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Metachromatic Leukodystrophy: New Therapy Advancements and Emerging Research Directions. 异色性脑白质营养不良:新的治疗进展和新兴的研究方向。
IF 7.7 1区 医学
Neurology Pub Date : 2025-07-22 Epub Date: 2025-06-27 DOI: 10.1212/WNL.0000000000213817
Marije A B C Asbreuk, Daphne H Schoenmakers, Laura Ann Adang, Shanice Beerepoot, Caroline Bergner, Annette Bley, Jaap Jan Boelens, Marianna Bugiani, Valeria Calbi, Àngeles García-Cazorla, Erik A Eklund, Francesca Fumagalli, Sabine Weller Grønborg, Samuel Groeschel, Peter M Van Hasselt, Carla E M Hollak, Simon A Jones, Tom J de Koning, André B P van Kuilenburg, Lucia Laugwitz, Caroline Lindemans, Fanny Mochel, Andreas Øberg, Dipak Ram, Ludger Schöls, Caroline Sevin, Jigyasha Sinha, Frédéric M Vaz, Ayelet Zerem, Nicole I Wolf
{"title":"Metachromatic Leukodystrophy: New Therapy Advancements and Emerging Research Directions.","authors":"Marije A B C Asbreuk, Daphne H Schoenmakers, Laura Ann Adang, Shanice Beerepoot, Caroline Bergner, Annette Bley, Jaap Jan Boelens, Marianna Bugiani, Valeria Calbi, Àngeles García-Cazorla, Erik A Eklund, Francesca Fumagalli, Sabine Weller Grønborg, Samuel Groeschel, Peter M Van Hasselt, Carla E M Hollak, Simon A Jones, Tom J de Koning, André B P van Kuilenburg, Lucia Laugwitz, Caroline Lindemans, Fanny Mochel, Andreas Øberg, Dipak Ram, Ludger Schöls, Caroline Sevin, Jigyasha Sinha, Frédéric M Vaz, Ayelet Zerem, Nicole I Wolf","doi":"10.1212/WNL.0000000000213817","DOIUrl":"10.1212/WNL.0000000000213817","url":null,"abstract":"<p><p>Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the gene coding for arylsulfatase A, leading to deficient enzyme activity and subsequent accumulation of sulfatides. MLD is characterized by demyelination and neurodegeneration of the central and peripheral nervous system, manifesting as progressive motor and cognitive defects in affected individuals. This review provides a comprehensive overview of the significant progress made in MLD research in the past decade, regarding natural history, disease and treatment mechanisms, and newborn screening (NBS). Traditionally, MLD has been classified according to age at onset (late-infantile, early-juvenile and late-juvenile, and adult MLD), with earlier forms leading to more rapid neurologic decline. New data show that the type of presenting symptoms further influences the dynamic of disease progression. Patients with a cognitive presentation have a much slower or even no motor decline than patients with a mixed motor and cognitive presentation. Research advancements have enabled improved understanding of the effects of allogeneic hematopoietic stem cell transplantation and the development of novel therapeutic approaches, including hematopoietic stem cell gene therapy, which is now authorized in the EU, United Kingdom, and United States as treatment for selected patients with early-onset forms of MLD. Both hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy are most effective when administered before disease onset. To identify presymptomatic patients, NBS for MLD is becoming available in several countries, resulting in new challenges. Decisions regarding patient eligibility for these treatments in already symptomatic individuals, as well as the timing of treatment for patients identified through NBS, require thorough understanding of disease progression. Biomarkers may be helpful for disease staging and prediction of disease evolution. Moreover, apart from timing, challenges remain regarding optimal treatment strategies across MLD subtypes, especially late-onset MLD, and management of the clinical heterogeneity and course of the disease. Another important issue is ensuring therapy accessibility, which forms a substantial barrier for equitable care. Continued research and international collaboration are essential to address these challenges, with the goal of improving care and outcomes for patients with MLD and their families.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 2","pages":"e213817"},"PeriodicalIF":7.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
GFAP for Early ICH Detection: A New Prehospital Tool Emerges? 用于早期脑出血检测的GFAP:一种新的院前工具?
