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Glusoce-6-phosphate dehydrogenase- History and diagnosis

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  • Samyak Diagnostic Pvt. Ltd.

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p>Glucose-6-phosphate dehydrogenase deficiency is the most common enzymatic defect of red blood cells, which increases the vulnerability of erythrocytes to oxidative stress leading to hemolytic anemia. Since its identification more than 60 years ago, much has been done with respect to its clinical diagnosis, laboratory diagnosis and treatment. Association of G6PD is not just limited to anti malarial drugs, but a vast number of other diseases. In this article, we aimed to review the history of Glucose-6-phosphate dehydrogenase, the diagnostic methods available along with its association with other noncommunicable diseases. </p
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Journal of
of Nepal
PATHOLOGY
www.acpnepal.com
Journal of Pathology of Nepal (2016) Vol. 6, 1034 -
Review Article
Glusoce-6-phosphate dehydrogenase- History
and diagnosis
Correspondence:
Dr. Keyoor Gautam, MBBS, MD
Consultant Pathologist
Department of Pathology, Samyak Diagnostic Pvt. Ltd, Lalitpur, Nepal
Email: drkeyoor@gmail.com
Glucose-6-phosphate dehydrogenase deciency is the most common enzymatic defect of red blood cells,
which increases the vulnerability of erythrocytes to oxidative stress leading to hemolytic anemia. Since
its identication more than 60 years ago, much has been done with respect to its clinical diagnosis,
laboratory diagnosis and treatment. Association of G6PD is not just limited to anti malarial drugs, but
a vast number of other diseases. In this article, we aimed to review the history of Glucose-6-phosphate
dehydrogenase, the diagnostic methods available along with its association with other noncommunicable
diseases.
ABSTRACT
INTRODUCTION
Glucose-6-phosphate dehydrogenase (G6PD) deciency
is the most common enzymatic defect of red cells. G6PD
deciency increases the vulnerability of erythrocytes
to oxidative stress leading to hemolytic anemia. Sixty
years ago 3 enzyme deciencies that produce disease in
humans had been identied, all in human erythrocytes.
These enzymes were catalase, galactose-1-phosphate
uridyltransferase, and glucose-6-phosphate dehydrogenase.1
Although the technology was not so advance at that time,
a lot was accomplished regarding the diagnosis of G6PD
Gautam K1
1Department of Pathology, Samyak Diagnostic Pvt. Ltd, Lalitpur, Nepal
deciency, its genetic predisposition as well as the disease
management. Globally, 400 million people are estimated
to be affected with this enzymatic disorder of red blood
cells (RBCs), most of which are seen in the tropical and
subtropical zones of eastern hemisphere.2,3 Although a
large number of individuals are affected with this enzyme
deciency, fortunately only few present with a clinically
relevant symptom.
History
In the year 1926, Cordes reported the occurrence of
acute hemolysis in individuals treated for malaria
with 6-methoxy-8-aminoquinoline drugs, however the
mechanism of hemolysis could not be understood for
the next three decades.4 The discoveries that lead to the
Keywords:
G6PD;
Primaquine;
Neonatal Jaundice
1039
1035
recognition of G6PD deciency were the result of several
convergent events. The biochemical pathways through
which red cells metabolize sugar were established.5,6 The
tools available then seem incredibly primitive today, but
by 1950, virtually every step in red cell glycolysis was
established. Secondly, the development of isotopic methods
permitting the accurate estimation of red blood cell
survival was essential. It was the 51Cr method of labeling
erythrocytes, rst devised by Sterling and Gray to measure
the red cell mass and subsequently adapted for measuring
the cell survival, that set the stage for the studies that had
to be performed.7 Finally the circumstances surrounding
World War II and the Korean War had created the necessity
for the development of new, synthetic antimalarial drugs.
The funding required to carry out the studies materialized
from the United States Army. Volunteers serving sentences
in the Illinois State Penitentiary at Joilet were selected for
conducting the clinical investigation on understanding why
8-amino quinoline antimalarials caused hemolysis.6 When
normal volunteers were given 30 mg of primaquine daily,
some developed acute hemolytic anemia; most did not. Did
those who developed hemolytic anemia metabolized this
6-methozy-8-amino quinoline anitmalarial drug differently,
or did their red ells differ in some manner? Development
of 51Cr technique made it possible to answer this question.
