[A forgotten fraudulent bean--a case of favism. Fava bean may cause life-threatening hemolysis in predisposed persons].
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Favism by proxy in nursing glucose-6-phosphate dehydrogenase-deficient neonates.
Two nursing neonates deficient in glucose-6-phosphate dehydrogenase developed severe hyperbilirubinemia despite phototherapy. Mothers of both the infants had recently eaten fava beans. The hemolytic triggers found in fava beans may have been absorbed by the mothers and excreted in their breast milk. Carboxyhemoglobin determination performed on one of the infants reflected ongoing hemolysis.
Breast Feeding↗
Contributions of superoxide, hydrogen peroxide, and transition metal ions to auto-oxidation of the favism-inducing pyrimidine aglycone, divicine, and its reactions with haemoglobin.
The influence of O2-, H2O2 and metal ions on the auto-oxidation of divicine, a pyrimidine aglycone, was studied. In air at pH 7.4, the hydroquinonic form oxidized within a few minutes. Superoxide dismutase (SOD) markedly decreased the initial rate, giving a lag phase followed by rapid oxidation. Although catalase or diethylenetriamine-penta-acetic acid (DTPA) alone had little effect, each in the presence of SOD further slowed the initial rate and increased the lag. H2O2 decreased the lag time, as did Cu2+, Fe2+ or haemoglobin. GSH substantially increased the lag phase, but it eventually reacted with the divicine to form a 305 nm-absorbing adduct. These results indicate that an O2(-)-dependent mechanism of divicine auto-oxidation normally predominates. Auto-oxidation can also occur by a mechanism involving H2O2 and transition metal ions or haemoglobin, and if both these reactions are prevented by SOD and DTPA or catalase, a third mechanism, requiring build-up of an autocatalytic intermediate, becomes operative. Oxyhaemoglobin did not react directly with divicine, but reacted with the H2O2 produced by divicine auto-oxidation to give mainly an oxidized derivative presumed to be ferrylhaemoglobin. Divicine was shown to reduce ferylhaemoglobin to methaemoglobin, and this reaction was probably responsible for the acceleratory effect of haemoglobin on divicine oxidation. These results indicate that O2 rather than oxyhaemoglobin is likely to initiate divicine oxidation in the erythrocyte. Haemolytic crises, which are thought to result from this oxidation, occur only sporadically in glucose-6-phosphate dehydrogenase deficient individuals following ingestion of fava beans. A characteristic of the crises is acute depletion of erythrocyte GSH, and the vulnerability of these cells could relate to the ability of GSH, in combination with SOD, to protect against the autocatalytic mechanism of divicine auto-oxidation. Our demonstration of a variety of auto-oxidation pathways also suggests possible areas of individual variation.
Catalase↗
[Prevalence of glucose-6-phosphate dehydrogenase deficiency in a student population on the island of Menorca].
BACKGROUND: The G6PD deficiency is a red cell enzymopathy very frequent in certain Mediterranean countries. In Menorca (Balearic Islands), a relatively high incidence of favism carried us to study the prevalence of this alteration, taking advantage of the "Campaign for detection of heterozygous beta-thalassaemia to prevent the homozygous beta-thalassaemia" that we make annually. METHODS: We studied a total of 1139 school boys between 13-14 years old for three consecutive school years. We used the methylene blue as screening test and the deficiency of G6PD was confirmed with enzymatic quantification in the haemolysate. We also analysed the clinical manifestations and studied the relatives. RESULTS: We have confirmed 11 cases of G6PD deficiency (prevalence of 9.7/1000), all of them native of the island. The clinical manifestations were: in 6 cases (54.5%) no clinical manifestations were found, 5 cases (45.4%) had presented neonatal jaundice and 2 cases (18.2%) had suffered a favism crisis. The study of relatives permitted us to analyse 26 additional samples (17 women and 9 men), detecting in 8 of them (4 women and 4 men) the enzymopathy . CONCLUSIONS: The prevalence of G6PD deficiency in Menorca is one of the highest in Spain. Most of the carriers are asymptomatic, the most important clinical manifestations being the neonatal jaundice and favism. The screening test used is efficient for unmistakable hemizygotes detection.
Adolescent↗
Impairment of the calcium pump of human erythrocytes by divicine.