IF 7.7 1区 医学
Neurology Pub Date : 2025-07-22 Epub Date: 2025-06-26 DOI: 10.1212/WNL.0000000000213910
Lauren Mamer, Frederick K Korley
{"title":"GFAP for Early ICH Detection: A New Prehospital Tool Emerges?","authors":"Lauren Mamer, Frederick K Korley","doi":"10.1212/WNL.0000000000213910","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213910","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 2","pages":"e213910"},"PeriodicalIF":7.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pearls & Oy-Sters: Pan-Neurofascin Nodo-Paranodopathy Presenting as Fulminant Guillain-Barré Syndrome. 珍珠和y- sters:泛神经束蛋白淋巴结副病表现为暴发性格林-巴勒综合征。
IF 9.9 1区 医学
Neurology Pub Date : 2025-07-22 DOI: 10.1212/wnl.0000000000213848
Andrea Cabral,Cristina Lopes da Mota,Sofia Rodrigues Casanova,António Martins de Campos,José Augusto Mendes Ribeiro,Maria João Malaquias
{"title":"Pearls & Oy-Sters: Pan-Neurofascin Nodo-Paranodopathy Presenting as Fulminant Guillain-Barré Syndrome.","authors":"Andrea Cabral,Cristina Lopes da Mota,Sofia Rodrigues Casanova,António Martins de Campos,José Augusto Mendes Ribeiro,Maria João Malaquias","doi":"10.1212/wnl.0000000000213848","DOIUrl":"https://doi.org/10.1212/wnl.0000000000213848","url":null,"abstract":"Autoimmune nodo-paranodopathy (AINP) associated with antibodies against pan-neurofascin (Ab-PanNF) is a rare subtype of autoimmune neuropathy. It can present as a severe, prolonged, and sometimes fatal disease. However, with appropriate treatment, it generally follows a monophasic course, and many patients achieve complete or near-complete recovery. Antibody-depleting therapy with rituximab (RTX) is currently the best therapeutic option. In this article, we report a patient with progressive weakness who was initially misdiagnosed with Guillain-Barré syndrome (GBS). Intravenous immunoglobulin (IVIg) led to partial improvement, but the patient deteriorated abruptly weeks later, developing tetraplegia, lower cranial nerve involvement, and dysautonomia. Eventually, a diagnosis of AINP with Ab-PanNF was reached, prompting the initiation of RTX. The patient improved dramatically and remains in remission. We discuss the pathophysiology underlying Ab-PanNF-mediated AINP, its clinical and electrodiagnostic features, and considerations regarding antibody testing and treatment. Specifically, red flags that should prompt early Ab-PanNF testing include age older than 60 years, severe and rapidly progressive GBS, prolonged mechanical ventilation, fulminant relapse after initial improvement, and resistance to standard treatments. Finally, we review the literature and summarize the main features of the 40 cases reported so far. Ab-PanNF-mediated AINP is a potentially life-threatening disease; its early recognition is of utmost importance because early antibody-depleting therapy significantly alters outcomes and can be lifesaving.","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"98 1","pages":"e213848"},"PeriodicalIF":9.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pregnancy Outcomes in Patients Exposed to OnabotulinumtoxinA Treatment: A Cumulative 29-Year Safety Update. 暴露于肉毒杆菌毒素治疗的患者的妊娠结局:累积29年的安全性更新
IF 7.7 1区 医学
Neurology Pub Date : 2025-07-22 Epub Date: 2025-06-26 DOI: 10.1212/WNL.0000000000213772
{"title":"Pregnancy Outcomes in Patients Exposed to OnabotulinumtoxinA Treatment: A Cumulative 29-Year Safety Update.","authors":"","doi":"10.1212/WNL.0000000000213772","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213772","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 2","pages":"e213772"},"PeriodicalIF":7.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetic Risk and Prognosis of the First Incident Stroke Survivors: Findings from China Kadoorie Biobank and UK Biobank. 首次中风幸存者的遗传风险和预后:来自中国嘉理生物银行和英国生物银行的研究结果。