When 51Cr labeled cells form a primaquine-sensitive subject
were transfused into a nonsensitive subject, primaquine
administration resulted in rapid destruction of the labeled
erythrocytes. But when 51Cr labeled cells from a non sensitive
subject were transfused into a primaquine sensitive subject,
they survived normally even when the host’s red cells were
being rapidly destroyed. These studies established clearly
that sensitivity to the hemolytic effect of primaquine was
due to an intrinsic defect of the erythrocyte.6
There were few morphological changes in the red cells of
subjects undergoing primaquine-induced hemolysis, but
Heinz bodies could be detected in the circulation before
the onset of hemolysis. Heinz bodies can be induced in
vitro by compounds such as phenylhydrazine or acetyl
phenlyhydrazine, and we were able to show that the pattern
of in vitro Heinze body formation was quite different in
sensitive and nonsensitive subjects.8 This made it possible,
for the rst time, to detect primaquine sensitivity in vitro.
The fact that iodoacetate and arsenite caused normal cells
to behave like primaquine sensitive cells focused attention
on the sulfhydryl groups of the erythrocyte. The amount of
glutathione in the cells was diminished, and the ability of
erythrocytes to maintain glutathione levels in the face of
oxidative stress was abnormal.9 Latter on Carson undertook
a study of the reduction of glutathione by hemolysates.
When it was found that hemolysates from primaquine
sensitive men could not utilize glucose-6-phosphate to
reduce glutathione, the more expensive NADPH was
added as the hydrogen donor. This substrate could reduce
glutathione in hemolysates from primaquine sensitive
men, making it apparent that the primary defect was in the
glucose-G-phosphate utilizing enzyme, G6PD.10
Genetics and Classication
G6PD enzyme is encoded by a human X-linked gene (Xq2.8)
consisting of 13 exons and 12 introns, spanning nearly 20
kb in total; the rst exon is noncoding, while the remaining
12 range from 120 to 235 bp. It has over 400 allelic variants
know. These variants have been biochemically characterized
based on: (a) the different residual enzyme activities, (b)
electrophoretic mobility patterns, and (c) physiochemical
or kinetic properties.11 G6PD variants are grouped into ve
classes based on WHO guidelines (Table 1).
Pathophysiology
Red cells are vulnerable to injury by oxidants. Abnormalities
in the hexose monophosphate shunt or glutathione
metabolism resulting from decient or impaired enzyme
function reduce the ability of red cells to protect themselves
against oxidative injuries, leading to hemolytic disease. As
noted in Figure 1, G6PD reduces NADP to NADPH while
oxidizing glucose-6-phosphate. NADPH then provides
reducing equivalents needed for conversion of oxidized
glutathione to reduced glutathione, which protects against
Table 1 : Classication of G6PD deciencies following the WHO recommendations
Class Residual enzymatic
activity Protein location Clinical symptoms Frequency and geo-
graphical distribution Type of mutation
I<1% or not detectable Dimer interface Struc-
tural NADP
Chronic hemolytic ane-
mia
Rare and without a pre-
cise geographical distri-
bution
G6PD-Buenos Aires,
G6PD Durban
II <10% Dimer interface NADP
binding site
Acute hemolytic anemia
fava beans and drug de-
pendent
Frequent and distributed
throughout the world
G6PD-Mediterranean
G6PD-Cassano G6PD-
Santamaria
III 10-60% Scattered throughout the
whole enzyme
Occasionally acute he-
molytic anemia
Very frequent in malaria
areas
G6PD-A- G6PD-Seattle
G6PD-Canton G6PD-
Rignano
IV 60-90% normal activity Neutral protein site Asymptomatic Undened frequency G6PD-Montalbano
G6PD-Orissa
V>110% increased activity Neutral protein site or
promoter mutations Asymptomatic Undened frequency Not reported
Glusoce-6-phosphate Dehydrogenase
1036
oxidant injury by catalyzing the breakdown of compounds
such as H2O2. In simpler terms, the disposal of H2O2, a
potential oxidant, is dependent on the adequacy of reduced
glutathione (GSH), which is generated by the action of
NADPH. The synthesis of NADPH is dependent on the
activity of G6PD.11
Clinical spectrum of G6PD deciency
The clinical spectrum of G6PD deciency has been identied
in a vast number of conditions. Clinical manifestations
depend on the degree of the enzyme deciency, which
in turn is determined by the characteristics of the G6PD
variant. Majority of individuals are asymptomatic and do
not have hemolysis in the steady state. They have neither
anemia, evidence of increased red blood cell destruction,
nor an alteration in blood morphology, although a modest
shortening of RBC survival can be demonstrated by isotopic
techniques. However, episodes of acute hemolysis with
hemolytic anemia may be triggered by medications, certain
foods, and acute illnesses, especially infection.12
Drug induced hemolysis
The hemolytic effect of primaquine in G6PD decient
individuals were already established. But later on it was
realized that the spectrum of drugs that caused hemolysis
was much more than that had been anticipated. Transfusing
labeled red cells from a few primaquine sensitive donors
into a larger number of nonsensitive recipients and then
challenging the sensitive cells with a variety of drugs made
it possible to quantitate the extend to which each drug
produced hemolysis.6,13,14 Table 2 lists drugs that have been
shown to be capable of producing clinically signicant
hemolytic anemia in doses that are normally used. Table 3
indicates qhich drugs can be given safely to most patients
with G6PD deciency.15,16
Foods inciting hemolysis
Certain foods can induce hemolysis in a G6PD decient
individual. Intravascular hemolysis induced by ingestion
of fava beans, known to as favism, is a well know cause
and is seen predominantly in young males age 1 to 5 years.
