post-malarial diagnosis and the feasibility and reliability of using dried blood spots (DBS) as samples for screening. A total of 562 samples were analyzed for G6PD and parallel measurement of G6PD activity by the colorimetric method in whole blood and DBS was carried out in the neonatal subset. Among 466 adults, 27 (5.7%) showed G6PD deficiency, out of whom 22 (81.48%) were diagnosed after the malarial encounter. In the pediatric group, 8 neonates showed G6PD deficiency. G6PD activity estimated from DBS samples agreed with whole blood, with a statistically significant strong positive correlation. Screening of G6PD deficiency at birth to prevent future unwarranted complications, using DBS is feasible.
Article
Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is an X‐linked genetic disease caused by a pathogenic G6PD mutation. An 8‐year‐old Chinese male child was investigated because of chronic nonspherocytic hemolytic anemia (CNSHA) associated with hepatosplenomegaly. Genetic analysis unraveled co‐inheritance of a hemizygous mutation c.1225C>T (p.Pro409Ser) in G6PD (G6PD Utrecht, previously reported only in The Netherlands) and heterozygote HBB mutation c.316‐197C>T (IVS‐Ⅱ‐654 C>T). Because IVS‐Ⅱ‐654 C>T on its own does not cause CNSHA, we believe that the clinical manifestations in this patient are essentially due to the G6PD c.1225C>T mutation. The boy gained transfusion independence after splenectomy.
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Glucose-6-phosphate dehydrogenase (G6SPD) is an ubiquitous enzyme which by determinig the NADPH level has a crucial role in NADPH-mediated reductive processes in all cells (1). The structural gene for G6PD, Gd, is X-linked in mammals and on the basis of its expression in many tissues, it can be regarded as a typical “housekeeping” gene (2). Over 300 variants of the protein are known, many of which have deficient enzyme activity. Nearly 100 of these variants are polymorphic in various populations (3). The mammalian enzyme is a homodimer or a homotetramer with a subunit moleculat weight of ˜ 54000 daltons (4). Here we report the isolation of cDNA clones from HeLa cells, SV40-transformed human fibroblasts, human placenta and human teratocarcinoma cell lines. These clones have enabled us to sequence the entire coding region of Gd . Thus, the entire amino acid sequence of human G6PD is provided for the first time. This work is the first step for structural analysis of G6PD variants and for an understanding of the biological features of this enzyme at the molecular level .
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The cloning and sequencing of the normal glucose-6-phosphate dehydrogenase (G6PD) gene has led to the study of the molecular defects that determine enzymatic variants. In this paper, we describe the mutations responsible for the Ferrara I variant in an Italian man with a family history of favism, from the Po delta. Nucleotide sequencing of this variant showed a GA mutation at nucleotide 202 in exon IV causing a ValMet amino acid exchange, and a second AG mutation at nucleotide 376 in exon V causing an AsnAsp amino acid substitution. Although on the basis of its biochemical properties this variant was classified as G6PD Ferrara I, it has the same two mutations as G6PD A(-), which is common in American and African blacks, and as the sporadic Italian G6PD Matera. The mutation at nucleotide 202 was confirmed by NlaIII digestion of a polymerase chain reaction amplified DNA fragment spanning 109 bp of exon IV. The 109-bp mutated amplified sequence is not distinguishable from the normal sequence in single strand conformation polymorphism analysis.
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The relationship between glucose-6 phosphate dehydrogenase (G6PD) deficiency and jaundice in the newborn period is well recognized. However, there is concern about the increasing incidence of kernicterus being reported worldwide, especially due to unrecognized G6PD deficiency and early discharge from hospital after birth. We report a case series of kernicterus from a set-up where the high prevalence rate of G6PD deficiency is known. Fourteen cases of kernicterus were seen during a time period of 6 years, 71 per cent of them had G6PD deficiency. Recent literature is reviewed and possible preventive measures in the light of current information and practices are suggested.
In four cases of newborns with hyperbilirubinemia and no blood group incompatibilities between mother and infant, neither mothers nor infants had previously received drugs associated with hemolytic anemia. Investigations of the infants and their families revealed that the infants had glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in the red blood cells (RBC). Prematurity, acidosis, hypoxia, and factors normally associated with the newborn in addition to the inability of the RBC deficient in G-6-PD to metabolize hydrogen peroxide may cause acute hemolytic episode in these infants even in the absence of drug ingestion or infection. Infants, especially those from ethnic groups known to have a high incidence of G-6-PD deficiency, with hyperbilirubinemia and no evidence of blood group incompatibilities should be screened for G-6-PD deficiency.