IF 7.7 1区 医学
Neurology Pub Date : 2025-07-22 Epub Date: 2025-06-27 DOI: 10.1212/WNL.0000000000213832
Yuting Han, Hongjing Shi, Canqing Yu, Pei Pei, Ling Yang, Iona Y Millwood, Robin G Walters, Yiping Chen, Huaidong Du, Meiyu Guan, Daniel Avery, Junshi Chen, Zhengming Chen, Liming Li, Dianjianyi Sun, Jun Lv
{"title":"Genetic Risk and Prognosis of the First Incident Stroke Survivors: Findings from China Kadoorie Biobank and UK Biobank.","authors":"Yuting Han, Hongjing Shi, Canqing Yu, Pei Pei, Ling Yang, Iona Y Millwood, Robin G Walters, Yiping Chen, Huaidong Du, Meiyu Guan, Daniel Avery, Junshi Chen, Zhengming Chen, Liming Li, Dianjianyi Sun, Jun Lv","doi":"10.1212/WNL.0000000000213832","DOIUrl":"10.1212/WNL.0000000000213832","url":null,"abstract":"<p><strong>Background and objectives: </strong>Stroke is known for its poor prognosis. Although genetic instruments have shown promise in stratifying first stroke risk in the general population, it is unknown whether they are associated with stroke prognosis. Our study aims to explore the role of genetic risk of stroke in the progression from stroke-free to first stroke and then to recurrent stroke, subsequent coronary heart disease (CHD), and death in China and the United Kingdom.</p><p><strong>Methods: </strong>We used data from 2 prospective population-based cohorts, China Kadoorie Biobank (CKB) and UK Biobank (UKB). Participants who were unrelated and free of stroke and CHD at baseline were included. Genetic risks of stroke were quantified using integrative polygenic risk scores (iPRSs), which incorporated summary statistics from multiple genome-wide association studies for stroke outcomes and its subtypes, and vascular-risk traits. We used a multistate model to analyze the roles of genetic risk in the transitions from baseline to first incident stroke and then to recurrent stroke, subsequent CHD, and death.</p><p><strong>Results: </strong>Our study included 80,908 CKB participants and 380,348 UKB participants, with mean ages (% female) of 54.0 years (58.6%) and 56.1 years (55.4%). During median follow-ups of 11.9 years and 13.4 years in the CKB and UKB, respectively, 13,481 and 5,772 participants had their first stroke, neither experienced a CHD, or died within 28 days. These survivors had 5,707 and 943 recurrent strokes, as well as 1,196 and 418 CHD events, respectively. iPRSs were associated with recurrent stroke and CHD among stroke survivors in both populations. The corresponding hazard ratios (HRs) and 95% CIs per SD of iPRSs were 1.08 (1.05-1.11) and 1.08 (1.02-1.15) in CKB and 1.11 (1.03-1.19) and 1.23 (1.10-1.37) in UKB, respectively. There was no association between iPRSs and mortality risk. When we further divided the first stroke into 4 pathologic subtypes, both populations revealed statistically significant associations between iPRSs and the transitions from first ischemic stroke to recurrent stroke and CHD.</p><p><strong>Discussion: </strong>Our study shows that the genetic risk of first stroke also influences the prognosis of stroke survivors, indicating that PRS has the potential to improve stroke prognosis.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 2","pages":"e213832"},"PeriodicalIF":7.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Teaching NeuroImage: X-Linked Adrenoleukodystrophy With Rare Temporal Pole Involvement. 教学神经影像:罕见颞极受累的x联肾上腺脑白质营养不良。
IF 9.9 1区 医学
Neurology Pub Date : 2025-07-22 DOI: 10.1212/wnl.0000000000213896
Yixin Kang,Xiaosheng Zheng,Zhidong Cen,Biao Jiang,Wei Luo