Divicine (2,6-diamino-4,5-dihydroxypyrimidine), an aglycone implicated in the pathogenesis of favism, produces a remarkable and consistent inactivation of the Ca2+-ATPase activity of the erythrocyte calcium pump. The patterns of inactivation are similar in normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes. Inactivation of Ca2+-ATPase is apparently unrelated to the cellular GSH system, to the proteolytic machinery of mature erythrocytes, and to calmodulin, and also occurs in hemoglobin-free, unsealed erythrocytes membranes at 50-100 microM concentrations of divicine. Analysis of erythrocytes that have escaped destruction during the acute hemolytic crisis of a number of favic patients revealed a dramatic elevation of erythrocyte calcium and a significant decrease of Ca2+-ATPase activity. These results support the view that divicine plays a toxic role in the pathogenesis of favism and suggest that acute electrolyte imbalances, mostly affecting calcium homeostasis, are involved in the mechanisms of erythrocyte damage and destruction in this hemolytic disease.
Calcium↗
Glucose-6-phosphate dehydrogenase deficiency in Sicily. Incidence, biochemical characteristics and clinical implications.
This report deals with the incidence, type and clinical implications of G6PD deficiency in Sicily. Of 3347 male subjects examined, 56 were deficient in G6PD. They were distributed throughout the island. The G6PD levels in RBC were almost zero; in leukocytes, platelets and saliva they were found to be 26%, 18% and 16%, respectively, of controls. The Michaelis constant for NADP and G6PD was lower than for controls. Conversely, the utilization of the analogous Ga16P and 2dG6P was higher. The thermostability of the enzyme was lower and the pH optima (6.5 and 9.5) were different from the controls. An identical electrophoretic pattern was found both in normal and deficient subjects. This pattern is superimposable on that described as Mediterranean variant. The analysis among 270 subjects admitted to our Clinic with hemolysis due to G6PD deficiency demonstrated that the most frequent disease is favism, followed by neonatal jaundice, while hemolysis due to drugs is very rare. Ingestion of fresh fava beans was the most frequent cause of favism, but cases occurred after breast feeding and inhalation of pollen.
Adolescent↗
[Molecular analysis of glucose-6-dehydrogenase deficiency in Spain].
PURPOSE: G6PD deficiency is the most frequent enzymopathy-producing genetic polymorphism in humans. Up to now, over 400 putative variants of G6PD have been distinguished on the basis of biochemical characterization of the deficient enzyme. Analysis of the G6PD gene has made possible a precise classification of the G6PD molecular variants by identification of about 80 different point mutations causing much of the phenotypic heterogeneity. In the Spanish population, the analysis of G6PD has led to the identification of 15 different point mutations that underlay the phenotypic heterogeneity of G6PD previously reported by biochemical analysis. The purpose of the study has been to identify the genetic mutation responsible of the G6PD deficiency and to improve the knowledge of its genetic homogeneity. PATIENTS AND METHODS: From 50 Spanish males with G6PD deficiency 34 came from out consultation and 16 from the Spanish Study Group on Red Cell Pathology (GEHBTA-Eritropatología) The methods employed included screening of prevalent mutations by ER-PCR, SSCP-PCR, genetic segmentation and biochemical characterization of the deficient enzyme. RESULTS: In 31 cases the mutations were characteristic of the four most frequent polymorphic variants found in Spain (G6PD A-376G/202A, G6PD Mediterranean 563T G6PD Union 1360T and G6PD Seattle 344C). Since these mutations either create or abolish a specific site recognized by a restriction endonuclease (RE), they can be rapidly detected by RE digestion of a PCR-amplified product (PCR-RE). In patients where none of these mutations were present (17 cases), the G6PD gene was subjected to PCR single-strand conformation polymorphism (PCR-SSCP) analysis combined with direct PCR-sequencing. By using this procedure, 9 new mutations have been identified, five of them have been also found in other geographical areas and were associated with favism (G6PD A-376G/968C, G6PD Santamaria 376G/542T, G6PD Aures 143C and G6PD Chatham 1003A) or chronic haemolytic anaemia (G6PD Tomah 1153C). The other four mutations are unique and not reported so far: Three of them are associated with favism (G6PD Málaga 542T, G6PD Murcia 209G and G6PD Valladolid 406T) and one with chronic haemolytic anaemia (G6PD Madrid 1155G). The remaining eight cases are under study. CONCLUSION: The present study confirms the marked genetic heterogeneity of G6PD deficiency in Spain and demonstrate that the PCR-RE analysis is an easy tool for rapid diagnosis of the molecular defect in subjects with the common forms of G6PD deficiency. Furthermore the fact that G6PD A-376G/202A is the most common variant within Spanish population and the finding of G6PD Aures 43C and G6PD Santamaría 76G/542T, who are polymorphic in Algeria is consistent with a significant gene flow from Africa to Europe through Spain.
Africa, Northern↗
G6PDdb, an integrated database of glucose-6-phosphate dehydrogenase (G6PD) mutations.
