Annals of Clinical and Translational Neurology最新文献

{"title":"Prominent Movement Disorders in RNU2-2-Related Spliceosomopathy","authors":"Magdalena Krygier,&nbsp;Ugo Sorrentino,&nbsp;Matias Wagner,&nbsp;Marta Zawadzka,&nbsp;Anna Lemska,&nbsp;Maria Mazurkiewicz-Bełdzińska,&nbsp;Michael Zech","doi":"10.1002/acn3.70442","DOIUrl":"10.1002/acn3.70442","url":null,"abstract":"<p>Pediatric movement disorders often overlap with neurodevelopmental diseases, suggesting shared molecular mechanisms. Variants in small nuclear RNA (snRNA) genes encoding spliceosome components have recently been associated with neurodevelopmental disorders, termed “RNUopathies.” We analyzed genome sequencing data from 14 patients with undiagnosed pediatric movement disorders for pathogenic variants in snRNA genes. We identified recurrent <i>de novo RNU2-2</i> variants (n.35A &gt; G and n.4G &gt; A) in two patients with intellectual disability, epilepsy, and hyperkinetic movement disorders. RNA sequencing of fibroblasts in one patient showed no characteristic transcriptomic signature. Spliceosomopathies should be considered in neurodevelopmental disorders and developmental and epileptic encephalopathies with hyperkinetic features.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1951-1955"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex Representation in US Stroke Clinical Trials: A Decade of Trends and Challenges","authors":"Chaitali Dagli,&nbsp;Mudasir Andrabi,&nbsp;Tova Cohen,&nbsp;Pranali G. Patel,&nbsp;Tapasya Katta,&nbsp;Chen Lin","doi":"10.1002/acn3.70355","DOIUrl":"10.1002/acn3.70355","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Stroke remains a major cause of disability and mortality in the US, with significant sex-based disparities, and females remain underrepresented in stroke clinical trials. We aimed to examine sex representation in US-based stroke clinical trials, identify trial characteristics associated with higher female enrollment (≥ 50%), and explore factors influencing recruitment strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This mixed-methods study analyzed US-based stroke clinical trials registered on ClinicalTrials.gov between January 1, 2010 and December 31, 2020. A thematic analysis of recruitment strategies and eligibility criteria was conducted for trials with ≥ 50% female enrollment. We examined the proportion of female participants enrolled in each trial and trial characteristics, including funding source, principal investigator sex, participant age, and recruitment strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 456 eligible trials, only 102 (22%) enrolled ≥ 50% female participants. Compared with trials with &lt; 50% female enrollment, these trials more often included both sexes (99.0% vs. 65.5%) and enrolled a greater median number of female participants (22.5 vs. 10). Female-led studies were more common among trials with higher female representation (40.2% vs. 37.6%). Qualitative analysis revealed that broader inclusion criteria, hybrid recruitment strategies (e.g., combining hospital outreach), and targeted accommodations for stroke-related disability were associated with higher female enrollment. Common barriers included exclusionary eligibility criteria, logistical challenges (e.g., transportation), and language limitations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretations</h3>\u0000 \u0000 <p>Inclusive design, community-engaged recruitment, and structural accommodations including support for sex-based roles like caregiving are potentially influential in promoting equitable participation. Addressing sex disparities in stroke research is essential for improving the relevance, effectiveness, and fairness of stroke interventions in clinical practice.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1772-1779"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147375548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Onasemnogene Abeparvovec in Type I Spinal Muscular Atrophy: 24-Month Follow-Up From the Italian Registry","authors":"Marika Pane,&nbsp;Giorgia Coratti,&nbsp;Chiara Cutrì,&nbsp;Antonio Varone,&nbsp;Riccardo Masson,&nbsp;Adele D'Amico,&nbsp;Valeria Sansone,&nbsp;Sonia Messina,&nbsp;Federica Ricci,&nbsp;Chiara Ticci,&nbsp;Claudio Bruno,&nbsp;Caterina Agosto,&nbsp;Francesca Benedetti,&nbsp;Antonella Pini,&nbsp;Sabrina Siliquini,&nbsp;Massimiliano Filosto,&nbsp;Alberto Zambon,&nbsp;Ilaria Bitetti,&nbsp;Maria Rosaria Manna,&nbsp;Claudia Dosi,&nbsp;Riccardo Zanin,&nbsp;Stefano Parravicini,&nbsp;Roberto De Sanctis,&nbsp;Giulia Stanca,&nbsp;Michela Catteruccia,&nbsp;Michele