Glucose-6-phosphate Dehydrogenase Deficiency Research Articles

A computational study of structural analysis of Class I human glucose-6-phosphate dehydrogenase (G6PD) variants: Elaborating the correlation to chronic non-spherocytic hemolytic anemia (CNSHA)

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect that affects more than 500 million people worldwide. Individuals affected with G6PD deficiency may occasionally suffer mild-to-severe chronic hemolytic anemia. Chronic non-spherocytic hemolytic anemia (CNSHA) is a potential result of the Class I G6PD variants. This comparative computational study attempted to correct the defect in variants structure by docking the AG1 molecule to selected Class I G6PD variants [G6PDNashville (Arg393His), G6PDAlhambra (Val394Leu), and G6PDDurham (Lys238Arg)] at the dimer interface and structural NADP+ binding site. It was followed by an analysis of the enzyme conformations before and after binding to the AG1 molecule using the molecular dynamics simulation (MDS) approach, while the severity of CNSHA was determined via root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), hydrogen bonds, salt bridges, radius of gyration (Rg), solvent accessible surface area analysis (SASA), and principal component analysis (PCA). The results revealed that G6PDNashville (Arg393His) and G6PDDurham (Lys238Arg) had lost the direct contact with structural NADP+ and salt bridges at Glu419 - Arg427 and Glu206 - Lys407 were disrupted in all selected variants. Furthermore, the AG1 molecule re-stabilized the enzyme structure by restoring the missing interactions. Bioinformatics approaches were also used to conduct a detailed structural analysis of the G6PD enzyme at a molecular level to understand the implications of these variants toward enzyme function. Our findings suggest that despite the lack of treatment for G6PDD to date, AG1 remains a novel molecule that promotes activation in a variety of G6PD variants.

Etiology analysis for term newborns with severe hyperbilirubinemia in eastern Guangdong of China

Neonatal hyperbilirubinemia is one of the common diseases of newborns that typically presents with yellow staining of skin, resulting in sequelaes such as hearing loss, motor and intellectual development disorders, and even death. The pathogenic factors of neonatal hyperbilirubinemia are complex. Different cases of hyperbilirubinemia may have a single or mixed etiology. To explore the etiological characteristics of severe hyperbilirubinemia in term newborns of eastern Guangdong of China. Term newborns with severe hyperbilirubinemia in one hospital from January 2012 to December 2021 were retrospectively analyzed. The etiology was determined according to the laboratory results and clinical manifestations. Among 1602 term newborns with hyperbilirubinemia in eastern Guangdong of China, 32.20% (580/1602) was severe hyperbilirubinemia. Among the causes of severe hyperbilirubinemia, neonatal hemolysis accounted for 15.17%, breast milk jaundice accounted for 12.09%, infection accounted for 10.17%, glucose-6-phosphate dehydrogenase (G6PD) deficiency accounted for 9.14%, and the coexistence of multiple etiologies accounted for 6.55%, unknown etiology accounted for 41.72%. ABO hemolysis and G6PD deficiency were the most common causes in the 20 cases with bilirubin encephalopathy. 94 severe hyperbilirubinemia newborns were tested for uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1)*6 variant (rs4148323, c.211G>A, p.Arg71Gly), 9 cases were 211 G to A homozygous variant, 37 cases were 211 G to A heterozygous variant, and 48 cases were wild genotypes. The main cause for severe hyperbilirubinemia and bilirubin encephalopathy in eastern Guangdong of China were the hemolytic disease of the newborns, G6PD deficiency and infection. UGT1A1 gene variant was also a high-risk factor for neonatal hyperbilirubinemia. Targeted prevention and treatment according to the etiology may reduce the occurrence of bilirubin encephalopathy and kernicterus.