G6PDdb (http://www.rubic.rdg.ac.uk/g6pd/ or http://www.bioinf.org.uk/g6pd/) is a newly created web-accessible locus-specific mutation database for the human Glucose-6-phosphate dehydrogenase (G6PD) gene. The relational database integrates up-to-date mutational and structural data from various databanks (GenBank, Protein Data Bank, etc.) with biochemically characterized variants and their associated phenotypes obtained from published literature and the Favism website. An automated analysis of the mutations likely to have a significant impact on the structure of the protein has been performed using a recently developed procedure. The database may be queried online and the full results of the analysis of the structural impact of mutations are available. The web page provides a form for submitting additional mutation data and is linked to resources such as the Favism website, OMIM, HGMD, HGVBASE, and the PDB. This database provides insights into the molecular aspects and clinical significance of G6PD deficiency for researchers and clinicians and the web page functions as a knowledge base relevant to the understanding of G6PD deficiency and its management.
Databases, Genetic↗
The ocular findings in glucose-6-phosphate dehydrogenase deficiency.
57 cases with G6PD deficiency and 62 with normal G6PD activities as controls in Chonghua County, Guangdong Province were examined in the respects of visual acuity, color vision, corneal sensitivity, lens, vitreous and fundus. The results showed that the incidences of congenital lenticular opacities and congenital color blindness in G6PD deficiency group were higher than those in the controls. However, there were no findings such as pale conjunctiva, sallow sclera, pallor papillae and macular edema, which could be seen frequently in patients with favism. The hemoglobin values of all the cases were within normal range, which indicated that the subjects with G6PD deficiency usually didn't manifest hemolysis but only had a hereditary susceptibility, and the ocular findings in favism might result from hemolytic anemia, tissue anoxia and unknown toxic substances from vicia faba.
Cataract↗
Red cell acid phosphatase: another polymorphism correlated with Malaria?
The frequency of PC allele for acid phosphatase in fourteen Sardinian villages correlates positively with the altitude and negatively with past malarial morbidity and GdMed prevalence. The susceptibility towards hemolytic favism in Sardinian males with G6PD deficiency is dependent on the erythrocyte acid phosphatase and thalassemia phenotypes. Thalassemia trait exerts a protective action only in subjects carrying PA allele for acid phosphatase. The data suggest that the gradient for malaria morbidity directly or indirectly, through interactions with thalassemia and G6PD polymorphisms, mediated by the habit of eating Vecia faba, may have had a significant role in determining the heterogeneous distribution of acid phosphatase polymorphism in Sardinia. Besides malaria, other environmental factors related with altitude seem to have been very important in shaping the present pattern of distribution of both acid phosphatase and G6PD polymorphisms in Sardinia.
Acid Phosphatase↗
Naturally occurring toxicants in foods and their significance in the human diet.
Among the many biologically active and potentially toxic factors known to be present in plant foodstuffs normally consumed by man, those that are present in legumes have received the most attention. Two categories of legume toxins will be considered - those whose effects have been extensively studied in experimental animals but whose significance in man must remain open to conjecture, and those which are known to produce toxic effects in man but whose identity remains uncertain because similar effects are not readily reproduced in animal models. The protease inhibitors have, over the years, been the object of much study in experimental animals where they have been observed to have an adverse effect on growth and to cause pancreatic enlargement. The relevance of these observations to human nutrition remains obscure, however, because of our lack of knowledge concerning the effect of soybean trypsin inhibitors on the human pancreas. Lectins from certain legumes such as the common bean (Phaseolus vulgaris) have been shown to be toxic to animals upon oral ingestion presumably because of the damage which they inflict upon binding to the cells lining the intestinal mucosa. Lectins may therefore be responsible for reported cases of human intoxication associated with the consumption of inadequately cooked beans. Lathyrism and favism are diseases in man which are associated with the consumption of Lathyrus sativus and Vicia faba respectively. Evidence leading to the probable identification of the causative factors of these diseases and the steps necessary for their elimination will be discussed.
Diet↗
ACP1 and human adaptability. 1. Association with common diseases: a case-control study.
Human red cell acid phosphatase (ACP1) is a polymorphic enzyme closely related to cytosolic low molecular weight acid phosphatases, a protein family broadly conserved among eukaryotes. Two different functions have been proposed for ACP1: flavin mononucleotide (FMN) phosphatase and phosphotyrosine phosphatase (PTPase). Given that genetic variants of ACP1 activity are common, the enzyme could have a role in regulating a large spectrum of cellular functions and, in turn, disease susceptibility. In the present paper we report a study of ACP1 genetic polymorphism in 1088 normal subjects and in 1267 subjects from the population of Rome admitted to hospital for a number of common diseases. All ACP1 parameters investigated show highly significant differences among samples, suggesting that the enzyme may have a significant role in some of the diseases considered. In particular, consistent associations of ACP1 with developmental disturbances and with hemolytic favism have been observed. In the majority of diseases showing association with ACP1, only one of the two ACP1 isoforms, f and s, is involved, supporting the hypothesis of a functional differentiation between the two enzymatic fractions.
