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Background Patients affected by glucose-6-phosphate dehydrogenase (G6PDH) deficiency are often asymptomatic until an oxidative stress occurs, causing acute hemolytic anemia. The coexistence of hemolytic crisis secondary to G6PDH deficiency and methemoglobinemia is an already known phenomenon, especially after the ingestion of fava beans. While past literature described this association primarily in adult patients, it remains an unusual finding in pediatric population. Our patient's age, as long as her gender, and a negative family history represent, indeed, the peculiarity of what we described. Case presentation We present the case of a 7-year-old female patient with a clinical history of hyperpyrexia, several episodes of yellowish vomit, hypercromic urine, loose stools, asthenia with jaundice. At home paracetamol and a single dose of ibuprofen were administered. No recent history of fava bean ingestion or relevant events were reported in physiological and pathological anamnesis. Family history was negative for hematological comorbidities. Blood tests performed at the emergency room showed a picture of severe anemia with negative direct and indirect Coombs tests, mild acute renal failure, increased inflammation markers and a methemoglobin level equal to 13.7% on blood gas analysis. The detection of vital parameters showed O2-Sat equal to 75% without signs of respiratory distress. A broad-spectrum antibiotic therapy with ceftriaxone and oxygen-therapy were administered, hospitalization was then arranged. Immune-mediated anemia and lymphoproliferative diseases were excluded. G6PDH dosage was requested, resulting indicative of deficiency. Fecal virus testing revealed a positivity for Norovirus. Transfusions of red cell concentrates (RCC) were performed, and the methemoglobin value gradually decreased with stabilization of the hemoglobin, so that methylene blue therapy was not administrated. The patient’s clinical conditions improved in almost 5 days. Conclusions When G6PDH deficiency and methemoglobinemia coexist, a prompt diagnosis is essential. The administration of methylene blue, therapy of choice for the treatment of methemoglobinemia, in fact, may cause a worsening of hemolytic crises in patients affected by G6PDH deficiency. Considering our patient’s clinical features, not clearly evocative of G6PDH deficiency, this case represented a challenge for both diagnosis and treatment, reminding to always consider G6PDH deficiency in case of hemolytic anemia associated with methemoglobinemia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a widely distributed genetic abnormality,1 affecting an estimated 500 million people worldwide.2 Although mostly asymptomatic, G6PD deficiency can manifest clinically in three forms: (i) neonatal jaundice; (ii) acute haemolytic anaemia triggered by fava beans, infection or drugs (including some antimalarial drugs); and (iii) chronic non-spherocytic haemolytic anaemia, which is very rare. The G6PD gene, located on the X chromosome, is highly polymorphic and researchers have identified over 230 variants at the molecular level.2,3 Soon after G6PD deficiency was discovered,4 the World Health Organization (WHO) recognized its public health implications and summoned an ad hoc study group in December 1966. At that time, research showed that G6PD deficiency was heterogeneous,5 and about 20 variants had been characterized with respect to percentage residual activity (measured by the gold standard spectrophotometric assay), electrophoretic mobility, substrate affinity for G6P and NADP (nicotinamide adenine dinucleotide phosphate), activity on substrate analogues, pH dependence and thermostability.

Newborn screening (NBS) for glucose-6-phosphate dehydrogenase (G6PD) deficiency by biochemical tests is being used worldwide, however, the outcomes arising from combined genetic and biochemical tests have not been evaluated. This research aimed to evaluate the outcomes of application of combined genetic and biochemical NBS for G6PD deficiency and to investigate the molecular epidemiological characteristics, variant spectrum, and genotype-phenotype correlation of G6PD deficiency in China. A population-based cohort of 29,601 newborns were prospectively recruited from eight NBS centers in China between February 21 and December 30, 2021. Biochemical and genetic NBS was conducted simultaneously. The overall prevalence of G6PD deficiency was 1.12% (1.86% for male, and 0.33% for female; 1.94% for South China and 0.08% for North China). Genetic NBS identified 10 male patients undetected by biochemical NBS. The overall positive predictive values (PPVs) of biochemical and genetic NBS were 79.95% and 47.57%, respectively. A total of 15 variants were identified, with the six most common variants being c.1388G > A, c.1376G > T, c.95A > G, c.871G > A, c.1024C > T and c.392G > T (94.2%). The activity of G6PD was correlated with the type and WHO classification of variants. This study highlighted that combined screening could enhance the efficiency of current NBS for diagnosing G6PD deficiency. The prevalence, variant spectrum and allele frequency of G6PD deficiency vary across different regions. Our data provide valuable references for clinical practice and optimization of future screening strategies for G6PD deficiency.