Symptoms include headache, back pain, chills, fever
within 24 hours of ingestion, followed by hemoglobinuria
and jaundice. An important thing to be noted is that all
patient with favism are G6PD decient, but many G6PD
decient individuals can eat fava beans with impunity.
Thus, the deciency is a necessary but not sufcient cause
of hemolysis. It has been suggested that the glycosides
divicine and isouramil are the components of the bean
responsible for a hemolysis, but there is no rigorous proof
that this is the case, and the additional factor that makes a
minority of G6PD decient individuals develop hemolysis
when they ingest the bean is still unknown, although it is
probably inherited.
Infection
Infection is the most common cause of acute hemolysis in
G6PD-deceinet persons, although the exact mechanism
by which this occurs is unknow. Leukocytes may release
oxidants during phagocytosis that cause oxidative stress
to the erythrocytes; however, this explanation alone would
not account for the variety of infections associated with
hemolysis in G6PD decient persons. The most common
infections agents causing hemolysis include Salmonella,
Escherichia coli, beta-hemolytic streptococci, rickettsial
infections, viral hepatitis, and inuenza A.17
Neonatal Jaundice
Anemia and jaundice are often rst noted in neonates
with severe G6PD deciency. The principle cause of
neonatal icterus in G6PD decient infants is the inability
of the liver to adequately conjugate bilirubin. This
problem is compounded when the infant also inherits the
UDP glucuronosyl transferase promoter polymorphism
that is associated with Gilbert disease. As noted,
hyperbilirubinemia is likely secondary to impairment of
bilirubin conjugation and clearance by the liver leading to
indirect hyperbilirubinemia. G6PD deciency can lead to
an increased risk and earlier onset of hyperbilirubinemia,
which may require phototherapy or exchange transfusion.
In certain populations, hyperbilirubinemia secondary to
G6PD deciency results in an increased rate of kernicterus
and death, whereas in other populations this has not been
observed. This may reect genetic mutations specic to
different ethnic groups.
Table 2: Drugs and chemicals to be avoided by persons
with G6PD deciency
Acetanilide
Diaminodiphenyl sulfone
Furazolidone (Furoxone)
Glibenclamide
Henna (Lawsone)
Isobutyl nitrate
Methylene blue
Naphthalene
Niridazole (Ambilhar)
Nitrofurantoin
Phenazopyridine
Phenylhydrazine
Primaquine
Sulfacetamide
Sulfanilamide
Sulfapyridine
Thiazolesulfone
Trinitrotoluene
Urate oxidase
Gautam K et al.
1037Glusoce-6-phosphate Dehydrogenase
Table 3: Drugs that probably can be safely given in normal
therapeutic doses to G6PD-decient patients without nons-
pherocytic hemolytic anemia
Acetaminophen
Acetophenetidin
Acetylsalicylic acid
Aminopyrine
Antazoline
Antipyrine
Ascorbic acid
Benzhexol
Chloramphenicol
Chlorguanidine
Chloroquine
Colchicines
Diphenyldramine
Isoniazid
L-dopa
Menadione sodium bisulfate
p-Aminobenzoic acid
p-Aminosalicylic acid
Phenylbutazone
Phenytoin
Probenecid
Procainamide hydrochloride
Pyrimethamine
Quinine
Spectromycin
Sulfacytine
Sulfadiazine
Sulfametazine
Sulfamethoxazole
Sulfamethoxypyridazine
Sulsoxazole
Tiaprofenic acid
Trimethoprim
Tripelennamine
Vitamin K
Congenital nonspherocytic hemolytic anemia and
chronic hemolysis
Chronic hemolysis is not characteristic of most individuals
with G6PD deciency, but those with severe deciency can
have chronic hemolysis with or without chronic anemia.
