Coenzyme A (CoA) is a vital cofactor involved in 8-10% of all metabolic reactions in human cells. Different inherited enzyme deficiencies in which the oxidation of acyl-CoAs is hampered have been hypothesised to share a phenotype characterised by toxic accumulation of acyl-CoA and a concomitant decline in free CoA (CoASH) levels, whereby CoASH becomes limiting for other metabolic reactions. This is referred to as CoASH sequestration. There is, however, limited experimental evidence for this hypothesis. Using a combination of approaches, we test this hypothesis in medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common deficiency of mitochondrial fatty acid oxidation (mFAO), under energetic stress. Both in vitro MCAD-knockout (KO) HepG2 cells and a kinetic model of mFAO showed decreased CoASH, elevated medium-chain acyl-CoA, and decreased long-chain acyl-CoA levels. MCAD-KO mice exposed to fasting and cold as energetic stressors had a significantly increased total CoA pool and increased expression of CoA biosynthetic enzymes in the liver, indicative of an upregulated CoA biosynthesis. Expression of carnitine acyltransferases and acyl-CoA thioesterases, enzymes that liberate CoASH from acyl-CoAs, was also upregulated, suggesting an adaptive response of CoA metabolism to decreased CoASH. Finally, computational model simulations showed that a combination of elevated total CoA and thioesterase activity led to normalisation of both CoASH and medium-chain acyl-CoA levels. Together, the results provide the first evidence for the CoA sequestration hypothesis in MCADD. The observed adaptation of CoA metabolism under energetic stress may act as a compensatory response that counteractsCoASH depletion and accumulation of toxic medium-chain acyl-CoAs.

Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is traditionally recognized as a risk factor for drug- or infection-induced hemolytic anemia. Emerging evidence implicates potential roles of G6PD in neurodevelopment, yet its association with rare neurological disorders remains underexplored in population-based genetic studies, especially within the Chinese population. Methods We conducted a retrospective case-control study utilizing whole-exome sequencing (WES) data from a Chinese cohort. Six most prevalent pathogenic G6PD variants in China were screended in children with rare neurological disorders (n = 211) and in controls without neurological involvement (n = 202). Genotype and carrier frequency comparisons were performed. Stratified analyses were performed based on diagnostic certainty and the presence of de novo mutations. Multivariable logistic regression was employed to calculate sex-adjusted odds ratios (ORs) to control for potential sex-related confounding. Results After adjusting for sex, the overall carrier rate of pathogenic G6PD variants was significantly higher in patients with neurological disorders than in controls (adjusted OR = 2.44, 95% CI: 1.18–5.06, p = 0.014). Further comparisons across specific groups revealed distinct patterns: affected male patients had a higher carrier rate than their own unaffected fathers (OR = 2.30, 95% CI: 1.08–4.91, p = 0.043), and mothers of case patients showed a higher carrier rate than mothers of controls (OR = 2.03, 95% CI: 1.09–3.78, p = 0.030). The variants NM_001042351.3: c.1376G>T (G6PD Canton) and NM_001042351.3:c.1388G>A (G6PD Kaiping) were the most prevalent across all groups. Conclusion This population-based genetic analysis provides preliminary evidence that G6PD deficiency may be a underrecognized genetic risk factor for rare neurological disorders in Chinese children. The findings suggest a potential maternal genetic contribution and indicate that the phenotypic spectrum of G6PD deficiency may extend beyond hematological manifestations to include neurodevelopmental vulnerability. Important limitations include the lack of functional validation and the use of a clinical control group. Further prospective studies incorporating G6PD enzyme activity assessment and functional investigations are warranted to elucidate the underlying mechanisms.