Background Glucose-6-Phosphate Dehydrogenase deficiency (G6PDd) is a common genetic enzymopathy that can induce haemolysis triggered by various factors, including some anti-malarial drugs. Although many Point-of-Care (PoC) tests, such as Standard G6PD™ are available to detect G6PDd, its pooled diagnostic test accuracy (DTA) remains unknown. Methods To estimate the DTA of StandG6PD-BS at various thresholds of G6PDd, a systematic review with a DTA meta-analysis were conducted, searching EMBASE, MEDLINE, and SciELO databases up to April 4, 2024.The included studies were those that measured G6PD activity using StandG6PD-BS (reference test) and spectrophotometry (gold standard) in patients suspected of having G6PDd. The risk of bias (RoB) of the studies was assessed using the QUADAS-2 tool and the certainty of evidence (CoE) with the GRADE approach. For the estimation of within-study DTA, a random-effect bivariate meta-analysis was performed to determine the pooled sensitivity and specificity for 30%, 70%, and 80% enzyme levels’ thresholds, and a graphical analysis of the heterogeneity using crosshair and Confidence Regions on receiver operating characteristic (ROC) space plots. Results After screening 2496 reports, four studies were included with 7864 participants covering all thresholds. Two studies had high RoB in QUADAS-2 domains 2 and 3, and the others had low RoB, with low, moderate, and high heterogeneity at the 30%, 70%, and 80% thresholds, respectively. The pooled sensitivity was 99.1%, 95.7%, and 90% for 30%, 70%, and 80% thresholds, respectively. The pooled specificity was 97.4%; 92.9%; and 89.0% for 30%, 70%, and 80% thresholds, respectively. Conclusion StandG6PD-BS is a PoC test with high sensitivity and specificity to detect G6PDd at different thresholds.

Glucose-6-Phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy worldwide, no reliable bedside diagnostic tests to quantify G6PD activity exist. This study evaluated two novel quantitative G6PD diagnostics. Participants with known G6PD activity were enrolled in Bangladesh. G6PD activity was measured by spectrophotometry, Biosensor (BS; AccessBio/CareStart, USA) and STANDARD G6PD (SG; SDBiosensor, ROK). G6PD activity was measured repeatedly in a subset of samples stored at room temperature and 4°C. 158 participants were enrolled, 152 samples tested by BS, 108 samples by SG and 102 samples were tested by all three methods. In comparison to spectrophotometry BS had sensitivity and specificity of 72% (95%CI: 53-86) and 100% (95%CI: 97-100) at 30% cut off respectively, while SG had a sensitivity of 100% (95%CI: 88-100) and specificity of 97% (95%CI: 91-99) at the same cut off. The sensitivity and specificity at 70% cut off activity were 71% (95%CI: 59-82) and 98% (95%CI, 92-100) respectively for BS and 89% (95%CI: 77-96) and 93% (95%CI: 83-98) respectively for SG. When an optimal cut-off was applied the sensitivity of the BS at 70 cut off rose to 91% [95%CI: 80-96] and specificity to 82% [95%CI: 83-89]; a diagnostic accuracy comparable to that of the SG (p = 0.879). G6PD activity dropped significantly (-0.31U/gHb, 95%CI: -0.61 to -0.01, p = 0.022) within 24 hours in samples stored at room temperature, but did not fall below 90% of baseline activity until day 13 (-0.87U/gHb, 95%CI: (-1.11 to -0.62), p<0.001). BS and SG are the first quantitative diagnostics to measure G6PD activity reliably at the bedside and represent suitable alternatives to spectrophotometry in resource poor settings. If samples are stored at 4°C, G6PD activity can be measured reliably for at least 7 days after sample collection.