Factors hindering coverage of targeted mass treatment with primaquine in a malarious township of northern Myanmar in 2019–2020

Targeted mass primaquine treatment (TPT) might be an effective intervention to facilitate elimination of vivax malaria in Myanmar by 2030. In this study, we explored the factors hindering coverage of a TPT campaign conducted in a malarious township of northern Myanmar. From August 2019 to July 2020, a cross-sectional exploratory design including quantitative and qualitative data was conducted in five villages with high P. vivax prevalence following a TPT campaign. Among a targeted population of 2322; 1973 (85.0%) participated in the baseline mass blood survey (MBS) and only 52.0% of the total targeted population (1208, 91.9% of total eligible population) completed the TPT. G6PD deficiency was found among 13.5% of total MBS participants and those were excluded from TPT. Of 1315 eligible samples, farmers and gold miners, males, and those aged 15 to 45 years had higher percentages of non-participation in TPT. Qualitative findings showed that most of the non-participation groups were outside the villages during TPT because of time-sensitive agricultural and other occupational or education-related purposes. In addition to mitigating of some inclusion criteria (i.e. including young children or offering weekly PQ treatment to G6PD deficient individuals), strengthening community awareness and increasing engagement should be pursued to increase community participation.

Moving towards malaria elimination with safer treatment for children with G6PD deficiency

“An elephant which kills a rat is not a hero.” This African proverb highlights the necessity of moving towards malaria elimination, but not in a way that risks harm to people with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Frequency of Glucose 6 Phosphate Dehydrogenase Deficiency in Neonates Presenting with Jaundice

Objective: Frequency of Glucose – 6- Phosphate Dehydrogenase deficiency in neonates presenting with jaundice Study design: A cross-sectional study Place and Duration: Pediatric department, civil hospital Karachi from January to June 2019 Methodology: The study included all infants who were hospitalized in the neonatology unit with jaundice. At the beginning of the trial, the parents of each neonate gave their assent after being assured that there would be no monitoring burden placed on the parents for the examinations. When entering the hospital, the researcher himself completed a predesigned proforma that asked for specific details about the patient's age, sex, ethnicity, jaundice onset age, consanguinity, and family history of G6PD deficiency. Investigations on newborns included measuring serum bilirubin and looking for signs of G6PD deficiency. (Estimation of G6PD enzymes). Sigma Diagnostic G6PD Reagent was used to estimate the G6PD enzymes for the qualitative, visual, and calorimetric assessment of G6PD deficit in red blood cells. When the sample's deep blue colour changes Results: 174 infants with jaundice in total were included during the study period. Participants in the study had an average age of 16.12 +/- 7.2 days. 95 (54.6%) of the 174 study participants were men, and the male-to-female ratio was 1.2:1. It started at an average age of 8.83.8 days. 79 (45.5%) out of a total of 117 (67.2%) participants are Pathans by consanguineous marriage. 23 (13.2%) of the 174 subjects were G6PD deficient. According to a stratified analysis, out of 23 G6PD-deficient newborns, 11 (47.8%) were between 1 and 11 days old, 19 (82.6%) were between 0 and 6 days old, and 14 (60.8%) had blood bilirubin levels below 15 mg/dl. Conclusion: It was concluded that G6PD is a common cause of neonatal jaundice in our setup. Keywords: Neonates, Jaundice, G6PD deficiency

Association of Glucose-6-Phosphate Dehydrogenase Deficiency With Outcomes in US Veterans With COVID-19