Variants that produce chronic hemolytic anemia are referred
to as class I variants. These individuals have such severe
G6PD deciency that they may have hemolysis even in the
absence of oxidant injury from medications or illnesses.18,19
These individuals may also be referred to as having
congenital nonspherocytic hemolytic anemia. The term
nonspherocytic is somewhat of a misnomer, since these
individuals may have spherocytes on the pheripheral
blood smear. However, this term is useful in distinguishing
individuals with G6PD deciency, in whom spherocytes are
relatively infrequent at baseline, from those with hereditary
spherocytosis, in whom spherocytes are abundant. The
severity of hemolysis varies, causing mild hemolysis to
transfusion dependent anemia. Exposure to oxidative stress
can cause acute hemoysis in these persons.20
Cardiovascular disease
The clinical effects of G6PD deciency on the heart remains
largely unexplored despite it being the most common
known enzyme deciency in the world. Although studies
suggest that G6PD deciency may decrease superoxide
production in failing myocardium and that G6PD deciency
may decrease the risk of developing coronary heart disease,
recent studies in mice indicate increased oxidative stress
in G6PD decient failing myocardium and that G6PD
deciency adversely affects the development of heart
failure.
The effects of G6PD deciency on the development and
progression of heart failure in human patients could be
explored by screening hypertensive patients for G6PD
deciency and then following these patients over an
extended period to see whether g6PD deciency affects
the development of heart failure in these patients. Another
study could examine G6PD decient patients who have
already developed heart failure to determine whether G6PD
deciency positively or negatively affects prognosis. Thus
Figure 1: : Role of glucose-6-phosphate dehydrogenase
in defense against oxidant injury.
1038
the development of heart failure should be examined in
G6PD decient patients. Overall, G6PD deciency may
decrease the rate of cardiovascular disease development
among humans through its effect on atherogenesis.21
Meloni has concluded that subjects with G6PD decient
phenotype are less prone to coronary heart disease (CHD).
They suggest that such a protective effect may be ascribable
to a reduced 3-hydroxy-3-methylglutaryl-coenzyme A
reductase (HMG-CoA R) activity, a statin-like effect, as well
as to a downregulation in NADPH oxidase activity with a
consequent reduction in oxygen free radical production.22
G6PD activity in Diabetic patients
Diabetes mellitus is a common and complicated disease.
Activities of enzyme G6PD is important in preventing
its complications. Unsuitable control of blood glucose
decreases G6PD activity and increases diabetes mellitus
complications. This issue itself aggravates diabetic injury
due to inappropriate antioxidation process. Simultaneous
dyslipidemia and obesity may intensity the effect of
hyperglycemia and oxidative stress. G6PD activity level can
reect the gylcemic control, and even predict subsequent
complications while they are not present Literature has
shown that G6PD mean activity in diabetics is signicantly
lower than non diabetics. Various studies have concluded
that reduced activity of G6PD is a risk factor for DM. Since
diabetic patients simultaneously suffer from other endocrine
problems like dyslipidemia, it is worthy to evaluate the
impact of such associated abnormalities on G6PD activity.
Comparing G6PD activity between dyslipidemic and non
dyslipidemic patients within diabetics and comparing
G6PD activity between non diabetic and dyslipidemic
diabetic patients, the researchers showed that its activity
was signicantly lower in dyslipidemic patients.23
On the other hand studies have also concluded that G6PD
deciency showed a trend for protection against diabetes
with proliferative diabetic retinopathy. Further experimental
and clinical studies are necessary for a better understanding
of the mechanism by which G6PD deciency may affect
diabetes and its retinal vascular complications.24
Laboratory Tests
Enzymatic evaluation: The WHO recommends the diagnosis
of G6PD deciency utilizing universal tests, mainly based
on the generation of NADPH from NADP.
Semiquantitative assays are as follows: (i) uorescent spot
test, which is rapid, simple, sensitive and inexpensive. This
test method is used in countries where G6PD deciency is
both frequent and malaria endemic, before starting treatment
with antimalarial drugs, such as primaquine. A variant of
the spot test, not requiring the sue of an ultraviolet lamp
but a naked eye evaluation, allows the larger population
screening in the tropical areas. (ii) other screening tests
available which determine the NADPH concentration
indirectly, by measuring the reduced methemoglobin levels
produced after NADPH oxidation. (iii) Finally, the Heinz
body examination and GSH stability test may be employed
to distinguish G6PD decient from normal individuals.