Tosi,&nbsp;Irene Mizzoni,&nbsp;Emilio Albamonte,&nbsp;Valentina Franchino,&nbsp;Maria Sframeli,&nbsp;Ilaria Cavallina,&nbsp;Elena Procopio,&nbsp;Michele Sacchini,&nbsp;Simone Morando,&nbsp;Noemi Brolatti,&nbsp;Federica Trucco,&nbsp;Gaia Scarpini,&nbsp;Elena Briganti,&nbsp;Beatrice Berti,&nbsp;Concetta Palermo,&nbsp;Daniela Leone,&nbsp;Stefano C. Previtali,&nbsp;Eugenio Mercuri,&nbsp;the ITASMAC working group","doi":"10.1002/acn3.70356","DOIUrl":"10.1002/acn3.70356","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Onasemnogene abeparvovec (OA) is an AAV9-based gene therapy for spinal muscular atrophy type I (SMA I). Real-world outcomes show increased response variability compared to clinical trials, and follow-up data beyond 12–18 months are limited. The aim of this 24-month prospective observational study is to comprehensively describe the clinical outcomes of an Italian cohort of SMA I patients treated with OA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Based on recent literature, patients' treatment status was categorized as: monotherapy (OA only), bridge therapy (transition to OA within 3 months of starting nusinersen or risdiplam), or switch therapy (transition to OA after &gt; 3 months of 1st treatment). Linear mixed-effects models examined predictors of improvement (CHOP-INTEND), adjusting for baseline motor function, SMN2 copy number, age, and prior treatment. Descriptive analyses were used to show changes in motor, respiratory, and nutritional milestones.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The cohort included 64 patients: 27 monotherapy, 9 bridge, and 28 switch. All patients showed significant improvement over 24 months (<i>β</i> = 20.40 points/year, <i>p</i> &lt; 0.001). Patients who switched showed slower improvement (<i>β</i> = −3.76, <i>p</i> = 0.038) compared to monotherapy, while those who bridged showed no difference. Older age at treatment was associated with slower improvement (<i>β</i> = −1.48 points/year per month, <i>p</i> = 0.002). Of 49 non-sitters at baseline, 39 (80%) achieved sitting and 5 (10%) achieved walking. No new safety signals emerged in the second year of follow-up.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Age and baseline motor functional status significantly influence outcomes; however, substantial confounding, particularly the initial treatment, limits the ability to isolate individual effects. Longer follow-up is essential for evaluating therapeutic responses in heterogeneous SMA I populations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1866-1877"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IV Thrombolysis Facilitates Interventional Reperfusion in Non-Cardioembolic but Not Cardioembolic Stroke","authors":"Annahita Sedghi,&nbsp;Daniel P. O. Kaiser,&nbsp;Martin Arndt,&nbsp;Norma J. Diel,&nbsp;Erik Simon,&nbsp;Witold H. Polanski,&nbsp;Volker Puetz,&nbsp;Hagen B. Huttner,&nbsp;Timo Siepmann","doi":"10.1002/acn3.70370","DOIUrl":"10.1002/acn3.70370","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Intravenous thrombolysis (IVT) before thrombectomy for ischemic stroke may alter clot structure and procedural performance. We investigated how IVT relates to thrombectomy metrics across stroke etiologies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a time-to-event analysis of consecutive patients with anterior circulation large vessel occlusion (acLVO) stroke from a prospective thrombectomy registry at a German tertiary stroke center (January 2017–January 2023). The associations between IVT and groin-to-recanalization time and number of aspiration attempts were assessed using multivariable stratified Cox regression adjusted for demographic, cardiovascular, and stroke-related variables.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 1702 patients screened, 798 (413 female [51.8%], median age 77 years [66, 84; IQR]) underwent thrombectomy. IVT was administered to 395 (49.5%) patients, and successful reperfusion (mTICI ≥ 2b) was achieved in 680 (85.2%) patients. In non-cardioembolic stroke, IVT facilitated clot removal, yielding a 40% higher likelihood of successful reperfusion at any time point compared with direct thrombectomy (aHR 1.40; 95% CI [1.08, 1.81]; <i>p</i> = 0.01) and a 36% reduction of aspiration attempts (IRR = 0.64, 95% CI [0.50–0.84], <i>p</i> = 0.001). In cardioembolic stroke, IVT did not alter the incidence of successful reperfusion during thrombectomy (aHR 1.13; 95% CI [0.92, 1.39]; <i>p</i> = 0.26) or the number of aspiration attempts (combined IRR ≈ 1.00, 95% CI [0.82–1.22]) but was associated with a 43% lower likelihood of successful reperfusion throughout the intervention if distal thrombus migration occurred (aHR 0.57; 95% CI [0.33, 0.96]; <i>p</i> = 0.03).