Annals of Clinical and Translational Neurology最新文献

{"title":"Compound Heterozygote Friedreich Ataxia Patients With Covert Proximal FXN Gene Deletions","authors":"Michael P. Lazaropoulos,&nbsp;Morgan C. Devore,&nbsp;Christina Lam,&nbsp;Courtney Park,&nbsp;Sanjay Bidichandani,&nbsp;David R. Lynch","doi":"10.1002/acn3.70408","DOIUrl":"10.1002/acn3.70408","url":null,"abstract":"<p>We present Friedreich ataxia patients with frataxin gene deletions. Data and records were collected at the Children's Hospital of Philadelphia from patients enrolled in the FACOMS natural history study. Patients with proximal deletions initially diagnosed with only one GAA expanded allele had more severe disease than their homozygous expansion counterparts, including increased frequency of cardiomyopathy, diabetes, and optic neuropathy. Their phenotypes were like those of individuals with distal deletions and null pathogenic variants in the frataxin gene. Covert proximal frataxin gene deletions should be suspected when genetic testing fails to demonstrate two distinct expanded alleles in patients with severe phenotypes.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 10","pages":"2134-2137"},"PeriodicalIF":3.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142093","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":"The Price of Precision: A Critical Review of Molecular Diagnostics in Glioma, From Guidelines to Global Disparities","authors":"Maria Guarnaccia,&nbsp;Sebastiano Cavallaro","doi":"10.1002/acn3.70503","DOIUrl":"10.1002/acn3.70503","url":null,"abstract":"<p>Gliomas have undergone a profound redefinition over the past decade, transitioning from morphology-based entities to biologically coherent diseases defined by molecular alterations. The 2021 WHO Classification of Tumors of the Central Nervous System and its 2022 update formalize this shift, establishing integrated diagnosis as the global standard and identifying essential biomarkers—including <i>IDH</i> mutations, 1p/19q codeletion, <i>ATRX</i> loss, <i>TP53</i> mutation, <i>TERT</i> promoter mutation, <i>EGFR</i> amplification, and +7/−10 cytogenetics—that shape prognosis, therapeutic decision-making, and clinical trial eligibility. In this review, we synthesize the current molecular taxonomy of gliomas and compare recommendations from major international guidelines (WHO, NCCN, EANO) and the Italian Association of Neuro-Oncology (AINO). Recognizing that contemporary practice employs a complementary, purpose-driven array of diagnostic modalities—from immunohistochemistry and PCR-based methods to next-generation sequencing and DNA methylation profiling—we critically examine the profound global disparities that hinder implementation, focusing on economic constraints, infrastructural limitations, regulatory barriers, and workforce shortages. By integrating health-economic evidence, we demonstrate that the societal and financial burden of non-implementation far exceeds the investment required for molecular testing. We propose a tiered implementation framework in which clinically actionable information is obtainable for most glioma patients through accessible, cost-effective technologies, with more resource-intensive modalities reserved for specific clinical scenarios. Ensuring equitable access to integrated diagnostics, defined as the right test for the right clinical question, is essential not only for precision neuro-oncology but also for global healthcare justice and scientific progress.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 10","pages":"1968-1977"},"PeriodicalIF":3.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13408693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148596997","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":"[18F]Fluorodeprenyl-D2 PET as a Tool to Monitor Disease Activity in GAD65-Ab Autoimmune Encephalitis","authors":"Julia S. Dorneich,&nbsp;Jonathan A. Gernert,&nbsp;Hanna Zimmermann,&nbsp;Lisa Tagnin,&nbsp;Marianthi Zeinaki,&nbsp;Laura Sanzo,&nbsp;Letizia Vogler,&nbsp;Elisabeth Kaufmann,&nbsp;Justina Dargvainiene,&nbsp;Frank Leypoldt,&nbsp;Gérard N. Bischof,&nbsp;Robert Perneczky,&nbsp;Boris-Stephan Rauchmann,&nbsp;Simon Lindner,&nbsp;Günter U. Höglinger,&nbsp;Rudolf A. Werner,&nbsp;Martin Kerschensteiner,&nbsp;Tania Kümpfel,&nbsp;Matthias Brendel,&nbsp;Franziska S. Thaler","doi":"10.1002/acn3.70377","DOIUrl":"10.1002/acn3.70377","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate [¹⁸F]fluorodeprenyl-D2 ([¹⁸F]F-DED) positron-emission tomography (PET) imaging as a biomarker of disease activity in autoimmune encephalitis (AIE) associated with glutamic acid decarboxylase 65 (GAD65) antibodies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>[¹⁸F]F-DED PET was performed in 25 GAD65-AIE patients and 8 controls using dynamic (0–60 min) and static (30–60 min) acquisitions. Global astrogliosis was assessed by volumes of distribution (VT; 1-tissue-compartment model with carotid input) and standardized uptake values (SUV). Regional cerebellar and mesiotemporal (MT) uptake was normalized to global uptake (SUVr). PET measures were correlated with clinical phenotypes, MRI findings, and serum biomarkers (neurofilament light chain [sNfL], GAD65-Ab titers, and glial fibrillary acidic protein [sGFAP]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Clinical phenotypes included limbic encephalitis/temporal lobe epilepsy (LE/TLE; <i>n</i> = 17), stiff-person syndrome (<i>n</i> = 4), and cerebellar ataxia (CA; <i>n</i> = 4), with overlap in nine patients. Global [¹⁸F]F-DED uptake was higher in patients than controls. VT analysis showed increased cortical and MT uptake, while SUVr analysis demonstrated elevated MT uptake across the cohort. LE/TLE patients exhibited increased MT uptake, and CA patients showed higher cerebellar uptake. [¹⁸F]F-DED uptake did not correlate with sNfL or GAD65-Ab titers, but sGFAP showed associations with cerebellar and white-matter uptake. Regional uptake correlated with clinical severity in LE/TLE (MT lobe) and CA (cerebellar white matter).