The underlying biological risk factors for severe outcome due to SAR-CoV-2 infection are not well defined. To determine the association between glucose-6-phosphate dehydrogenase (G6PD) deficiency and severity of COVID-19. This retrospective cohort study included analysis of 24 700 veterans with G6PD enzyme testing prior to January 1, 2020, obtained through the US Veterans Health Administration national databases. These veterans were cross-referenced with the Veterans Administration COVID-19 Shared Data Resource for SARS-CoV-2 testing from February 15, 2020, to January 1, 2021. The final study population consisted of 4811 veterans who tested positive for SARS-CoV-2. Statistical analysis was performed from June to December 2021. G6PD deficiency. COVID-19 severe illness, as defined by the Centers for Disease Control and Prevention: hospitalization, need for mechanical ventilation and/or intensive care unit admission, or in-hospital mortality after a positive SARS-CoV-2 test. Among 4811 veterans in the Veterans Health Administration who had historical G6PD enzyme activity test results and SARS-CoV-2 positivity included in this study, 3868 (80.4%) were male, 1553 (32.3%) were Black, and 1855 (39%) were White; 1228 (25.5%) were 65 years or older and 3583 (74.5%) were younger than 65 years. There were no significant differences in age, body mass index, or Charlson Comorbidity Index were present between the veterans with G6PD deficiency and without G6PD deficiency. Among these veterans with SARS-CoV-2 infection, G6PD deficiency was more prevalent in Black male veterans (309 of 454 [68.1%]) compared with other racial and ethnic groups. Black male veterans less than 65 years of age with G6PD deficiency had approximately 1.5-fold increased likelihood of developing severe outcomes from SARS-CoV-2 infection compared with Black male veterans without G6PD deficiency (OR, 1.47; 95% CI, 1.03-2.09). In the small subset of White male veterans with G6PD deficiency, we observed an approximately 3.6-fold increased likelihood of developing severe outcomes from SARS-CoV-2 infection compared with White male veterans aged 65 years or older without G6PD deficiency (OR, 3.58; 95% CI, 1.64-7.80). This difference between veterans with and without G6PD deficiency was not observed in younger White male veterans or older Black male veterans, nor in smaller subsets of other male veterans or in female veterans of any age. In this cohort study of COVID-19-positive veterans, Black male veterans less than 65 years of age and White male veterans 65 years of age or older with G6PD deficiency had an increased likelihood of developing severe COVID-19 compared with veterans without G6PD deficiency. These data indicate a need to consider the potential for G6PD deficiency prior to treatment of patients with SARS-CoV-2 infection as part of clinical strategies to mitigate severe outcomes.

Secondary Reporting of G6PD Deficiency on Newborn Screening

In April 2019, the Alberta Newborn Screening Program expanded to include screening for classic galactosemia using a two-tier screening approach. This approach secondarily identifies infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The goals of this study were (i) to evaluate the performance of a two-tier galactosemia screening protocol, (ii) to explore the impact on and acceptability to families of reporting G6PD deficiency as a secondary finding, and (iii) assess the communication and follow-up process for positive G6PD deficiency screening results. The two-tiered galactosemia approach increased the positive predictive value (PPV) for galactosemia from 8% to 79%. An additional 119 positive newborn screen results were reported for G6PD deficiency with a PPV of 92%. The results show that there may be utility in reporting G6PD deficiency results. Most parents who participated in the study reported having some residual worry around the unexpected diagnosis; however, all thought it was helpful to know of their child's diagnosis of G6PD deficiency. Finally, the communication process for reporting G6PD deficiency newborn screen results was determined to result in appropriate follow up of infants.

The Prevalence of G6PD Deficiency and its Associated Factors Among the National University Students in the Middle Province (Ibb City), Yemen

The Prevalence of G6PD Deficiency and its Associated Factors Among the National University Students in the Middle Province (Ibb City), Yemen

Effect of iron fortification on anaemia and risk of malaria among Ghanaian pre-school children with haemoglobinopathies and different ABO blood groups

BackgroundHaemoglobinopathies such as sickle cell disorder and glucose-6-phosphate dehydrogenase (G6PD) deficiency as well as differences in ABO blood groups have been shown to influence the risk of malaria and/or anaemia in malaria-endemic areas. This study assessed the effect of adding MNP containing iron to home-made weaning meals on anaemia and the risk of malaria in Ghanaian pre-school children with haemoglobinopathies and different ABO blood groups.MethodsThis study was a double-blind, randomly clustered trial conducted within six months among infants and young children aged 6 to 35 months in rural Ghana (775 clusters, n = 860). Participants were randomly selected into clusters to receive daily semiliquid home-prepared meals mixed with either micronutrient powder without iron (noniron group) or with iron (iron group; 12.5 mg of iron daily) for 5 months. Malaria infection was detected by microscopy, blood haemoglobin (Hb) levels were measured with a HemoCue Hb analyzer, the reversed ABO blood grouping microtube assay was performed, and genotyping was performed by PCR–RFLP analysis.ResultsThe prevalence of G6PD deficiency among the study participants was 11.2%. However, the prevalence of G6PD deficiency in hemizygous males (8.5%) was significantly higher than that in homozygous females (2.7%) (p = 0.005). The prevalence rates of sickle cell traits (HbAS and HbSC) and sickle cell disorder (HbSS) were 17.5% and 0.5%, respectively. Blood group O was dominant (41.4%), followed by blood group A (29.6%) and blood group B (23.3%), while blood group AB (5.7%) had the least frequency among the study participants. We observed that children on an iron supplement with HbAS had significantly moderate anaemia at the endline (EL) compared to the baseline level (BL) (p = 0.004). However, subjects with HbAS and HbAC and blood groups A and O in the iron group had a significantly increased number of malaria episodes at EL than at BL (p < 0.05). Furthermore, children in the iron group with HbSS (p < 0.001) and the noniron group with HbCC (p = 0.010) were significantly less likely to develop malaria.ConclusionsIron supplementation increased anaemia in children with HbAS genotypes and provided less protection against malaria in children with HbAC and AS and blood groups A and O.Trial registrationclinicaltrials.gov Identifier: NCT01001871. Registered 27/10/2009.Registration number: https://clinicaltrials.gov/ct2/show/record/NCT01001871.