{"title":"Teaching NeuroImage: X-Linked Adrenoleukodystrophy With Rare Temporal Pole Involvement.","authors":"Yixin Kang,Xiaosheng Zheng,Zhidong Cen,Biao Jiang,Wei Luo","doi":"10.1212/wnl.0000000000213896","DOIUrl":"https://doi.org/10.1212/wnl.0000000000213896","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"76 1","pages":"e213896"},"PeriodicalIF":9.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Amelogenesis Imperfecta and Epilepsy: A Diagnostic Clue to a Neurogenetic Epilepsy Syndrome. 无胚性发育不全与癫痫:神经遗传性癫痫综合征的诊断线索。
IF 7.7 1区 医学
Neurology Pub Date : 2025-07-22 Epub Date: 2025-06-13 DOI: 10.1212/WNL.0000000000213838
Reon Dexter A, Yathwin Kanagavel M, Ranjith Kumar Manokaran
{"title":"Amelogenesis Imperfecta and Epilepsy: A Diagnostic Clue to a Neurogenetic Epilepsy Syndrome.","authors":"Reon Dexter A, Yathwin Kanagavel M, Ranjith Kumar Manokaran","doi":"10.1212/WNL.0000000000213838","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213838","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 2","pages":"e213838"},"PeriodicalIF":7.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Time for Education and Research in Academic Neurology: An Update and Recent Events. 学术神经学的教育和研究时间:更新和最近的事件。
IF 7.7 1区 医学
Neurology Pub Date : 2025-07-22 Epub Date: 2025-06-13 DOI: 10.1212/WNL.0000000000213813
Kimford J Meador
{"title":"Time for Education and Research in Academic Neurology: An Update and Recent Events.","authors":"Kimford J Meador","doi":"10.1212/WNL.0000000000213813","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213813","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 2","pages":"e213813"},"PeriodicalIF":7.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
What Is the Role of Glucocorticoids in the Effects of Stress on the Brain? 糖皮质激素在压力对大脑的影响中的作用是什么?
IF 7.7 1区 医学
Neurology Pub Date : 2025-07-22 Epub Date: 2025-06-13 DOI: 10.1212/WNL.0000000000213874
Eduardo Benarroch
{"title":"What Is the Role of Glucocorticoids in the Effects of Stress on the Brain?","authors":"Eduardo Benarroch","doi":"10.1212/WNL.0000000000213874","DOIUrl":"https://doi.org/10.1212/WNL.0000000000213874","url":null,"abstract":"","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 2","pages":"e213874"},"PeriodicalIF":7.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Phenotypic Spectrum in Individuals With Pathogenic GABRG2 Loss- and Gain-of-Function Variants. 致病性GABRG2丧失和功能获得变异个体的表型谱。
IF 7.7 1区 医学
Neurology Pub Date : 2025-07-22 Epub Date: 2025-06-26 DOI: 10.1212/WNL.0000000000213644
Alessandra Rossi, Susan X N Lin, Nathan L Absalom, Sebastian Ortiz-De la Rosa, Vivian W Y Liao, Nazanin A Mohammadi, Sindhu Viswanathan, Tommy Stödberg, Alberto Danieli, Paolo Bonanni, Alec Aeby, Alessandro Orsini, Alice Bonuccelli, Andrea Rüegger, Beatriz G Giraldez, Bertrand Isidor, Burkhard Stüve, Carla Marini, Elisabetta Cesaroni, Christina D Fenger, Christophe Philippe, Colombine Meunier, Damien Lederer, Stéphanie Moortgat, Egidio Spinelli, Elisa Fallica, Fiona Zeiner, Matthias Bauman, Laura Licchetta, Francesca Bisulli, Francesca F Operto, Ira Benkel-Herrenbrueck, Kathleen M Gorman, Katrine M Johannesen, Konrad Platzer, Franziska Schnabel, Lieven Lagae, Mirjam Laufs, Riina Zordania, Stephen Malone, Tullio Messana, Wendy Werckx, Charlotta Jonsson, Zaid Afawi, Thomas Foiadelli, Yosra Halleb, Radka Stoeva, Mélanie Jennesson-Lyver, Gaetan Lesca, Renzo Guerrini, Samuel F Berkovic, Ingrid E Scheffer, Mary Chebib, Elena Gardella, Rikke S Møller, Guido Rubboli, Philip K Ahring