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: Three white G6PD-deficient patients suffered severe hemolytic reactions during treatment for typhoid fever with chloramphenicol. Two of these patients were studied when free of infection to determine the hemolytic potential of chloramphenicol in the noninfected G6PD-deficient white person. It was found to be mildly hemolytic under these conditions, suggesting that a drug- disease synergism was primarily responsible for the clinical hemolytic reactions. The febrile state itself, or changes in plasma amino acids accompanying infection, may be responsible for disease-related hemolysis.
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Human glucose-6-phosphate dehydrogenase is expressed in all cells by a housekeeping gene whose regulatory 5′-flanking sequence includes at least nine GC boxes. By transient transfection of HeLa and HepG2 cells with constructs containing glucose-6-phosphate dehydrogenase gene regions linked to a reporter gene, we have now delineated the core promoter and have located upstream stimulatory and inhibitory sequences. By mutational analysis, we demonstrate that the activity of the core promoter requires two out of seven GC boxes. We show that stimulatory protein 1 (Sp1)-related factors and activator protein 2 (AP-2)-related proteins bind to these two boxes in band-shift experiments. One point mutation that affects the binding of only the Sp1-related factors to one or both boxes causes a marked decrease of promoter activity in HepG2 cells but not in HeLa cells. We conclude that (a) two out of many seemingly redundant GC boxes are necessary to drive a Grich housekeeping promoter; (b) factors that bind to GC boxes may exert cell-type-specific regulation of housekeeping gene promoter activity; (c) point mutations in the promoter of the glucose-6-phos-phate dehydrogenase gene can inhibit its transcription.
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End-tidal carbon monoxide was measured in 108 newborn infants who had been screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency. The mean ± SD end-tidal carbon monoxide did not differ significantly between the G6PD-deficient and the normal neonates, 2.1 ± 0.6 μl/L and 2.0 ± 0.5 μl/L, respectively, within 12 hours of birth and 1.9 ± 1.4 μl/L and 1.5 ± 0.7 μl/L, respectively, at 48 to 72 hours after birth. On the basis of these measurements, hemolysis is not a sufficient explanation for jaundice in G6PD-deficient newborn infants in the transitional period. (J PEDIATR 1995;127:804-6)
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Many types of hemolytic anemia may be associated with liver disease. Liver injury can be caused by the adherence of deformed or hemolyzed erythrocyses to hepatic vascular endothelium. Adhesion of large numbers of hemolyzed red blood cells to hepatic macrophages, or occlusion of hepatic sinusoids by fragmented red cells, can also result in injury of the liver. Thrombosis of the hepatic or portal vein is associated with some types of hemolytic anemia, and can cause severe liner injury. These are some examples of hepatic injury that can be caused by hemolytic anemias. This article discusses some aspects of liver disease that is associated with sickle cell anemia, paroxysmal nocturnal hemoglobinuria, glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis, and HELLP syndrome.
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The first reported case of hereditary spherocytosis (HS) and glucose-6-phosphate dehydrogenase deficiency in a black is presented. The recent literature is reviewed, with emphasis on the frequency of multiple inherited RBC defects in this ethnic group. Despite a coexisting hemoglobinopathy or enzyme deficiency, HS can be diagnosed in most cases by the peripheral blood smear, osmotic fragility curve, and family history. The implications of the double RBC abnormality are discussed, stressing the importance of splenectomy in relieving the hemolytic component due to spherocytosis. (JAMA 237:797-798, 1977)
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SUMMARHGlucose-6-phosphate dehydrogenase (G6PD) deficiency is common in Italy and recent biochemical and kinetic studies have demonstrated the presence of polymorphic variants associated with severe or mild enzyme deficiency. We performed a biochemical characterization of G6PD in a large number of Italian G6PD deficient men in an attempt to identify the most reliable biochemical indices for discriminating polymorphic G6PD variants and to define their distribution throughout the country. Three polymorphic G6PD variants, respectively named Mediterranean, Cagliari and Sassari, were identified. The elution profile on DEAE-Sephadex column chromatography, substrate analogue utilization and the Michaelis constant for G6P were the most significant parameters to discriminate polymorphic variants among the variants with activity levels lower than 0.8 IU/g Hb. The distribution of the polymorphic variants, in relation to the origin of the subjects studied, differs throughout the country.
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We have determined the causative mutation in 12 cases of glucose-6-phosphate dehydrogenase deficiency associated with chronic non-spherocytic haemolytic anaemia. In 11 of them the mutation we found had been previously reported in unrelated individuals. These mutations comprise seven different missense mutations and a 24 base pair deletion, G6PD Nara, previously found in a Japanese boy. Repeated findings of the same mutations suggests that a limited number of amino acid changes can produce the CNSHA phenotype and be compatible with normal development. The one new mutation we have found, G6PD Serres, is 1082 C → T causing a 361 Ala → Val