Acquired multiple acyl-CoA dehydrogenase deficiency (MADD) provoked by sertraline: an emerging and treatable disorder.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency impairs cellular redox balance through reduced NADPH production and is the most common enzymatic disorder-causing anemia. Venetoclax combined with azacitidine (Ven-Aza) targets leukemic stem cells by disrupting oxidative phosphorylation and inducing mitochondrial stress. This study hypothesized that G6PD deficiency may enhance the efficacy of Ven-Aza in acute myeloid leukemia (AML) by reducing leukemic cell metabolic resilience. The authors studied 73 consecutive patients with newly diagnosed (ND) AML treated with Ven-Aza. G6PD activity was systematically assessed at diagnosis in all patients and categorized as normal (n=47), borderline (n=11), or deficient (n=15). Composite complete remission rates were 93% in the G6PD deficient group versus 69% in the normal/borderline group (p=.03). Patients with G6PD deficiency had a significantly longer median overall survival (23.8 months; 95% confidence interval [CI], 8.9-38.7), as compared to 8.96 months (95% CI, 2.9-15.0) in the normal/borderline group (p=.034). In multivariate analysis, G6PD-deficiency was associated with improved survival as compared to patients with normal G6PD activity (hazard ratio, 0.417; 95% CI, 0.181-0.965, p=.043). No significant differences were observed across groups in rates of febrile neutropenia, pneumonia, sepsis, or grade 3-4 cytopenia. G6PD deficiency is associated with higher response rates and improved survival in patients with ND-AML treated with Ven-Aza. These findings support G6PD deficiency as a potential biomarker of therapeutic sensitivity to Ven-AZA and may uncover metabolic vulnerabilities in AML with potential therapeutic implications.

Patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a mitochondrial fatty acid oxidation (FAO) disorder, frequently present with cardiomyopathy and can suffer from life-threatening arrhythmias and heart failure. Although these remain the leading causes of death, the pathophysiology remains unknown. We used an LCHADD mouse model to examine the mechanisms of impaired cardiac function. We previously determined that LCHADD mice (Hadha c.1528G>C homozygotes) recapitulate human disease and develop cardiomyopathy. We performed electrophysiological tests on LCHADD and wild-type (WT) mice, followed by cardiac tissue and molecular expression analysis. LCHADD mice showed significantly increased frequency of atrial premature beats, premature ventricular contractions, atrial flutter, atrial fibrillation, and nonsustained ventricular tachycardia (NSVT) after β-agonist stimulation compared with WT mice. Long QRS and long QT intervals were also observed when compared with WT mice. LCHADD heart sections demonstrated increased cardiomyocyte cross-sectional area, increased lipid and collagen deposition, and decreased glycogen deposits. There was global sympathetic denervation in LCHADD hearts compared with WT. Differentially expressed gene analysis showed increased expression of glycolytic and glutathione synthesis enzymes, and decreased expression of tricarboxylic acid (TCA) cycle enzymes, Ca++ signaling, and cardiac muscle contraction proteins. LCHADD cardiomyopathy has a hypertrophic phenotype with diffuse fibrosis, accumulation of lipids, and lower glycogen storage in the absence of obesity. LCHADD cardiomyocyte metabolism suggests a shift from FAO toward glycolysis with chronic oxidative stress. Energy deficiency and lipotoxicity likely influence Ca++ signaling and cardiac contraction. Long QRS and QT intervals with global sympathetic denervation may predispose the heart to repolarization abnormalities susceptible to arrhythmias and increased risk of sudden cardiac arrest and death.NEW & NOTEWORTHY As major cardiac events and heart failure are the leading causes of death among individuals with LCHADD, we are committed to identify better treatment options. To undertake this, we characterized LCHADD cardiomyopathy using a mouse model. We identified a hypertrophic cardiomyopathy with diffuse fibrosis, extensive lipid accumulation, increased oxidative stress, and global sympathetic denervation with long QT intervals and arrhythmia susceptibility likely caused by cardiomyocyte energetic remodeling, altered homeostasis, and cardiac conduction dysregulation.

ABSTRACTSuccinate dehydrogenase (SDH) serves a dual function as complex II of the electron transport chain and an enzyme of the tricarboxylic acid cycle. Pathogenic variants in subunits of SDH result in diverse clinical presentations, including typically autosomal recessive neurodegenerative disorders. Biallelic variants in the SDHA subunit most often cause Leigh syndrome. However, epilepsy phenotypes of these patients are ill‐defined and there is only one prior report of epilepsy in a patient with SDHA deficiency. Here we report the seizure and EEG phenotypes of three autosomal recessive SDHA patients with refractory epilepsy, two of whom are siblings. These patients exhibit multiple seizure types and a variety of EEG findings, including a patient with rhythmic high‐amplitude delta with superimposed spikes (RHADS), a finding closely associated with polymerase gamma (POLG)‐related disorders.