For a biochemical denitive diagnosis, a quantitative analysis
is mandatory done by spectrophootometry. Diagnostic issues
can arise when G6PD activity is measured after or during
an episode of acute hemolysis, or in the presence of high
blood reticulocyte count, being the reticulocytes activity
about ve times higher than that of old RBCs, resulting in
a false negative result. Because protein synthesis is absent
in RBCs, the activity of G6PD, and of other enzymes
gradually decreases during RBCs aging, which will be
selectively destroyed. If any acute intravascular hemolytic
G6PD dependent anemia is suspected, any potentially
dangerous drugs must be discontinued and the test should
be rerun 10-15 days after, or later, if the patient has been
transfused. In these cases, genetic analysis or family study,
when available, can improve the diagnostic tool. For a
complete diagnostic assessment of the G6PD deciency
rate, the following laboratory parameters are also important:
RBCs and reticulocyte counts, total and indirect plasma
bilirubin, plasma iron and lactate dehydrogenase levels,
serum haptoglobin and urine hemoglobin concentration.11
Molecular diagnosis
Molecular analysis may be useful for population screening,
family studies, or parental diagnosis, although this approach
is not used routinely. For a correct laboratory practice, the
molecular diagnosis of G6PD deciency should employ two
analytical steps: 1) a rst screening level, to research the
most frequent mutations belonging to a specic geographical
area. In this case, a PCR coupled to RFLP represents a
rapid valid, and reliable molecular screening approach; 2) a
second level, based on the whole gene sequencing, nalized
to the identication of the less frequent, or novel, mutation.
25
DNA based test for the screening of the most frequent
mutations in a specic geographical area can be used as
an alternative tool to the biochemical assay. The costs for
chemicals dedicated to molecular test are comparable to
those used for the enzyme assay. In the future, more advance
systems should be utilized to improve the efciency of the
molecular assay.11
CONCLUSION
G6PD deciency is one of the most common enzyme defect
of red cells which has been studied for more than 50 years
since its identication. Point of care testing has helped in
screening individuals prior to administration of malarial
drugs. Molecular testing has been important in identifying
the different variants which have clinical signicance.
Gautam K et al.
1039
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Glusoce-6-phosphate Dehydrogenase
... Glucose-6-phosphate dehydrogenase activity is one of the most common tests administered when pregnant women attend antenatal care for the first time. The WHO glucose-6-phosphate dehydrogenase activity classification ranges from undetectable (<1% enzyme activity), partially detectable (≤60%) to normal or increased (>60%) (Gautam, 2016). Pregnant women who are glucose-6-phosphate dehydrogenase deficient are likely to experience oxidative stress when they contract certain infections (beta-hemolytic streptococci, rickettsial disease, viral hepatitis, salmonella, Escherichia coli and influenza A), take certain medications (sulfur-containing drugs) or eat certain foods (fava beans) (Richardson and O'Malley, 2022). ...
... These findings are consistent with other studies, which have reported that glucose-6-phosphate dehydrogenase prevents oxidative damage to red blood cells. This defence mechanism is weakened by a deficit of the enzyme, potentially increasing the risk of red blood cell oxidation and anaemia (Gautam, 2016). ...
Article
Full-text available
Background/Aims: Glucose-6-phosphate dehydrogenase deficiency worsens the risk of anaemia and complicates gestation and birth if poorly managed. This study investigated the prevalence and factors associated with anaemia and this deficiency in pregnant women. Methods: This cross-sectional study was conducted among 369 pregnant women at the Cape Coast Metropolitan Hospital, Ghana. Multiple logistic regression was used to investigate the relationship between anaemia and various sociodemographic variables. Results: The prevalence of anaemia was 41.2% at 13 weeks' and 66.7% at 36 weeks' gestation. Overall, 29.8% of participants were glucose-6-phosphate dehydrogenase deficient. Age (P=0.024)and marital status (P=0.009) were significantly associated with anaemia at 13 weeks. Gravidity (P=0.014) and employment status (P=0.001) were significantly associated with anaemia at 36 weeks. Conclusions: There was a high prevalence of co-morbid anaemia and glucose-6-phosphate dehydrogenase deficiency at 13 and 36 weeks' gestation. Future studies should consider genetic and dietary factors that may contribute to gestational anaemia. Implications for practice: Clinicians and midwives should be aware of the factors that can affect anaemia and glucose-6-phosphate dehydrogenase deficiency, particularly in areas where deficiency is prevalent. Early detection could allow individualised treatment.
... Class I and II variants retain <1% and <10% of enzymatic activity respectively, whereas class III variants retain up to 10-60% of activity. Classes I-III are deemed more severe as they can lead to anaemia, whereas classes IV and V are not so harmful [3,11]. Although different mutations are located at various domains of the protein (Figure 1(A)), mutational hotspots have been identified. ...
... For instance, majority of the mutation sites for class I variants are located at the dimer interface and structural NADP (s.NADP) binding site, class II at the tetramer interface, and class III at the catalytic domain [12]. The severity of these mutations reduces in the order of class I > II > III, emphasising that the structural integrity of the dimer interface and s.NADP binding influences overall enzyme activity [11,12]. ...
... Class I and II variants retain <1% and <10% of enzymatic activity respectively, whereas class III variants retain up to 10-60% of activity. Classes I-III are deemed more severe as they can lead to anaemia, whereas classes IV and V are not so harmful [3,11]. Although different mutations are located at various domains of the protein (Figure 1(A)), mutational hotspots have been identified. ...
