Glucose 6-phosphate dehydrogenase deficiency in an elite long-distance runner

Demir, Ayşe; Solinge, Wouter W. van; Oirschot, B. van; Wesel, Annet van; Vergouwen, Peter; Thimister, Erwin; Maase, Kamiel; Rijksen, Gert; Schutgens, Roger E. G.; Wijk, Richard van

doi:10.1182/blood-2008-12-194746

Cited by 8 publications

(5 citation statements)

References 8 publications

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“…Interestingly, this patient was diagnosed with exercise-induced PH which showed increased pulmonary pressure during exercise, at rest, this patient had normal mPAP. Increased ROS production during exercise can trigger the underlying G6PD mutation and produce hemolysis [ 20 ]. In the future, the possibility of exercise-induced hemolysis due to G6PD deficiency and possible connections with PAH need to be explored.…”

Section: Discussionmentioning

confidence: 99%

New cases of Glucose-6-Phosphate Dehydrogenase deficiency in Pulmonary Arterial Hypertension

et al. 2018

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Pulmonary Arterial Hypertension (PAH) is a fatal disorder with limited treatment options and reduced life expectancy after diagnosis. Complex genetic backgrounds in PAH complicates identification of causative mutations that is essential for an understanding of the disease diagnostics and etiology especially for idiopathic PAH (iPAH). Hemolysis has been implicated as contributing to the pathobiology of PAH. Glucose-6-Phosphate Dehydrogenase (G6PD) expression and activity define erythrocyte’s antioxidant capacity, and its decrease contributes to erythrocyte fragility. As G6PD deficiency was previously reported in a limited number of PAH cases, we tested whether iPAH patients exhibit underlying G6PD alterations in erythrocytes. A cohort of 22 PAH patients and 8 non-PAH patients were recruited for this study. DNA isolated from Peripheral Blood Mononuclear Cells (PBMC) was used for detection of mutations in the coding region of the G6PD gene. RNA isolated from PBMC was used for determination of G6PD mRNA expression level. G6PD activity was measured in Red Blood Cell (RBC) pellets. Three patients had missense mutations in G6PD (Val291Met, Asn126Asp, Asp194Glu), however, only one mutation (Val291Met) results in a severe G6PD deficiency. A single patient with mutation (Asn126Asp) showed a 21% decrease in G6PD activity, two subjects showed G6PD deficiency without mutations, and one patient had a decreased level of G6PD mRNA and reduced enzyme levels. This study demonstrates that a moderate decrease in G6PD activity is associated with PAH. Screening for G6PD activity and mutations in the G6PD gene may provide early detection of individuals predisposed to PAH.

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Section: Discussionmentioning

confidence: 99%

New cases of Glucose-6-Phosphate Dehydrogenase deficiency in Pulmonary Arterial Hypertension

et al. 2018

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“…In contrast, severe G6PD deficiency does indeed have a detrimental effect on the immune system and causes higher susceptibility to infections [79]. In addition, G6PDH-deficient athletes and patients with this genetic defect may have severe hemolytic crises after physical exertion [80]; however, the severity of susceptibility of individual subjects may vary widely [81]. Complete G6PD knockout in mammals is incompatible with life, but in embryonic mice stem cells it led to the severe susceptibility of cells to oxidative stress induced by hydrogen peroxide or diamide and reduced cloning efficiency.…”

Section: The Evidence From Glucose-6 Phosphate Dehydrogenase Deficiencymentioning

confidence: 99%

Glucose as a Major Antioxidant: When, What for and Why It Fails?

et al. 2020

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A human organism depends on stable glucose blood levels in order to maintain its metabolic needs. Glucose is considered to be the most important energy source, and glycolysis is postulated as a backbone pathway. However, when the glucose supply is limited, ketone bodies and amino acids can be used to produce enough ATP. In contrast, for the functioning of the pentose phosphate pathway (PPP) glucose is essential and cannot be substituted by other metabolites. The PPP generates and maintains the levels of nicotinamide adenine dinucleotide phosphate (NADPH) needed for the reduction in oxidized glutathione and protein thiols, the synthesis of lipids and DNA as well as for xenobiotic detoxification, regulatory redox signaling and counteracting infections. The flux of glucose into a PPP—particularly under extreme oxidative and toxic challenges—is critical for survival, whereas the glycolytic pathway is primarily activated when glucose is abundant, and there is lack of NADP+ that is required for the activation of glucose-6 phosphate dehydrogenase. An important role of glycogen stores in resistance to oxidative challenges is discussed. Current evidences explain the disruptive metabolic effects and detrimental health consequences of chronic nutritional carbohydrate overload, and provide new insights into the positive metabolic effects of intermittent fasting, caloric restriction, exercise, and ketogenic diet through modulation of redox homeostasis.

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“…Future studies will expand on the present analyses, also including additional measurements of cardiovascular function beyond critical speed. Interesting signatures—such as the negative correlation between pentose phosphate pathway and exercise tolerance in SCD patients (for which unfortunately hematocrit levels were not accessible for meta-analysis) and mice—are suggestive of a potential, as of yet unexplored role of G6PD deficiency ( Demir et al, 2009 ) in the context of exercise-induced oxidant stress ( Radak et al, 2013 ; Cavalli et al, 2017 ), which will be the focus of follow up investigations.…”

Section: Discussionmentioning

confidence: 99%

Metabolic correlates to critical speed in murine models of sickle cell disease

Cendali

Nemkov²,

Lisk³

et al. 2023

Front. Physiol.

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Introduction: Exercise intolerance is a common clinical manifestation in patients with sickle cell disease (SCD), though the mechanisms are incompletely understood.Methods: Here we leverage a murine mouse model of sickle cell disease, the Berkeley mouse, to characterize response to exercise via determination of critical speed (CS), a functional measurement of mouse running speed upon exerting to exhaustion.Results: Upon observing a wide distribution in critical speed phenotypes, we systematically determined metabolic aberrations in plasma and organs—including heart, kidney, liver, lung, and spleen—from mice ranked based on critical speed performances (top vs. bottom 25%). Results indicated clear signatures of systemic and organ-specific alterations in carboxylic acids, sphingosine 1-phosphate and acylcarnitine metabolism. Metabolites in these pathways showed significant correlations with critical speed across all matrices. Findings from murine models were thus further validated in 433 sickle cell disease patients (SS genotype). Metabolomics analyses of plasma from 281 subjects in this cohort (with HbA < 10% to decrease confounding effects of recent transfusion events) were used to identify metabolic correlates to sub-maximal exercise test performances, as measure by 6 min walking test in this clinical cohort. Results confirmed strong correlation between test performances and dysregulated levels of circulating carboxylic acids (especially succinate) and sphingosine 1-phosphate.Discussion: We identified novel circulating metabolic markers of exercise intolerance in mouse models of sickle cell disease and sickle cell patients.

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Glucose 6-phosphate dehydrogenase deficiency in an elite long-distance runner

Cited by 8 publications

References 8 publications

New cases of Glucose-6-Phosphate Dehydrogenase deficiency in Pulmonary Arterial Hypertension

New cases of Glucose-6-Phosphate Dehydrogenase deficiency in Pulmonary Arterial Hypertension

Glucose as a Major Antioxidant: When, What for and Why It Fails?

Metabolic correlates to critical speed in murine models of sickle cell disease

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