Invasion and development of Plasmodium falciparum in erythroblasts of humans carrying G6PD viangchan.

Development and implementation of droplet digital PCR assays for accurate quantification of Plasmodium vivax parasitemia and G6PD viangchan genotyping.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits high prevalence in malaria-endemic regions and areas along the historic Maritime Silk Road. This study investigated the burden and genetic architecture of G6PD deficiency in Nanning, the ethnically diverse capital of Guangxi in southern China, where Southeast Asian gene flow has shaped population genetics. We screened 14 403 individuals for G6PD activity at The First Affiliated Hospital of Guangxi Medical University, defining deficiency as activity < 60% of adjusted male median (AMM = 2045 U/L). Among 2513 deficient cases (prevalence: 17.45%), frequency was significantly higher in males (63.75%) vs. females (36.25%; p < 0.001) and Han Chinese (60.92%) vs. Zhuang (39.08%; p = 0.925). Multiplex melting curve analysis (MMCA) of 2513 enzyme-deficient samples identified pathogenic mutations in 1161 cases, revealing 13 distinct variants. The predominant mutations were: c.1388G>A (39.53%; 459/1161), c.1376G>T (24.81%; 288/1161), and c.95A>G (12.40%; 144/1161). Mutation c.871G>A exhibited male bias (p < 0.001), while c.95A>G was Zhuang-enriched (p < 0.001). Sanger sequencing of MMCA-negative cases identified two rare pathogenic variants (c.406C>T, c.196T>A). Our findings establish Nanning as a region of exceptionally high G6PD deficiency prevalence and delineate a distinct mutation profile with sex- and ethnicity-linked distributions. These results provide critical insights for designing precision screening programs and public health strategies tailored to this genetically diverse population.

Advancing Obstetric Care: The Role of Targeted Next-Generation Sequencing in Pregnancies with Structurally Normal Fetuses.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic X-linked recessive disorder that results from mutations in the G6PD gene, which provides instructions for manufacturing the G6PD enzyme. G6PD deficiency primarily impacts red blood cells. This deficiency can result in hemolytic anemia (HA), in which rapid destruction of red blood cells occurs due to the vulnerability of erythrocytes to reactive oxygen species. It is most commonly found in males and affects 1 in 10 Black males in the United States. Persons with G6PD deficiency may exhibit symptoms such as pallor, jaundice, dark urine, fatigue, tachycardia, shortness of breath, and splenomegaly. Exposure to certain medications such as rasburicase, sulfonamides, nitrofurantoin, antimalarials, dapsone, chloramphenicol, high-dose aspirin, methylene blue, and phenazopyridine may trigger a hemolytic crisis in those with G6PD deficiency. Tests used in the diagnosis of HA include the Coombs test, haptoglobin, complete blood count, urinalysis, lactate dehydrogenase, bone marrow tests, and a peripheral blood smear. This article summarizes the case of a patient who developed HA after an infusion of rasburicase and offers management strategies.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive disorder that affects over 400 million people worldwide. The deficit causes individuals susceptible to hemolysis during oxidative stress. In newborns, G6PD deficiency can lead to hyperbilirubinemia, bilirubin-induced neurologic dysfunction, and kernicterus, making early detection and screening crucial. Objectives: This study aimed to compare the diagnostic performance of three rapid screening tests for G6PD deficiency in newborns: the fluorescent spot test (FST), G6PD rapid test kit, and SD Biosensor, using spectrophotometry as the gold standard. Materials and methods: Blood samples from 70 newborns were tested using these three methods. The diagnostic performances, including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and efficiency of each method were analyzed. Results: Both the FST and G6PD rapid test kit exhibited higher specificity, PPV, and efficiency compared to the SD Biosensor. Nonetheless, the SD Biosensor exhibited superior sensitivity and NPV, but it was unable to identify G6PD activity in 16.4% of instances due to elevated hemoglobin concentrations. Conclusion: The FST and G6PD rapid test kit are reliable and suitable for G6PD deficiency screening in newborns, especially in settings with limited resources, due to their high efficiency, specificity, and rapid results. The SD Biosensor remains a valuable tool in clinical contexts requiring high sensitivity. For newborns with high hemoglobin levels, the FST or G6PD rapid test is recommended for accurate screening. Further studies with larger sample sizes are necessary to confirm the reliability of these tests in diverse populations.

IGlucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive disorder affecting approximately 400 million individuals globally, impairs red blood cells’ ability to counter oxidative stress, presenting primarily as neonatal jaundice and hemolytic anemia, with significant prevalence in malaria-endemic regions. This systematic review examines the prevalence, genotypic and phenotypic diversity, and demographic characteristics of G6PD deficiency specifically within the Gulf Region. The review was conducted according to PRISMA guidelines and registered with PROSPERO (ID: CRD42024514065). A comprehensive literature search was performed in February 2024 using PubMed and Web of Science databases via Rayyan, including studies published in English discussing G6PD deficiency in the Gulf region published up to January 2024, with data independently screened and extracted by multiple authors. Eligible study designs included randomized controlled trials, cohort studies, cross-sectional studies, case-control studies, case series, and case reports, with quality assessments performed using the Newcastle-Ottawa Scale for cohort studies and the Joanna Briggs Institute checklist for cross-sectional studies. The systematic search identified 181 articles, narrowed to 36 after screening. Most studies were cross-sectional (n=32) and conducted primarily in Saudi Arabia. Sample sizes ranged from 23 to 48,889 (total=145,174), showing prevalence between 0.67%-42.7%, highest in Saudi Arabia’s Eastern province. The Mediterranean mutation was most common; favism (55%-89%) was a frequent clinical manifestation, while many individuals remained asymptomatic, highlighting variable expressivity of G6PD deficiency. The review demonstrates that the prevalence of G6PD deficiency varies significantly across the Gulf region (0.67%–42.7%), influenced by geographic location, historical malaria endemicity, and consanguinity, with the Mediterranean variant being the most common genetic mutation. Limitations include variability in methodologies, underrepresentation of certain regions, and lack of longitudinal studies, highlighting the need for larger-scale studies to clarify prevalence, genetic variants, and long-term clinical outcomes.

Fast and accurate diagnosis of G6PD deficiency via NADPH monitoring using sequential injection analysis coupled with electrochemical detection.

Evaluation of pre-analytical and analytical variables affecting galactose-1-phosphate uridyltransferase assay performance in the diagnosis of classical galactosemia.

Phosphoglycerate dehydrogenase deficiency is a rare neurometabolic disorder with clinical features of congenital microcephaly, psychomotor retardation, intractable seizures, and spasticity. We report a 2.5-year-old boy presenting with speech delay, seizures, microcephaly, and hyperactive behavior. Genetic testing detected a likely pathogenic homozygous variant c.1129G>A in the PHGDH gene. Parents were carrier for the detected variant. Biochemical analysis showed low serine and treatment with oral serine and glycine resulted in seizure control, followed by catchup of developmental milestones. This case illustrates the need for evaluating underlying neurometabolic causes, particularly treatable entities, in clinical presentations similar to cerebral palsy.