... For instance, majority of the mutation sites for class I variants are located at the dimer interface and structural NADP (s.NADP) binding site, class II at the tetramer interface, and class III at the catalytic domain [12]. The severity of these mutations reduces in the order of class I > II > III, emphasising that the structural integrity of the dimer interface and s.NADP binding influences overall enzyme activity [11,12]. ...
... There have been reports of more than 400 G6PD variants, of which approximately 50% of variants lead to G6PD deficiency characterized by reduced enzyme activity and structural integrity of the protein structure [8]. G6PD variants resulting from different mutations lead to different clinical symptoms [9,10]. Furthermore, depending on the deleterious effects of a variant, they have been grouped into five classes (I, II, III, IV and V), classes I, II and III represent the most damaging variants, whereas classes IV and V are less harmful [9,11]. ...
... G6PD variants resulting from different mutations lead to different clinical symptoms [9,10]. Furthermore, depending on the deleterious effects of a variant, they have been grouped into five classes (I, II, III, IV and V), classes I, II and III represent the most damaging variants, whereas classes IV and V are less harmful [9,11]. ...
Article
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency disorder affecting over 400 million individuals worldwide. G6PD protects red blood cells (RBC) from the harmful effects of oxidative substances. There are more than 400 G6PD mutations, of which 186 variants have shown to be linked to G6PD deficiency by decreasing the activity or stability of the enzyme. Different variants manifest different clinical phenotypes which complicate comprehending the mechanism of the disease. In order to carry out computational approaches to elucidate the structural changes of different G6PD variants that are common to the Asian population, a complete G6PD monomerligand complex was constructed using AutoDock 4.2, and the molecular dynamics simulation package GROMACS 4.6.7 was used to study the protein dynamics. The G410D and V291M variants were chosen to represent classes I and II respectively and were created by in silico site-directed mutagenesis. Results from the Root mean square deviation (RMSD), Root mean square fluctuation (RMSF) and Radius of gyration (Rg) analyses provided insights on the structure e function relationship for the variants. G410D indicated impaired dimerization and structural NADP binding while the impaired catalytic activity for V291M was indicated by a conformational change at its mutation site.
... G6PD deficiency causes hemolysis-prone red blood cells, resulting in a wide range of medical consequences [1,2]. Patients with G6PD deficiency often suffer from acute hemolytic anemia, chronic non-spherocytic hemolytic anemia, favism, and neonatal jaundice [38]. Additionally, it increases the likelihood of developing diabetes mellitus, hypertension, cancer, and cataracts [3]. ...
Article
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An inherent genetic enzyme disorder in humans, known as glucose-6-phosphate dehydrogenase (G6PD) deficiency, arises due to specific mutations. While the prevailing approach for investigating G6PD variants involves biochemical analysis, the intricate structural details remain limited, impeding a comprehensive understanding of how different G6PD variants of varying classes impact their functionality. This study 22 examined the dynamic properties of G6PD wild types and six G6PD variants from 23 different classes using molecular dynamic simulation (MDS). The wild-type and variant 24 G6PD structures unveil high fluctuations within the amino acid range of 274–515, the structural NADP⁺ binding site, pivotal for enzyme dimerization. Specifically, two variants, G6PDZacatecas (R257L) and G6PDDurham (K238R), demonstrate compromised structural stability at the dimer interface, attributable to the disruption of a salt bridge involving Glu 206 and Lys 407, along with the disturbance of hydrogen bonds formed by Asp 421 at the βN-βN sheets. Consequently, this impairment cascades to affect the binding affinity of crucial interactions, such as Lys 171-Glucose-6-Phosphate (G6P) and Lys 171-catalytic NADP⁺, leading to diminished enzyme activity. This study underscores the utility of computational in silico techniques in predicting the structural alterations and flexibility of G6PD variants. This insight holds promise for guiding future endeavors in drug development targeted at mitigating the impacts of G6PD deficiency.
... Other classes are II -V and have higher enzyme activities between 1 and 110 %. They areprimarily asymptomatic throughout life.[9] ...
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We report a case of G6PD deficiency in a male Nigerian neonate who presented with features of acute bilirubin encephalopathy and severe anemia within the first week of life in the absence of ABO and Rhesus incompatibilities requiring multiple exchange blood transfusions (EBTs) and intensive phototherapy. The hyperbilirubinemia worsened following the commencement of IV Ciprofloxacin and improved significantly once it was discontinued. He was lost to follow-up, having been discharged in a satisfactory neurological state.