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>IVT was associated with faster reperfusion during thrombectomy in non-cardioembolic acLVO, whereas in cardioembolic stroke with distal clot migration it was associated with delayed reperfusion.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1893-1902"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multidimensional Profiling of MRI-Negative Temporal Lobe Epilepsy Uncovers Distinct Phenotypes","authors":"Alice Ballerini,&nbsp;Alessia Casarini,&nbsp;Niccolò Biagioli,&nbsp;Laura Mirandola,&nbsp;Daniela Ballotta,&nbsp;Paul Summers,&nbsp;Simona Scolastico,&nbsp;Laura Madrassi,&nbsp;Maurilio Genovese,&nbsp;Marcella Malagoli,&nbsp;Gaetano Cantalupo,&nbsp;Giada Giovannini,&nbsp;Matteo Pugnaghi,&nbsp;Niccolò Orlandi,&nbsp;Laura Tassi,&nbsp;Valeria Cuccarini,&nbsp;Domenico Aquino,&nbsp;Elena Tartara,&nbsp;Fulvia Palesi,&nbsp;Giuseppe Didato,&nbsp;Paolo Vitali,&nbsp;the 3TLE Study Group,&nbsp;Stefano Meletti,&nbsp;Anna Elisabetta Vaudano","doi":"10.1002/acn3.70349","DOIUrl":"10.1002/acn3.70349","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Although hippocampal sclerosis (TLE-HS) represents the most frequent cause of temporal lobe epilepsy (TLE), up to 30% of patients show no lesion on visual MRI inspection (TLE-MRIneg). These cases pose diagnostic and therapeutic challenges and are underrepresented in surgical series. We investigated whether TLE-MRIneg constitutes a distinct clinical and neuroanatomical entity compared to TLE-HS and aimed to identify subtypes within the TLE-MRIneg group.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed MRI and clinical data from 209 patients with TLE and 102 healthy controls from the multicenter “3TLE project”. Based on expert radiological review, 96 patients were classified as TLE-MRIneg and 76 as TLE-HS; the remaining 37 were excluded due to other focal lesions. We compared clinical characteristics and brain morphometry between TLE-MRIneg and TLE-HS and applied clustering techniques to detect TLE-MRIneg subtypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with TLE-HS, TLE-MRIneg was associated with later onset, shorter disease duration, and milder clinical presentation. TLE-HS patients exhibited widespread cortical and subcortical atrophy, while TLE-MRIneg showed only subtle cortical thinning. Cluster analysis revealed two subtypes of TLE-MRIneg: one characterized by ipsilateral amygdala enlargement (AE) and the other by diffuse cortical atrophy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>These findings demonstrate that TLE-MRIneg represents a distinct clinical-imaging entity from TLE-HS. The identification of morphologically defined subtypes, particularly AE, highlights the heterogeneity of TLE-MRIneg and its potential clinical relevance. This work supports the use of advanced imaging and data-driven methods to improve diagnosis and guide individualized management in non-lesional epilepsies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1878-1892"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of Inebilizumab in N-MOmentum Trial Participants With or Without Prior Immunosuppressants","authors":"Bruce A. C. Cree,&nbsp;Beatrice Suero,&nbsp;Sarah Walsh,&nbsp;Romain Marignier,&nbsp;John W. Lindsey,&nbsp;Ho Jin Kim,&nbsp;Dewei She,&nbsp;Daniel Cimbora,&nbsp;Dustin Cavida,&nbsp;Friedemann Paul","doi":"10.1002/acn3.70426","DOIUrl":"10.1002/acn3.70426","url":null,"abstract":"<p>This post hoc analysis examined the impact of prior immunosuppressants on the long-term efficacy and safety of inebilizumab, a cluster of differentiation 19⁺ B-cell–depleting monoclonal antibody, in participants with aquaporin-4–seropositive neuromyelitis optica spectrum disorder from the N-MOmentum trial (NTC02200770). Inebilizumab treatment resulted in a sustained low annualized attack rate relative to the pretrial annualized attack rate and a high probability of remaining attack-free for up to 4 years among participants with and without prior immunosuppressant use. Based on modeling data, inebilizumab had greater long-term efficacy than historical immunosuppressants. Inebilizumab was well tolerated regardless of prior immunosuppressant use.