Genotypic and phenotypic characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Guangzhou, China

BackgroundG6PD deficiency is a common inherited disorder worldwide and has a higher incidence rate in southern China. Many variants of G6PD result from point mutations in the G6PD gene, leading to decreased enzyme activity. This study aimed to analyse the genotypic and phenotypic characteristics of G6PD deficiency in Guangzhou, China.MethodsIn this study, a total of 20,208 unrelated participants were screened from 2020 to 2022. G6PD deficiency was further analysed by quantitative enzymatic assay and G6PD mutation analysis. The unidentified genotype of the participants was further ascertained by direct DNA sequencing.ResultsA total of 12 G6PD mutations were identified. Canton (c.1376G>T) and Kaiping (c.1388G>A) were the most common variants, and different mutations led to varying levels of G6PD enzyme activity. Comparing the enzyme activities of the 6 missense mutations between the sexes, we found significant differences (P < 0.05) in the enzyme activities of both male hemizygotes and female heterozygotes. Two previously unreported mutations (c.1438A>T and c.946G>A) were identified.ConclusionsThis study provided detailed genotypes of G6PD deficiency in Guangzhou, which could be valuable for diagnosing and researching G6PD deficiency in this area.

Categorization of Glucose 6 Phosphate Dehydrogenase (G6PD) Deficiency on the Basis of Enzyme Activity and its Clinico Haematological Correlation

Objective: To categorize glucose-6-phosphate dehydrogenase (G6PD) deficiency based on enzyme activity and its clinical haematological correlation. Methodology: This Cross-sectional study was conducted at the Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from February 2022 to August 2022. Sampling was done using the nonprobability consecutive sampling technique. Test analysis included a complete blood picture, RBC morphology and reticulocyte count, G6PD quantitative test, and serum bilirubin. Thus, to categorize G6PDD based on its enzyme and clinic-haematological correlation, study included patients of both gender with an age ranging from 0-76 years. Descriptive statistics were expressed as mean ± standard deviation (SD) and categorical data were presented as frequency and percentage. Results: Out of 120 study participants, 30 (25%) were females and 90 (75%) were males. The mean age of study participants was 10.83±12.75. G6PD PCR was detected among participants having G6PD deficiency level &lt;1 U/g Hb and between 2-3 U/gm Hb. Hb levels below 8g/dL were found only in individuals with G6PD deficiency levels &lt;1 U/gm Hb. Conclusion: GDPD deficiency can be diagnosed by blood analysis comprising of complete blood count and RBC morphology aided by clinical correlation. The signs and symptoms increase in severity with a decline in GDPD enzyme function along with blood haemoglobin levels.