... *Correspondence: udysharma1000@gmail.com 1 Universal College of Medical Sciences, Bhairahawa, Nepal Full list of author information is available at the end of the article Not only primaquine but a large spectrum of drugs can induce hemolysis in G6PD deficient individuals [6]. Ingestion of fava beans (Vicia faba) has been associated with hemolytic anemia in G6PD deficient individuals since a very ancient period of time [7]. ...
Article
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Objectives: The study was carried out with the aim to find out the frequency of Glucose 6 phosphate dehydrogenase (G6PD) deficiency among the patients attending the hospital and to rationalize the qualitative methemoglobin reduction test in reference to the quantitative spectrophotometric assay. Timely screening of the patients for G6PD with appropriate screening method can play an important role in preventing hemolytic crisis that arises from therapeutic use of oxidative drugs like primaquine. Result: The frequency of G6PD deficient cases was 3% by both of the employed tests. The mean ± SD of G6PD activity in the patients under study was 15.34 ± 4.7 IU/g Hb in males and 16.01 ± 3.74 IU/g Hb in females. G6PD activity was positively associated with reticulocyte count (r = 0.289, p value = 0.004) and negatively with mean corpuscular hemoglobin concentration (r = -0.220, p-value = 0.028). The correlation of red blood corpuscular count and G6PD was statistically significant (p-value = 0.048).
... [5] Not only primaquine but a large spectrum of drugs can induce hemolysis in G6PD de cient individuals. [6] Ingestion of fava beans (Vicia faba) has been associated with hemolytic anemia in G6PD de cient individuals since a very ancient period of time. [7] Exposure of infant or mother to oxidant drugs or without exposure to such drugs leading neonatal jaundice due to G6PD de ciency can even lead to kernicterus. ...
Preprint
Full-text available
Objectives: The study was carried out with the aim to find out the frequency of Glucose 6 phosphate dehydrogenase (G6PD) deficiency among the patients attending the hospital and to rationalize the qualitative methemoglobin reduction test in reference to the quantitative spectrophotometric assay. Timely screening of the patients for G6PD with appropriate screening method can play an important role in preventing hemolytic crisis that arises from therapeutic use of oxidative drugs like primaquine. Result: The frequency of G6PD deficient cases was 3% by both of the employed tests. The mean ± SD of G6PD activity in the patients under study was 15.34 ± 4.7 IU/g Hb in males and 16.01 ± 3.74 IU/g Hb in females. G6PD activity was positively associated with reticulocyte count (r = 0.289, p-value = 0.004) and negatively with mean corpuscular hemoglobin concentration (r = -0.220, p-value = 0.028). The correlation of red blood corpuscular count and G6PD was statistically significant (p-value = 0.048).
Article
Anämien sind in der Bevölkerung weit verbreitet. Besonders im Kindes- und Jugendalter ist die Wahrscheinlichkeit hoch, an einer erworbenen Anämie zu erkranken. Die Basisdiagnostik und erweiterte Diagnostik und das Erkennen der unterschiedlichen Anämieformen sind essenziell für die richtige Therapieentscheidung. Insbesondere transfusionsbedürftige Kinder müssen rechtzeitig erkannt werden, um richtig handeln zu können.
Preprint
Full-text available
Objectives The study was carried out to with the aim to find out the frequency of G6PD deficiency among the patients attending the hospital and to rationalize methemoglobin reduction test (Qualitative method) in reference to the spectrophotometric assay (Quantitative method). Timely screening of the patients for Glucose 6 phosphate dehydrogenase deficiency with appropriate screening method can play an important role in preventing hemolytic crisis that arises from therapeutic use of oxidative drugs like primaquine. Result The frequency of Glucose 6 phosphate dehydrogenase deficient cases was 3% by both of the employed tests. The mean ± SD of Glucose 6 phosphate dehydrogenase activity in the patients under study was 15.34 ± 4.7 IU/l in males, 16.01 ± 3.74 IU/l in females. G6PD activity was positively associated with reticulocyte count (r = 0.289, p-value = 0.004) and negatively with mean corpuscular hemoglobin concentration (r = -0.220, p-value = 0.028). The correlation of Red blood corpuscular count and Glucose 6 phosphate dehydrogenase was statistically significant (p-value = 0.048).