{"title":"Phenotypic Spectrum in Individuals With Pathogenic <i>GABRG2</i> Loss- and Gain-of-Function Variants.","authors":"Alessandra Rossi, Susan X N Lin, Nathan L Absalom, Sebastian Ortiz-De la Rosa, Vivian W Y Liao, Nazanin A Mohammadi, Sindhu Viswanathan, Tommy Stödberg, Alberto Danieli, Paolo Bonanni, Alec Aeby, Alessandro Orsini, Alice Bonuccelli, Andrea Rüegger, Beatriz G Giraldez, Bertrand Isidor, Burkhard Stüve, Carla Marini, Elisabetta Cesaroni, Christina D Fenger, Christophe Philippe, Colombine Meunier, Damien Lederer, Stéphanie Moortgat, Egidio Spinelli, Elisa Fallica, Fiona Zeiner, Matthias Bauman, Laura Licchetta, Francesca Bisulli, Francesca F Operto, Ira Benkel-Herrenbrueck, Kathleen M Gorman, Katrine M Johannesen, Konrad Platzer, Franziska Schnabel, Lieven Lagae, Mirjam Laufs, Riina Zordania, Stephen Malone, Tullio Messana, Wendy Werckx, Charlotta Jonsson, Zaid Afawi, Thomas Foiadelli, Yosra Halleb, Radka Stoeva, Mélanie Jennesson-Lyver, Gaetan Lesca, Renzo Guerrini, Samuel F Berkovic, Ingrid E Scheffer, Mary Chebib, Elena Gardella, Rikke S Møller, Guido Rubboli, Philip K Ahring","doi":"10.1212/WNL.0000000000213644","DOIUrl":"10.1212/WNL.0000000000213644","url":null,"abstract":"<p><strong>Background and objectives: </strong>Variants in the <i>GABRG2</i> gene encoding the γ2 subunit of the γ-aminobutyric acid type A (GABA<sub>A</sub>) receptor are associated with a spectrum of epilepsy phenotypes. These range from simple febrile seizures to more severe conditions, including developmental and epileptic encephalopathies (DEEs). Despite previous analyses suggesting that pathogenic variants may lead to loss-of-function (LoF) receptors, a correlation between functional analysis and clinical phenotypic diversity remains elusive. We, therefore, aimed to determine why variants in the <i>GABRG2</i> gene can lead to highly diverse phenotypes.</p><p><strong>Methods: </strong>We assembled a cohort of unreported probands carrying presumed pathogenic <i>GABRG2</i> variants. Electroclinical information was systematically collected, and electrophysiologic measurements were conducted for missense variants to explore potential alterations in receptor function.</p><p><strong>Results: </strong>We examined 44 individuals with 35 <i>GABRG2</i> variants (18 null and 17 missense). Functional assessments of the missense variants revealed that 9 caused LoF and 3 caused gain-of-function (GoF). The remaining 5 did not alter receptor function and are likely not pathogenic. Based on functional analysis and electroclinical data, 37 affected individuals were categorized into 3 groups: null LoF, missense LoF, and GoF variants. Among 19 individuals with null variants, epilepsy was diagnosed in 13, with a median onset of 14 months. The remaining 6 of 19 only had febrile seizures. Developmental delay/intellectual disability (DD/ID) was observed in 1 of 19 and psychiatric features in 4 of 18. By contrast, all 12 individuals with missense LoF variants suffered from epilepsy with a median onset of 15 months. Most common epilepsy diagnoses were febrile seizures plus in 4 of 12 and DEE in 4 of 12. DD/ID affected 9 of 12, and psychiatric features were diagnosed in 8 of 12. Statistical comparisons revealed that null variants were associated with a milder phenotype than missense LoF variants. Finally, 5 of 6 individuals with GoF variants had DEE characterized by early infancy onset at 2 months and severe/profound DD/ID. The sixth individual exhibited mild DD/ID and hypotonia without seizures.</p><p><strong>Discussion: </strong>Our findings indicate that the severity of disease associated with pathogenic <i>GABRG2</i> variants depends on the functional consequences of the variants. Null variants are associated with a mild phenotype and missense LoF variants with an intermediate phenotype while GoF variants can lead to severe phenotypes.</p>","PeriodicalId":19256,"journal":{"name":"Neurology","volume":"105 2","pages":"e213644"},"PeriodicalIF":7.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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