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>[¹⁸F]F-DED PET reveals region-specific astrogliosis corresponding to clinical manifestations and disease severity in GAD65-AIE, supporting its potential as a monitoring tool for disease activity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 10","pages":"1978-1992"},"PeriodicalIF":3.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508204","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":"SPG4 and Dementia: Expanding the Clinical Spectrum","authors":"Emanuele Panza,&nbsp;Arun Meyyazhagan,&nbsp;Eliseo Picchi,&nbsp;Gustavo Ribas,&nbsp;Ingrid Faber,&nbsp;Ryosuke Miyamoto,&nbsp;Preethi Basavaraju,&nbsp;Paolo Eusebi,&nbsp;Haripriya Kuchi Bhotla,&nbsp;Mario Stasi,&nbsp;Fabrizio Gaudiello,&nbsp;Francesco Patti,&nbsp;Filippo Maria Santorelli,&nbsp;Marcondes Cavalcante França Jr,&nbsp;José Luiz Pedroso,&nbsp;Orlando Graziani Povoas Barsottini,&nbsp;Hélio Afonso Ghizoni Teive,&nbsp;Peter Henry St George-Hyslop,&nbsp;Toshitaka Kawarai,&nbsp;Antonio Orlacchio","doi":"10.1002/acn3.70371","DOIUrl":"10.1002/acn3.70371","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Hereditary spastic paraplegia (HSP) is a group of disorders characterized by progressive spasticity and lower limb weakness, with mutations in SPG4/<i>SPAST</i> being the most common cause. Detailed studies and clinical and molecular comparisons across different populations are missing. We examined the clinical, pathological, and genetic spectrum of the SPG4/<i>SPAST</i> gene in patients with HSP.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study involved 726 HSP patients recruited from Italy, Brazil, and Japan between 2001 and 2025, with analysis conducted in collaborative centers. SPG4/<i>SPAST</i> variants were identified using direct and next-generation sequencing. The pathogenicity of novel variants was confirmed through familial segregation and in silico analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Clinical and epidemiological differences were observed across populations, particularly in phenotype, age at onset, and disability, expanding the SPG4 clinical spectrum. Genetic analysis identified 52 pathogenic SPG4/<i>SPAST</i> mutations in 284 patients, including four novel variants. Several mutations were population-specific, and a possible founder effect was suggested for a recurrent variant in Italy. Dementia occurred in 44 HSP-SPG4 patients and was neuropathologically confirmed in four unrelated autopsied cases from four families comprising 28 individuals; atypical pathological features were observed in all four autopsied cases. Additionally, 18 patients with SPG4/<i>SPAST</i> mutations presented with thin <i>corpus callosum</i> and intellectual disability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>In this study, we investigated pathogenic SPG4/<i>SPAST</i> variants in an international cohort of HSP patients from three continents. Our findings expand the clinical spectrum of HSP-SPG4, identifying a new type complicated by an atypical pathological form of dementia. Careful assessment of genotype–phenotype relationships offers insights into patient counseling and future research planning.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 10","pages":"2002-2016"},"PeriodicalIF":3.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508238","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":"Copine-4 Paraneoplastic Autoimmune Encephalitis.","authors":"Mimi S Fang, Amy Ml Quek, Clement Yong, Amir Adeli, Gabrielle N Conway, Connie E Lesnick, Diana Anissian, Divyanshu Dubey, John R Mills, Sean J Pittock, Anastasia Zekeridou, Michael Gilligan, Andrew McKeon","doi":"10.1002/acn3.70545","DOIUrl":"https://doi.org/10.1002/acn3.70545","url":null,"abstract":"<p><p>We characterize copine-4 (CPNE4)-IgG and report clinical associations. Among 844 samples with unclassified neural IgGs identified by mouse-brain indirect immunofluorescence assay over 2 years, 5 samples (serum, 3; CSF, 2) from 3 patients produced a distinctive cerebrum-restricted synaptic pattern. Protein microarray disclosed CPNE4 \"top hit\" in those 3 patients; specificity was confirmed by 3 CPNE4-specific assays (confocal IFA, cell-based, and western blot). Median onset age was 67 years (range 60-68); all had encephalitis: a brainstem syndrome during immune checkpoint inhibitor therapy for lung cancer (2) and anti-NMDA-receptor encephalitis accompanied by neuroectoderm-lineage cancer (1). To date, CPNE4-IgG has paraneoplastic encephalitis significance.