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1930-1936"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147872823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental and Epileptic Encephalopathy due to Biallelic Pathogenic Variants in PIGM","authors":"Júlia Sala-Coromina,&nbsp;Anna Marcé-Grau,&nbsp;Barbara Masotto,&nbsp;Marta Codina,&nbsp;Lamia BenJemaa,&nbsp;Yasmina Elaribi,&nbsp;Mónica Martinez-Gallo,&nbsp;Roger Colobran,&nbsp;Angel Sanchez-Montañez,&nbsp;Irene Valenzuela,&nbsp;Yoshiko Murakami,&nbsp;Alfons Macaya","doi":"10.1002/acn3.70341","DOIUrl":"10.1002/acn3.70341","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p><i>PIGM</i> encodes a critical enzyme in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway. While promoter-region mutations in <i>PIGM</i> have been associated with a relatively mild phenotype characterized by portal vein thrombosis and absence seizures, recent evidence suggests that coding-region mutations result in a more severe multisystemic disorder.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Whole-exome sequencing reanalysis was performed in a patient with early-onset developmental and epileptic encephalopathy, and subsequent matchmaking identified another patient with a similar phenotype. The pathogenicity of the variant was evaluated through multiple functional assays. To further delineate the genotypic and phenotypic spectrum of PIGM, we reviewed all patients reported to date with <i>PIGM</i> variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We describe two unrelated patients, both carrying the same homozygous missense variant in <i>PIGM</i> (c.1001A &gt; C, p.Gln334Pro), presenting with early-onset developmental and epileptic encephalopathy, profound neurodevelopmental impairment, multi-organ involvement, and distinctive neuroimaging findings including hypomyelination. Both patients died in infancy due to super-refractory status epilepticus. Treatment with sodium phenylbutyrate was attempted in one patient without clinical benefit. Flow cytometry revealed partial GPI-anchor deficiency. Comparative analysis with previously reported cases highlights a potential genotype–phenotype correlation between coding region variants and disease severity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our findings establish <i>PIGM</i> as a causative gene of early-onset developmental and epileptic encephalopathy and expand the clinical and radiological spectrum of <i>PIGM</i> deficiency to include hypomyelination and prenatal onset. This study underscores the importance of including <i>PIGM</i> in the differential diagnosis of developmental and epileptic encephalopathy and leukoencephalopathies and provides further insight into the molecular mechanisms underlying phenotypic variability of GPI-anchor disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1759-1771"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147352993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Depolarizing Leak in Sodium Bicarbonate Cotransporter NBCe1 Causes Brain Edema","authors":"Quinty Bisseling,&nbsp;Mark D. Parker,&nbsp;Sven Kerst,&nbsp;Richard A. Pasternack,&nbsp;Jacob Tondreau,&nbsp;Marjolein Breur,&nbsp;Gemma M. van Rooijen-van Leeuwen,&nbsp;Davide Tonduti,&nbsp;Ettore Salsano,&nbsp;Alejandra Darling,&nbsp;Joanna A. E. van Wijk,&nbsp;Susanna Törnroth-Horsefield,&nbsp;Marianna Bugiani,&nbsp;Petra J. W. Pouwels,&nbsp;Quinten Waisfisz,&nbsp;Marjo S. van der Knaap,&nbsp;Rogier Min","doi":"10.1002/acn3.70363","DOIUrl":"10.1002/acn3.70363","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p><i>SLC4A4</i> encodes electrogenic sodium bicarbonate cotransporter NBCe1, prominently expressed in kidney and brain. Recessive loss-of-function variants in <i>SLC4A4</i> cause proximal renal tubular acidosis, no brain edema. In the brain, NBCe1 is expressed by astrocytes, where it regulates pH and mediates astrocyte volume changes. Here we describe a novel dominant variant in <i>SLC4A4</i> in patients with brain edema and investigate how it affects NBCe1 function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Genetic studies identified a novel gene variant in three unrelated pediatric patients with the same MRI pattern of cerebral subcortical white matter signal abnormality and swelling, and medulla lesions. Immunohistochemical and electrophysiological experiments were performed to determine the localization of the transporter in the brain and the functional consequence of the patient variant.