グルコーストランスポーター１欠損症

Background: Gliomas are primary malignant brain tumors. Among them, grade IV astrocytomas represent the most aggressive form with limited treatment options and a poor prognosis. There is a critical need for reliable prognostic biomarkers to predict patient outcomes. Methods: In this study, we evaluated the prognostic roles of glycomics in predicting outcomes of patients with glioma. To address this need, we collected a cohort of 86 patients and conducted N-linked glycomics analysis using matrix-assisted laser desorption/ionization mass spectrometry on a tissue microarray comprising 78 gliomas and 8 controls. We performed survival analyses and machine-learning-based predictive modeling to evaluate the prognostic roles of glycomic features. Results and Conclusion: Glycomic features alone displayed strong performance in classifying mortality status, achieving a mean area under the receiver operating characteristic curve (AUROC) value of 0.880 and a mean area under the precision-recall curve (AUPRC) value of 0.925, and demonstrating consistent prognostic value in survival analyses with a mean concordance index of 0.759 across repeated cross-validation. Glycomic features also showed strong performance in predicting the incidence of seizure status, with a mean AUROC value of 0.778 and a mean AUPRC value of 0.766. Additionally, top-ranked glycans from machine-learning models can effectively stratify patients based on their survival outcomes, demonstrating their potential role as prognostic biomarkers.

BACKGROUND AND OBJECTIVES: Movement disorders (MDs) are a prominent feature of GLUT1 Deficiency Syndrome (GLUT1DS), a rare and treatable neurometabolic disorder caused by impaired glucose transport across the blood-brain barrier. We aimed to provide a comprehensive overview of the prevalence, clinical features, and treatment response of MDs in GLUT1DS. METHODS: A systematic review was conducted across five databases in accordance with PRISMA guidelines. The protocol was registered in PROSPERO (CRD42025644449). Studies reporting individual patient data on MDs in GLUT1DS were included. Descriptive and comparative analyses were performed. RESULTS: Of 1178 records screened, 68 studies were included, comprising 94 published patients and two additional unpublished cases (n = 96). MDs were the presenting symptom in 34.4% of cases. The most frequent phenotypes were paroxysmal dyskinesias (63.5%) and ataxia (47.9%). Patients with MD-onset showed a later age at onset and fewer cognitive features. Non-missense variants were associated with earlier disease onset and a higher frequency of ataxia, whereas missense variants were independently associated with paroxysmal dyskinesias (OR 3.02, 95% CI 1.09-8.35). Ketogenic dietary therapies were associated with improvement in motor symptoms in most reported cases, although outcome data were heterogeneous and non-standardized. DISCUSSION: MDs in GLUT1DS are highly heterogeneous and frequently overlap, with distinct patterns across clinical and genetic subgroups. While ketogenic therapies appear beneficial for motor symptoms, current evidence is limited by methodological variability and potential reporting bias, highlighting the need for prospective studies with standardized outcome measures.

We constructed a spatially resolved metabolomic atlas of long-term exercise across six major organs in wild-type mice: brain, heart, lung, liver, kidney, and skeletal muscle, cataloguing 224 metabolic features and revealing coordinated inter-organ remodeling. Surprisingly, the brain showed particularly pronounced region-specific adaptation. Because pathological tau associates with synaptic mitochondria from early stages of tauopathy, we extended this multi-organ spatial metabolomic approach to PS19 mice and found that exercise reduced over 70% of observable tau pathology in PS19 hippocampus and restored the mitochondrial-related metabolome. Integrated proteomic and spatial metabolomic analyses identified NADH dehydrogenase Complex I as the convergent node. To test this finding biologically, we expressed the yeast NADH dehydrogenase, Ndi1, in PS19 neurons in the absence of exercise. This increased cerebral antioxidants, restored shuttle-linked metabolites, and reduced tau pathology. Increasing NADH dehydrogenase activity through NDI1 reproduces the core anti-tau and metabolic effects of exercise. These findings provide a molecular mechanism for how exercise may prevent or slow tau pathology accumulation, complementing the human-cohort literature linking exercise to delayed cognitive decline.

Glucose transporter type I (Glut1) deficiency syndrome (Glut1DS) is associated with paroxysmal exertion-induced dystonia (PED). Episodes are published as brief, lasting 20 to 30 minutes. Increasingly, Glut1DS patients report prolonged PED of more than 1 hour duration. In a cohort of 60 Glut1DS patients seen in our institution within a 4-year period, a total of 26/60 patients (43%) on ketogenic dietary therapy (KDT) experienced PED. In 18/26 patients (30%), episodes lasted less than 1 hour as previously described. In 8/26 patients (13%), prolonged episodes lasted more than 1 hour up to 1 day despite adequate dietary treatment. We conclude that PED is common in Glut1DS starting in late childhood despite adequate treatment with KDT. Prolonged PED in Glut1DS occurs in a subset of patients, also unresponsive to KDT, and represents a substantial burden to patients and families.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder marked by progressive cognitive decline. Metabolic disruptions are widely observed, yet their involvement in the molecular aetiology of AD remains underexplored. Here we identify hyperglycosylation as a driver of AD. Integrating spatial metabolomics, lipidomics and glycomics in transgenic AD mouse models and post-mortem human AD samples, along with advanced spatial isotopic tracing pulse-chase analysis of N-linked glycans, we demonstrate that the conserved phenotype of brain hyperglycosylation is driven by increased glycan biosynthesis. Genetic knockdown of glycan biosynthetic enzymes improves cognitive outcomes in AD mice whereas oral glucosamine supplementation impairs them. A retrospective analysis of electronic health records from patients with AD with varying disease severity shows that glucosamine supplementation is associated with accelerated AD progression and worsened survival. Overall, these results establish hyperglycosylation as a pathological driver of AD and highlight glycan metabolism as an actionable target in the fight against AD.