Sickle cell anemia (SCA) and the impact of G6PD activity on the Hematological parameters

Objectives: Sickle cell anemia (SCA) and glucose-6-phosphate dehydrogenase (G6PD) deficiency are the most common inherited red blood cell (RBC) disorders. The aim of this study was to determine, compare, and correlate G6PD activities with hematological parameters in SCD patients with deficient and non-deficient G6PD and healthy controls in Sana'a, Yemen. Materials and Methods: This cross-sectional study included 150 SCD patients (SCA = 84; SCT = 66) and 150 controls who attended some hospitals in Sana’a from April to June 2022. Five milliliters of venous blood were used for the estimation of CBC and G6PD activity. Data were analyzed using SPSS version 26 software. Results: The SCD patients had significantly lower Hb, PCV, and RBC and higher reticulocytes than controls (P ˂ 0.020). The SCA patients were significantly lower in Hb, PCV, and MCHC and higher in reticulocytes than SCT. G6PD deficiency was found in 26% of the SCD patients, and it was more prevalent in SCA than in SCT and in males than in females. The deficient patients had significantly lower Hb and PCV and higher reticulocytes than non-deficient patients. G6PD activity was found to be positively related to Hb and PCV. Conclusion: G6PD deficiency was more common in SCA patients and had an impact on hematological parameters, which could lead to increased RBC hemolysis. As a result, screening SCA patients for G6PD levels during diagnosis and treatment is advised.

Study protocol for development of an options assessment toolkit (OAT) for national malaria programs in Asia Pacific to determine best combinations of vivax radical cure for their given contexts.

Recent advances in G6PD deficiency screening and treatment are rapidly changing the landscape of radical cure of vivax malaria available for National Malaria Programs (NMPs). While NMPs await the WHO's global policy guidance on these advances, they will also need to consider different contextual factors related to the vivax burden, health system capacity, and resources available to support changes to their policies and practices. Therefore, we aim to develop an Options Assessment Toolkit (OAT) that enables NMPs to systematically determine optimal radical cure options for their given environments and potentially reduce decision-making delays. This protocol outlines the OAT development process. Utilizing participatory research methods, the OAT will be developed in four phases where the NMPs and experts will have active roles in designing the research process and the toolkit. In the first phase, an essential list of epidemiological, health system, and political & economic factors will be identified. In the second phase, 2-3 NMPs will be consulted to determine the relative priority and measurability of these factors. These factors and their threshold criteria will be validated with experts using a modified e-Delphi approach. In addition, 4-5 scenarios representing country contexts in the Asia Pacific region will be developed to obtain the expert-recommended radical cure options for each scenario. In the third phase, additional components of OAT, such as policy evaluation criteria, latest information on new radical cure options, and others, will be finalized. The OAT will be pilot-tested with other Asia Pacific NMPs in the final phase. Human Research Ethics Committee approval has been received from the Northern Territory, Department of Health, and Menzies School of Health Research (HREC Reference Number: 2022-4245). The OAT will be made available for the NMPs, introduced at the APMEN Vivax Working Group annual meeting, and reported in international journals.

Glucose-6-Phosphate Dehydrogenase (G6PD) Measurement Using Biosensors by Community-Based Village Malaria Workers and Hospital Laboratory Staff in Cambodia: A Quantitative Study.

Vivax malaria can relapse after an initial infection due to dormant liver stages of the parasite. Radical cure can prevent relapses but requires the measurement of glucose-6-phosphate dehydrogenase enzyme (G6PD) activity to identify G6PD-deficient patients at risk of drug-induced haemolysis. In the absence of reliable G6PD testing, vivax patients are denied radical curative treatment in many places, including rural Cambodia. A novel Biosensor, 'G6PD Standard' (SD Biosensor, Republic of Korea; Biosensor), can measure G6PD activity at the point of care. The objectives of this study were to compare the G6PD activity readings using Biosensors by village malaria workers (VMWs) and hospital-based laboratory technicians (LTs), and to compare the G6PD deficiency categorization recommended by the Biosensor manufacturer with categories derived from a locally estimated adjusted male median (AMM) in Kravanh district, Cambodia. Participants were enrolled between 2021 and 2022 in western Cambodia. Each of the 28 VMWs and 5 LTs received a Biosensor and standardized training on its use. The G6PD activities of febrile patients identified in the community were measured by VMWs; in a subset, a second reading was done by LTs. All participants were tested for malaria by rapid diagnostic test (RDT). The adjusted male median (AMM) was calculated from all RDT-negative participants and defined as 100% G6PD activity. VMWs measured activities in 1344 participants. Of that total, 1327 (98.7%) readings were included in the analysis, and 68 of these had a positive RDT result. We calculated 100% activity as 6.4 U/gHb (interquartile range: 4.5 to 7.8); 9.9% (124/1259) of RDT-negative participants had G6PD activities below 30%, 15.2% (191/1259) had activities between 30% and 70%, and 75.0% (944/1259) had activities greater than 70%. Repeat measurements among 114 participants showed a significant correlation of G6PD readings (rs = 0.784, p < 0.001) between VMWs and LTs. Based on the manufacturer's recommendations, 285 participants (21.5%) had less than 30% activity; however, based on the AMM, 132 participants (10.0%) had less than 30% activity. The G6PD measurements by VMWs and LTs were similar. With the provisions of training, supervision, and monitoring, VMWs could play an important role in the management of vivax malaria, which is critical for the rapid elimination of malaria regionally. Definitions of deficiency based on the manufacturer's recommendations and the population-specific AMM differed significantly, which may warrant revision of these recommendations.