Abortion, Habitual↗
G6PD Ferrara I has the same two mutations as G6PD A(-) but a distinct biochemical phenotype.
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 G-->A mutation at nucleotide 202 in exon IV causing a Val-->Met amino acid exchange, and a second A-->G mutation at nucleotide 376 in exon V causing an Asn-->Asp 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.
Cloning, Molecular↗
At least five polymorphic mutants account for the prevalence of glucose-6-phosphate dehydrogenase deficiency in Algeria.
The electrophoretic mobility and level of enzyme activity of glucose-6-phosphate dehydrogenase (G6PD) was established in 100 unrelated Algerian males with G6PD deficiency. DNA from these subjects was analysed for the presence of certain known G6PD mutations by the appropriate restriction enzyme digestion of fragments amplified by the polymerase chain reaction. Where the mutation could not be identified in this way, the samples were subjected to single-strand conformation polymorphism analysis and abnormal fragments were sequenced. In this way, eight different mutations have been identified, of which five are polymorphic and account for 92% of the samples. The most common variants are G6PD A- (46%) and G6PD Mediterranean (23%), both of which were associated with favism. A new polymorphic variant, G6PD Aures, has been identified during the course of this study, whereas another, G6PD Santamaria, has now been established as a polymorphic variant (11%). Thus, G6PD deficiency in Algeria is heterogeneous, suggesting that there has been significant gene flow, both from sub-Saharan Africa and from other parts of the Mediterranean.
Algeria↗
Leucocyte glucose-6-phosphate dehydrogenase (g-6-pd) activity in g-6-pd deficient subjects.
The activity of glucose-6-phosphate dehydrogenase (G-6-PD) in leucocytes was studied in the following group of Greek people. Group 1: 43 male children and 16 male students with mean values of enzyme activity of 27.7 +/- 16.6 units and 24.6 +/- 5.6 units, respectively. Group 2: 15 G-6-PD deficient male children who had never experienced an acute haemolytic episode with a mean value of 10.8 +/- 4.6 units. Group 3: 19 G-6-PD deficient male children during favism and 3 months after the haemolytic crisis with mean values of 8 +/- 4 units and 9.2 +/- 1.9 units, respectively. Group 4: 19 mothers of children from group 3 who by definition were carriers of G-6-PD deficiency had a mean value of 18.2 +/- 8.2 units. The difference between means for group 1 and groups 2, 3 and 4 is highly significant (P < 0.001). Therefore the enzymatic defect in Greek people is not limited to the erythrocytes but can be also demonstrated in leucocytes.
Adult↗
Anti-nutritional and toxic factors in food legumes: a review.
A comprehensive review on the presence of certain important anti-nutritional and toxic factors in food legumes has been conducted. These substances include proteolytic inhibitors, phytohemagglutinins, lathyrogens, cyanogenetic compounds, compounds causing favism, factors affecting digestibility and saponins. These factors are shown to be widely present in leguminous foods which are important constituents of the diet of a large section of the world's population, and particularly, of people in the developing countries.
Cooking↗
Selective inactivation of catalase during protoporphyrin induced photohemolysis of human red blood cells.
The level of some enzymatic activities in red blood cells before and after photohemolysis induced by protoporphyrin IX was studied. A 30% decrease in catalase activity was found both in normal erythrocytes and those from patients affected by favism. Other proteins though present in larger amounts inside the erythrocytes are not affected by the photohemolytic process.
Catalase↗
Molecular heterogeneity underlying the G6PD Mediterranean phenotype.
As part of a study aiming to define the molecular basis of glucose-6-phosphate dehydrogenase (G6PD) deficiency, we analysed a sample from a Portugese boy with a family history of favism. Although the biochemical properties of red-cell G6PD from this subject were similar to those of the common variant G6PD Mediterranean, the corresponding mutation (563 C----T) was not present. Instead, polymerase chain reaction (PCR) amplification and sequencing of the entire gene detected a C----T transition at nucleotide 592 in exon VI, changing an arginine residue to a cysteine residue only 10 amino acids downstream from the Mediterranean mutation. Single-strand conformation polymorphism analysis of a PCR-amplified DNA fragment spanning exons VI and VII of the G6PD gene has detected the same mutation, confirmed by sequencing, in a G6PD-deficient patient from Southern Italy. We name this new variant G6PD Coimbra.
Base Sequence↗