Red blood cells carry oxygen in the body and Glucose-6-Phosphate Dehydrogenase protects these cells from oxidative chemicals. If there is a lack of Glucose-6-Phosphate Dehydrogenase, red blood cells can go acute hemolysis. Convulsion is a rare presentation for acute hemolysis due to Glucose-6-Phosphate Dehydrogenase deficiency. Herein, we report a case report of a Glucose-6-Phosphate Dehydrogenase deficiency diagnosed patient after presentation with convulsion. A 70 year-old woman patient had been hospitalized because of convulsion and fatigue. She has not had similar symptoms before. She had ingested fava beans in the last two days. Her hypophyseal and brain magnetic resonance imaging were normal. Blood transfusion was performed and the patient recovered.

Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency, prevalent in many malaria-endemic countries. G6PD-deficient individuals are susceptible to hemolysis during oxidative stress, which can occur from exposure to certain medications, including 8-aminoquinolines used to treat Plasmodium vivax malaria. Accordingly, access to point-of-care (POC) G6PD testing in Brazil is critical for safe treatment of P. vivax malaria. Methodology/Principal findings This study evaluated the performance of the semi-quantitative, POC STANDARD G6PD Test (SD Biosensor, Republic of Korea). Participants were recruited at clinics and through an enriched sample in Manaus and Porto Velho, Brazil. G6PD and hemoglobin measurements were obtained from capillary samples at the POC using the STANDARD and HemoCue 201+ (HemoCue AB, Sweden) tests. A thick blood slide was prepared for malaria microscopy. At the laboratories, the STANDARD and HemoCue tests were repeated on venous samples and a quantitative spectrophotometric G6PD reference assay was performed (Pointe Scientific, Canton, MI). G6PD was also assessed by fluorescent spot test. In Manaus, a complete blood count was performed. Samples were analyzed from 1,736 participants. In comparison to spectrophotometry, the STANDARD G6PD Test performed equivalently in determining G6PD status in venous and capillary specimens under varied operating temperatures. Using the manufacturer-recommended reference value thresholds, the test's sensitivity at the <30% threshold on both specimen types was 100% (95% confidence interval [CI] venous 93.6%-100.0%; capillary 93.8%-100.0%). Specificity was 98.6% on venous specimens (95% CI 97.9%-99.1%) and 97.8% on capillary (95% CI 97.0%-98.5%). At the 70% threshold, the test's sensitivity was 96.9% on venous specimens (95% CI 83.8%-99.9%) and 94.3% on capillary (95% CI 80.8%-99.3%). Specificity was 96.5% (95% CI 95.0%-97.6%) and 92.3% (95% CI 90.3%-94.0%) on venous and capillary specimens, respectively. Conclusion/Significance The STANDARD G6PD Test is a promising tool to aid in POC detection of G6PD deficiency in Brazil. Trial registration This study was registered with ClinicalTrials.gov (identifier: NCT04033640).

Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is one of the most common genetic disorders worldwide and remains highly prevalent in malaria-endemic regions. Individuals with G6PDd are at risk of severe complications, including acute haemolytic anaemia, when exposed to oxidative triggers. In Malaysia, the Proto-Malay Orang Asli (PMOA), the second largest indigenous group in Peninsular Malaysia, represents a vulnerable population. This study aimed to estimate the prevalence and mutation spectrum of G6PDd in this community. A total of 258 peripheral blood samples (91 males, 167 females) were screened using a quantitative G6PD assay (OSMMR2000-D). DNA from 73 samples was genotyped with the Hybribio G6PD GenoArray test, and 39 underwent targeted sequencing. The adjusted male median (AMM) of G6PD activity was 9.6 U/gHb (95% CI: 8.9–10.3 U/gHb), with 30% and 80% thresholds corresponding to 2.9 and 7.7 U/gHb, respectively. At the 30% cut-off threshold, the overall estimated prevalence of G6PDd was 6.8% (16/237; 12 males and 4 females). A total of 21 subjects were G6PD-intermediate (7 males and 14 females), and the remaining 221 subjects were G6PD-normal (72 males and 150 females). Genotyping identified 18 hemizygous males, 13 heterozygous females, and 3 homozygous females. Five G6PD variants were detected: G6PD Viangchan (39.5%), G6PD Coimbra (28.9%), G6PD Union (23.7%), G6PD Kaiping (5.3%), and rs782038151 (2.6%). This study demonstrates that G6PDd is common in the PMOA population, with notable molecular diversity. These findings have important implications for malaria control and the safe use of antimalarial drugs in this high-risk community.

Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) is an common enzyme deficiency disease, inducing hemolysis, hyperbilirubinemia, and jaundice, as well as liver dysfunction, in approximately 400 million patients. Patients with G6PDd are more susceptible to viruses infection than those without. However, the incidence and severity of hepatitis E virus (HEV) infection in patients with G6PDd are largely unknown. Methods The prevalence of HEV in patients with G6PDd was investigated. Susceptibility to HEV was evaluated in a hepatoma cell line with G6PD knockdown, and the interaction between HEV and G6PD was assessed. Results The prevalence of HEV infection was higher in patients with G6PDd (23.8%, 25/105) than in patients with normal G6PD levels (0.65%, 2/307), indicating that patients with G6PDd are susceptible to HEV infection. Higher rates of hyperbilirubinemia (64% vs. 36.25%) and pneumonia (28% vs. 12.5%) were observed in HEV-infected patients with G6PDd than in patients with normal G6PD values. G6PD knockdown facilitated HEV entry and aggravated oxidative stress with the significant inhibition of glutathione to benefit viral replication but was restricted by NADPH reduction. Co-IP and colocation assays revealed that HEV ORF3 interacted with G6PD. HEV infection stimulated the expression of G6PD in a manner dependent on nuclear factor E2–related factor 2 activation. Consequently, severe apoptosis was observed in HEV-infected cells with G6PD knockdown. Conclusions Patients with G6PDd are susceptible to HEV infection. The facilitation of HEV entry and aggravation of oxidative stress may contribute to HEV susceptibility in patients with G6PDd and severe disease.

G6PD deficiency (G6PD-D) variants are associated with lower hemoglobin A1c (HbA1c) concentrations, raising concerns about the diagnostic efficacy of HbA1c for abnormal glucose tolerance (Abnl-GT) in Africans, in whom risk of G6PD-D and Abnl-GT is high. G6PD-D is assessed using genotyping or an enzymatic assay, but because G6PD-D is X-linked, the enzymatic assay is necessary for determining status for women heterozygous for deficiency variants. We assessed: 1) ability of HbA1c to detect Abnl-GT by G6PD-D; 2) concordance of genotyping and enzymatic assay for G6PD-D in sub-Saharan Africans living in the US. 534 participants of the Africans in America study were included, with HbA1c ranging from 3.1–11.3%. Abnl-GT determined by HbA1c (≥5.7%) was compared to the diagnostic standard, the oral glucose tolerance test (fasting glucose≥100 mg/dL and/or 2h glucose≥140 mg/dL). G6PD-D status was determined by genotype (n = 263), enzymatic assay (n = 83), or both (n = 188). G6PD-D could not be determined for 13 women heterozygotes with only genotype data. In the remaining participants, HbA1c was 0.9% lower among those with G6PD-D (4.6 ± 0.5; range 3.1–5.6) compared to those with normal G6PD activity (5.5 ± 0.6; range 4.2–11.3; P < 0.001). Glucose concentrations did not differ between groups. HbA1c sensitivity and specificity for Abnl-GT were 0% (0/17) and 100% (37/37) among those with G6PD-D, and 50% (98/195) and 80% (217/272) among those with normal activity. After excluding women heterozygotes, concordance for G6PD-D detection by genotype and the enzymatic assay was 100%. G6PD-D was associated with ~0.9% lower HbA1c in this study, leading to a failure of HbA1c to identify Abnl-GT in these participants. Such a dramatic difference in a screening tool could have consequences in practice, including late diagnosis, undertreatment, and increased complications among those with G6PD-D. Additionally, the results for the enzymatic assay were perfectly concordant with the genotype results for G6PD-D. However, as genotype alone cannot predict G6PD-D in heterozygous women, the enzymatic assay was more informative.