Hemolitic Anemia due to Glucose-6-Phosphate Dehydrogenase Deficiency Burdened by Cholelithiasis: Clinical Case

Background. Glucose-6-phosphate dehydrogenase deficiency is one of the most frequent enzyme defects leading to hemolysis. About 2% of Russian Federation population have this pathology. This clinical case demonstrates such complication of this disease as cholelithiasis.Clinical case description. Patient B., 17 years old, is followed up by hematologist for anemia due to glucose6-phosphate dehydrogenase deficiency. Biliary calculi were revealed in 2019. Skin and scleral icterus was noted during examination, as well as soreness in the right hypochondrium during palpation. Magnetic resonance cholangiopancreatography has shown two calculi in the distal parts of the ductus choledochus, gallstones, dilatation of the common hepatic and cystic ducts. Complete blood count: hyperchromic megalocytic anemia. Biochemical blood test: hyperbilirubinemia (mostly direct one) after 2 days of hospitalization. Endoscopic lithoextraction from ductus choledochus was performed. Drug therapy was prescribed. Positive dynamics were mentioned at control tests. The patient was discharged in a satisfactory condition on the 10th day.Conclusion. Adequate diagnosis and adequate management promote favorable disease outcome.

Abstract P560: Pilot Study Reveals Excellent Agreement in the Diagnosis of Diabetes Between the Newly Developed Pastry Sugar Tolerance Test and the OGTT: Africans in America Study

Introduction: Sub-Saharan Africa has the highest percentage of people in the world living with diabetes who are undiagnosed. To avoid end-organ damage, identification of undiagnosed diabetes needs prioritization. Glucola (75g glucose) used for the oral glucose tolerance test (OGTT) is expensive and rarely available in sub-Saharan Africa. Due to hemoglobinopathies, G6PD deficiency, and challenges associated with fasting, both A1C and fasting plasma glucose (FPG) may be diagnostically unreliable. As an alternative to the OGTT, we developed the Pastry Sugar Tolerance Test (PSTT). For the PSTT, pastry sugar (75g glucose powder) is dissolved in hot water. Pastry sugar is more widely available in sub-Saharan Africa and nine times less expensive than Glucola. Objective: Our goals were to determine the diagnostic agreement for the detection of diabetes between the OGTT and: (1) PSTT, (2) A1C and (3) FPG. Methods: The participants were 36 African-born Blacks enrolled in the Africans in America study (male: 67%; age: 42±10y (mean±SD); BMI: 28.5±5.2 kg/m2). At Visit 1, each enrollee had an OGTT, A1C and FPG. At Visit 2, which occurred 8±3 days after Visit 1, a PSTT was performed. Glucose tolerance status was based on glucose results from the OGTT. The kappa-statistic was used to determine the diagnostic agreement between the OGTT and each of the following: PSTT, A1C and FPG. Results: Based on the OGTT, diabetes, prediabetes and normal glucose tolerance occurred in 11%(4/36), 33%(12/36) and 56%(20/36) resp. For diabetes, diagnostic agreement between the OGTT and PSTT was excellent (κ=0.99) but much lower for the OGTT and A1C (κ=0.64) and the OGTT and FPG (κ=0.38) (Figure). Conclusions: This pilot study has revealed that for diabetes screening, the PSTT has excellent diagnostic agreement with the OGTT, is less expensive than the OGTT, and is more accurate than A1C or FPG.