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Background: Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is one of the most common human genetic abnormalities, with a high prevalence in Sardinia, Italy. Evidence indicates that G6PD-deficient patients are protected against vascular disease. Little is known about the relationship between G6PD deficiency and diabetes mellitus. The purpose of this study was to compare G6PD deficiency prevalence in Sardinian diabetic men with severe retinal vascular complications and in age-matched non-diabetic controls and ascertain whether G6PD deficiency may offer protection against this vascular disorder. Methods: Erythrocyte G6PD activity was determined using a quantitative assay in 390 diabetic men with proliferative diabetic retinopathy (PDR) and 390 male non-diabetic controls, both aged ≥50 years. Conditional logistic regression models were used to investigate the association between G6PD deficiency and diabetes with severe retinal complications. Results: G6PD deficiency was found in 21 (5.4 %) diabetic patients and 33 (8.5 %) controls (P=0.09). In a univariate conditional logistic regression model, G6PD deficiency showed a trend for protection against diabetes with PDR, but the odds ratio (OR) fell short of statistical significance (OR=0.6, 95% confidence interval=0.35-1.08, P=0.09). In multivariate conditional logistic regression models, including as covariates G6PD deficiency, plasma glucose, and systemic hypertension or systolic or diastolic blood pressure, G6PD deficiency showed no statistically significant protection against diabetes with PDR. Conclusions: The prevalence of G6PD deficiency in diabetic men with PDR was lower than in age-matched non-diabetic controls. G6PD deficiency showed a trend for protection against diabetes with PDR, but results were not statistically significant.
Article
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Background and objectives: Diabetes mellitus is a common and complicated disease. Studies imply blood glucose and its oxidant derivatives have a key role in pathogenesis of diabetes mellitus. Activity of enzyme "glucose-6-phosphate dehydrogenase" (G6PD), an anti-oxidant system, is important in preventing its complications. Unsuitable control of blood glucose decreases G6PD activity and increases diabetes mellitus complications. This study evaluated the difference of G6PD activity among diabetic and non diabetic patients, and the impact of hyperglycemia on the G6PD activity. Methodology: One hundred diabetic and one hundred non diabetic subjects were selected from patients 30 to 60 years old. Demographic data including gender, age, height, weight, duration of diabetes mellitus, type and duration of treatment, medical history (especially favism) were recorded. Blood pressure and body mass index were also measured. One blood sample was taken from each subject and 5 elements including G6PD presence and activity, fasting plasma glucose, plasma triglyceride and plasma high density lipoprotein were measured. Results: G6PD activity was significantly higher in non diabetic subjects (P
Article
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Glucose 6-phosphate dehydrogenase (G6PD) catalyzes the rate-determining step in the pentose phosphate pathway, and produces NADPH to fuel glutathione recycling. G6PD deficiency is the most common enzyme deficiency in humans, and affects over 400 million people worldwide; however its impact on cardiovascular disease is poorly understood. The glutathione pathway is paramount to antioxidant defense, and G6PD deficient cells do not cope well with oxidative damage. Limited clinical evidence indicates that G6PD deficiency may be associated with hypertension. However, there is also data to support a protective role of G6PD deficiency in decreasing the risk of heart disease and cardiovascular-associated deaths, perhaps through a decrease in cholesterol synthesis. Studies in G6PD deficient (G6PDX) mice are mixed, and provide evidence for both protective and deleterious effects. G6PD deficiency may provide a protective effect through decreasing cholesterol synthesis, superoxide production, and reductive stress. However, recent studies indicate that G6PDX mice are moderately more susceptible to ventricular dilation in response to myocardial infarction or pressure overload-induced heart failure. Further, G6PDX hearts do not recover as well as non-deficient mice when faced with ischemia-reperfusion injury, and G6PDX mice are susceptible to the development of age-associated cardiac hypertrophy. Overall, the limited available data indicate a complex interplay in which adverse effects of G6PD deficiency may outweigh potential protective effects in the face of cardiac stress. Definitive clinical studies in large populations are needed to determine the effects of G6PD deficiency on the development of cardiovascular disease and subsequent outcomes.
Book
The book is an excellent monograph on hereditary anemias, caused by defects in the metabolism of glucose, hexose monophosphate and some nucleotides. Especially, G6PD- and pyruvate kinase deficiency are extensively described. Less often occurring deficiencies, such as glucose phosphate isomerase, hexokinase, diphosphoglycerate mutase, etc., are critically reviewed. Most interesting is the chapter on disorders in nucleotide metabolism, such as ATPase deficiency, adenylate kinase deficiency, 'high ATP' syndromes, pyrimidine 5'-nucleotidase deficiency and increased adenosine deaminase activity.
Article
Glucose 6-phosphate dehydrogenase (G6PD) deficiency is the most common defect of red blood cells. Although some different laboratory techniques or methods are employed for the biochemical screening, a strict relationship between biochemists, clinicians, and molecular biologists is necessary for a definitive diagnosis. This article represents an overview on the current laboratory tests finalized to the screening or to the definitive diagnosis of G6PD-deficiency, underlying the problems regarding the biochemical and molecular identification of heterozygote females other than those regarding the standardization of the clinical and laboratory diagnostic procedures. Finally, this review is aimed to give a flow-chart for the complete diagnostic approach of G6PD-deficiency.