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101118","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":"Progressive Parkinsonism in PPP2R5D-Related Neurodevelopmental Disorder.","authors":"Katerina Bernardi, Enrique Gonzalez Saez-Diez, Joshua Rong, Beril Ay, Shabbir Merchant, Kathryn Yang, Darius Ebrahimi-Fakhari","doi":"10.1002/acn3.70492","DOIUrl":"10.1002/acn3.70492","url":null,"abstract":"<p><p>PPP2R5D-related neurodevelopmental disorder (Houge-Janssens syndrome type 1) is a rare autosomal dominant condition characterized by macrocephaly, intellectual disability, and epilepsy. Progressive parkinsonism is an emerging adult phenotype that neurologists should be aware of since timely genetic diagnosis opens the door to disease-modifying therapies currently in clinical trials. We describe a 33-year-old woman with this condition who developed progressive mixed-tremor parkinsonism in early adulthood. Dopamine transporter imaging confirmed presynaptic nigrostriatal dysfunction. Whole-genome sequencing identified the recurrent de novo pathogenic missense variant PPP2R5D p.Glu198Lys. The clinical triad of macrocephaly, intellectual disability, and early-onset parkinsonism is specific for this condition and should prompt targeted genetic evaluation even in adults with a longstanding diagnosis of a neurodevelopmental disorder.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":"2161-2165"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467867","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 Novel KCNA1 Variant in a Patient With Tremor and Autism Spectrum Disorder Causes Mixed LOF/GOF Defects of Kv1.1 Channels.","authors":"Juan Darío Ortigoza-Escobar, Laura Marti-Sánchez, Loreto Martorell, Giorgia Dinoi, Antonio Vittorio Buono, Annamaria De Luca, Antonella Liantonio, Paola Imbrici","doi":"10.1002/acn3.70536","DOIUrl":"10.1002/acn3.70536","url":null,"abstract":"<p><p>Variants in KCNA1, encoding the Kv1.1 potassium channel, cause neurological disorders including episodic ataxia and developmental and epileptic encephalopathy. We identified a novel KCNA1 variant (A401T) in a 16-year-old patient with autism spectrum disorder, borderline intellectual disability, and tremor, without episodic ataxia or epilepsy. Functional analysis in HEK293 cells showed that A401T markedly reduced potassium currents, slowed activation, and accelerated C-type inactivation, consistent with loss-of-function (LOF), while shifting channel activation to more negative potentials, indicating gain-of-function (GOF). Overall, our findings expand both the clinical and functional spectrum of KCNA1-related disorders by identifying autism spectrum disorder and tremor associated with a mixed LOF/GOF KCNA1 variant.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":"2166-2171"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014875","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":"Paramagnetic Rim Lesions and Choroid Plexus Volume at Diagnosis Are Associated With Cognitive Progression Independent of Relapse and MRI Activity in Early Relapsing-Remitting Multiple Sclerosis.","authors":"Stefano Ziccardi, Damiano Marastoni, Agnese Tamanti, Pietro Biasi, Valentina Visani, Annalisa Colombi, Tom A Fuchs, Monica Sicchieri, Chiara Eccher, Francesco Guarnaccia, Milena Calderone, Valentina Camera, Francesca Benedetta Pizzini, Roberta Magliozzi, Marco Castellaro, Massimiliano Calabrese","doi":"10.1002/acn3.70448","DOIUrl":"10.1002/acn3.70448","url":null,"abstract":"<p><p>Paramagnetic rim lesions (PRLs) and choroid plexus (CP) enlargement reflect smoldering inflammation in multiple sclerosis. Their role in cognitive progression remains unexplored. Eighty-seven early relapsing-remitting MS patients were enrolled at diagnosis and followed longitudinally. PRLs and CP volume were evaluated at diagnosis using 3 T-MRI. Cognitive decline over time was classified as cognitive progression independent of relapse/MRI activity (PIRMA). Fifty-five patients (63.2%) showed meaningful cognitive decline: 44 (80.0%) were cognitive PIRMA. PRLs and CP volume at diagnosis were associated with cognitive PIRMA. PRLs and larger CP reflect cognitive progression independent of clinical/MRI activity, supporting their role as smoldering disease activity markers.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":"2154-2160"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409669","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":"Alzheimer's Disease Beyond Amyloid: Lessons From Atherosclerosis.","authors":"Marcello Ciaccio, Luisa Agnello","doi":"10.1002/acn3.70533","DOIUrl":"10.1002/acn3.70533","url":null,"abstract":"","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":"2175-2183"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148981703","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 Case of a 40-year-old Female with Speech Disturbance.","authors":"Victoria Lorah, Michael V Robers","doi":"10.1002/acn3.70523","DOIUrl":"10.1002/acn3.70523","url":null,"abstract":"","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":"2172-2174"},"PeriodicalIF":3.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13571561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148954552","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}