A multicenter prospective study of next-generation sequencing-based newborn screening for monogenic genetic diseases in China

BackgroundNewborn screening (NBS) is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases. The development of next-generation sequencing (NGS) technology provides new opportunities to expand current newborn screening methodologies.MethodsWe designed a a newborn genetic screening (NBGS) panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS. With this panel, a large-scale, multicenter, prospective multidisease analysis was conducted on dried blood spot (DBS) profiles from 21,442 neonates nationwide.ResultsWe presented the positive detection rate and carrier frequency of diseases and related variants in different regions; and 168 (0.78%) positive cases were detected. Glucose-6-Phosphate Dehydrogenase deficiency (G6PDD) and phenylketonuria (PKU) had higher prevalence rates, which were significantly different in different regions. The positive detection of G6PD variants was quite common in south China, whereas PAH variants were most commonly identified in north China. In addition, NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants, which were normal in conventional NBS, but were confirmed later as abnormal in repeated biochemical testing after recall. Eighty percent of high-frequency gene carriers and 60% of high-frequency variant carriers had obvious regional differences. On the premise that there was no significant difference in birth weight and gestational age, the biochemical indicators of SLC22A5 c.1400C > G and ACADSB c.1165A > G carriers were significantly different from those of non-carriers.ConclusionsWe demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods. Our data also showed that the prevalence of diseases has significant regional characteristics, which provides a theoretical basis for screening diseases in different regions.

Glucose-6-phosphate dehydrogenase is dispensable for human erythroid cell differentiation in vitro

Glucose-6-phosphate dehydrogenase (G6PD) deficiency impairs cellular processes under oxidative stress. Individuals with severe G6PD deficiency still produce sufficient numbers of erythrocytes. Nevertheless, the G6PD independence of erythropoiesis remains questionable. This study elucidates the effects of G6PD deficiency on the generation of human erythrocytes. Peripheral blood-derived CD34-positive hematopoietic stem and progenitor cells (HSPCs) of human subjects with normal, moderate, and severe G6PD activities were cultured in two distinct phases: erythroid commitment and terminal differentiation. Regardless of G6PD deficiency, HSPCs were able to proliferate and differentiate into mature erythrocytes. There was no impairment in erythroid enucleation among the subjects with G6PD deficiency. To our knowledge, this study is the first report of effective erythropoiesis independent of G6PD deficiency. The evidence firmly indicates that the population with the G6PD variant could produce erythrocytes to an extent similar to that in healthy individuals.

Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals. Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult. Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976).

The potential role of vitamin E in patients with glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis.

As an antioxidant, vitamin E (VitE) may benefit the erythrocytes by protecting glutathione from oxidation by free radicals and peroxide-generating processes. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines when reporting this systematic review. We searched 6 electronic databases (PubMed, Scopus, Web of Science, and Cochrane Library) until May 8, 2022. We included all relevant studies. According to the study design, the Cochrane assessment tool (Risk of Bias 2), Risk Of Bias In Non-randomized Studies - of Interventions checklists, and National Institutes of Health tools were used to assess the risk of bias.Continuous data were pooled as a mean difference (MD) with a relative 95% confidence interval. The protocol was registered on PROSPERO (CRD42022333848). Six studies were included in the meta-analysis with a total of 181 patients. Compared with the control group, VitE significantly improved the hemoglobin level for chronic hemolysis (MD = 2.72 g/dL, P < .0001) and for acute hemolysis (MD = 1.18 g/dL, P < .0001). It also decreased the reticulocyte level for chronic hemolysis (MD = -1.39 P < .0001) and for acute hemolysis (MD = -1.42%, P < .0001). For before and after studies, the use of VitE significantly improved the level of packed cell volume (MD = 0.56%, P < .00001), red blood cell half-life (MD = 2.19 days, P < .0001), and decreased the reticulocytes level (MD = -1.41%, P < .00001). Among patients with glucose-6-phosphate dehydrogenase deficiency, VitE might provide benefits such as increasing the hemoglobin, packed cell volume levels, red blood cell half-life, and decreasing the reticulocyte level, so reducing hemolysis. Further high-quality, well-designed randomized controlled trials are recommended.