Objective: To determine the frequency of glucose-6-phosphate dehydrogenase deficiency among neonates presenting with jaundice. Methods: It was a Descriptive cross-sectional study using non-probability consecutive sampling conducted in the Department of Pediatrics, Saidu Group of Teaching Hospitals, Saidu Medical College, Swat, Pakistan, from 22nd July 2023 to 22nd January 2024. A total of 130 neonates aged 1–28 days with clinical jaundice were enrolled. Baseline demographic and clinical data were collected. Laboratory evaluation included serum bilirubin, hemoglobin, reticulocyte count, and glucose-6-phosphate dehydrogenase activity by decolorization test. A decolorization time exceeding 60 minutes was considered diagnostic for enzyme deficiency. Results: Of the 130 neonates, 70% were aged 1–14 days, and 30% were 15–28 days. Term neonates constituted 68%, while 32% were preterm. Male-to-female ratio was 1.3:1 (58% vs. 42%). Glucose-6-phosphate dehydrogenase deficiency was detected in 10% of neonates with significantly higher frequency in males (16%) compared to females (2%) (p=0.0077). Conclusion: Glucose-6-phosphate dehydrogenase deficiency was observed in 10% of neonates with jaundice, with a marked male predominance. Early screening is essential to prevent complications such as severe hyperbilirubinemia and kernicterus in high-risk populations. Keywords: Anemia, Hemolytic; Glucose-6-Phosphate Dehydrogenase Deficiency; Hyperbilirubinemia, Neonatal; Infant, Newborn; Jaundice.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a hereditary disorder of mitochondrial long-chain fatty acid oxidation. It is a syndrome characterized by rhabdomyolysis, muscle necrosis, and release of intracellular muscle components into the circulation. A 29-year-old male patient with hypertension, arrhythmia, and preemptive renal transplantation history was admitted to our clinic with complaints of recurrent hematuria attacks, body pain, and dizziness. No erythrocytes were observed in the microscopic field of urine sediment. In genetic analysis, a homozygous mutation was detected in the ACADVL gene in the NM_000018.4 C.1500_1502del CCT p. L502del variation, and VLCAD deficiency was diagnosed. We planned to discuss the case with the literature in order to emphasize that metabolic myopathies should also be evaluated in the etiology of patients who develop acute renal failure presenting with recurrent non-traumatic exercise-associated rhabdomyolysis.

BackgroundGlucose-6-phosphate dehydrogenase deficiency (G6PDd) is a common genetic disorder that impairs the cellular antioxidant response and has been hypothesized as a potential risk factor for severe outcomes in viral infections, including COVID-19. However, clinical evidence remains limited, especially in regions with high G6PDd prevalence.MethodsWe conducted a retrospective cohort study using secondary data from four health information systems from health facilities in the Brazilian Amazon (E-SUS Notifica, SIVEP-Gripe, SIM, and a G6PD enzyme activity database). The study population consisted of 3,955 male participants, including 206 with confirmed G6PDd. We used logistic regression to assess associations between G6PDd and COVID-19 infection, hospitalization, and death. Cox proportional hazards models and Kaplan-Meier curves were applied to evaluate time-to-event outcomes.ResultsNo statistically significant association was found between G6PDd and SARS-CoV-2 infection (OR = 1.15; 95% CI: 0.70–1.79; p = 0.6), hospitalization (OR = 1.13; 95% CI: 0.27–3.20; p = 0.8), or death (OR = 0.00; p > 0.9). Age was a significant risk factor for all outcomes, and individuals identified as Asian had a higher likelihood of infection (OR = 2.87; 95% CI: 1.57–5.29; p < 0.001).ConclusionIn this cohort from the Brazilian Amazon, G6PD deficiency was not associated with an increased risk of COVID-19 infection or severe outcomes. These findings emphasize the importance of considering ethnic and genetic diversity in epidemiological analyses and health policy planning, particularly in regions with high G6PDd prevalence.

Pyruvate dehydrogenase complex (PDC) deficiency is a rare mitochondrial disorder characterized by impaired oxidative metabolism, predominantly due to pathogenic variants in the PDHA1 gene. We present the clinical, biochemical, radiologic, and molecular characterization of 4 Argentine pediatric patients with PDHA1-related PDC deficiency, including a novel missense variant, c.260T>C p.(Ile87Thr). Clinical presentations ranged from severe neonatal encephalopathy with central apneas to a more slowly progressive neurodegenerative course in childhood. All patients exhibited lactic acidosis and structural brain abnormalities, with 3 fulfilling criteria for Leigh syndrome. Molecular studies identified 4 missense variants located in conserved regions of the E1α subunit. In silico analysis of the novel p.(Ile87Thr) variant suggested impaired thiamine pyrophosphate binding. All patients received thiamine and a ketogenic diet, with favorable outcomes in seizure control, neurodevelopment, and metabolic stability. Our findings expand the clinical and molecular spectrum of PDHA1-related PDC deficiency and underscore the importance of early diagnosis and targeted metabolic therapy. Furthermore, we report a previously undescribed radiologic pattern in one patient and propose potential structural implications of the novel variant based on protein modeling.