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The same heterozygous variant in <i>SLC4A4</i> was found in all three patients and one parent. The children displayed infantile-onset progressive macrocephaly, motor and cognitive impairment, autism, epilepsy, and recurrent episodes of increased intracranial pressure. Bicarbonate treatment of two patients led to clinical and MRI improvement. Immunohistochemistry revealed that brain NBCe1 is mainly present in astrocytes, more in cortex than white matter. Functional experiments revealed impaired transporter activity of mutant NBCe1 due to reduced membrane expression and a prominent depolarizing ion leak.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The most likely pathomechanism of this novel <i>SLC4A4</i>-related disease is that a depolarizing leak in NBCe1 disrupts astrocyte pH regulation, promoting swelling and impairing volume control. These findings uncover a previously unrecognized mechanism of genetic brain edema and establish NBCe1 as a critical modulator of astrocyte homeostasis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1817-1830"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic and Microvascular Risk Factors Associated With Brain Health in Type 1 Diabetes","authors":"Jihyun Park,&nbsp;Emily J. Koubek,&nbsp;Richard Beare,&nbsp;Lynn Ang,&nbsp;Brian C. Callaghan,&nbsp;Rodica Pop-Busui,&nbsp;Eva L. Feldman,&nbsp;Evan L. Reynolds","doi":"10.1002/acn3.70428","DOIUrl":"10.1002/acn3.70428","url":null,"abstract":"<p>We examined relationships between metabolic factors, microvascular complications, and brain health in adults with type 1 diabetes. Fifty-one adults were assessed for metabolic risk factors, microvascular complications, and cognitive function, with a subset completing brain MRI. Compared to normative data, participants showed reduced fluid cognition (<i>p</i> = 0.01) but elevated crystallized cognition (<i>p</i> = 0.0001). Microvascular complications and metabolic risk factors (including obesity, diabetes duration, and HbA1c) were not consistently linked to brain health outcomes. These exploratory findings suggest subtle cognitive changes in adults with type 1 diabetes, though larger longitudinal studies are needed to clarify how metabolic and microvascular factors influence brain health.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1937-1946"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147872762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Neurofilament Light Chain and Real-World Ambulatory Function in Progressive MS.","authors":"Gabby B Joseph, Megan McCune, Riley Bove, Ahmed Abdelhak, Bruce A C Cree, Valerie J Block","doi":"10.1002/acn3.70527","DOIUrl":"10.1002/acn3.70527","url":null,"abstract":"<p><strong>Objective: </strong>Neurofilament light chain (NfL) is a biomarker of neuroaxonal injury in multiple sclerosis (MS), yet associations with functional outcomes remain unclear. Longitudinal associations between serum NfL (sNfL) and daily step count (STEPS) from wearable devices were assessed in a large international progressive MS cohort.</p><p><strong>Methods: </strong>A post hoc analysis of the Phase III randomized controlled trial SPI2 (high-dose biotin vs. placebo RCT) pooled treatment arms due to no observed therapeutic benefit. Participants with sNfL and step count data were included. STEPS were calculated within ±15-days of baseline, 6, 12, 15, and 27-month visits. Mixed-effects models with 1000 bootstrap iterations assessed contemporaneous associations with each measure alternately specified as the outcome, adjusting for age and sex. Lagged models evaluated whether 0-6-month sNFL changes predicted subsequent 6-12-month STEPS changes.</p><p><strong>Results: </strong>Among 506 participants (53.8% female; mean age 52.7 [SD: 7.7] years; median EDSS 6.0 [4.5-6.0]), mean sNfL z-score was 1.00 (SD: 0.95), and median STEPS were 3029 [1708-5210]. Higher sNfL was associated with lower STEPS (IRR = 0.97, p = 0.014), consistent across sex, treatment, disability, and disease-modifying treatment status. Conversely, higher STEPS were associated with lower sNfL z-scores; a 10% increase in STEPS corresponded to a 0.015 decrease in sNfL z-score (95% CI -0.022 to -0.008; p < 0.001). Greater prior 6-month increases in sNfL were associated with a lower subsequent STEPS (β = -141; 95% CI -302 to 21; p = 0.088; trend), corresponding to 141 fewer steps per 1-SD sNfL increase.</p><p><strong>Interpretation: </strong>Higher sNfL was associated with reduced daily ambulatory activity in progressive MS, and vice versa. Rising sNfL may precede mobility decline, highlighting sNfL as a potential indicator of functional worsening.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov NCT02936037; EudraCT database 2016-000700-29.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13555231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}