Neurology-Genetics最新文献

{"title":"Targeted Therapy of <i>GRIA1</i>-Related Epilepsy and Intellectual Disability With Perampanel: A Case Report and Literature Review.","authors":"Elisabetta Cesaroni, Claudia Passamonti, Carla Marini","doi":"10.1212/NXG.0000000000200303","DOIUrl":"10.1212/NXG.0000000000200303","url":null,"abstract":"<p><strong>Objectives: </strong>This report details a patient with a <i>GRIA1</i> pathogenic variant presenting with intellectual disability (ID) and epilepsy. We describe clinical features, genetic findings, a personalized treatment approach, and a literature review of GRIA1-related disorders.</p><p><strong>Methods: </strong>We describe clinical presentation, neuropsychological assessment, and genetic analysis. We conducted a literature review of published GRIA1-related disorders using PubMed, Simons Foundation Autism Research Initiative (SFARI) Gene, and ClinVar databases.</p><p><strong>Results: </strong>An 8-year-old girl with ID, focal-to-bilateral tonic clonic seizure since age 5, and later atypical absences was diagnosed with a novel, de novo <i>GRIA1</i> c.2530T > G, p.Leu844Val pathogenic variant. After genetic diagnosis, she was titrated to 4 mg of perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, which led to seizure control and improvements in cognition and school performance. Literature review identified 31 patients carrying 15 different pathogenic variants. The c.1906G > A, p.Ala636Thr variant was recurrent in 17 individuals. Intellectual disability and autism spectrum disorder were common while epilepsy was reported in approximately a quarter of patients. Two patients with gain-of-function missense variants in <i>GRIA1</i> and <i>GRIA2</i>, successfully treated with perampanel, have also been reported.</p><p><strong>Discussion: </strong>This case emphasizes the role of targeted interventions in the management of rare genetic disorders and underscores the potential of precision medicine in addressing GRIA1-related symptoms.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 5","pages":"e200303"},"PeriodicalIF":3.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral Neuropathy in p.Val142Ile (Val122Ile) Variant Hereditary Transthyretin-Mediated Amyloidosis: United Kingdom Experience.","authors":"Victor Jia Wei Zhang, Luke F O'Donnell, Mariola Skorupinska, Roy Carganillo, Alexander M Rossor, Marianna Fontana, Dorota Rowczenio, Janet Gilbertson, Julian D Gillmore, Mary M Reilly","doi":"10.1212/NXG.0000000000200304","DOIUrl":"10.1212/NXG.0000000000200304","url":null,"abstract":"<p><strong>Background and objectives: </strong>p.Val142Ile (p.V142I) is one of the most common pathogenic transthyretin (TTR) variants typically presents as transthyretin amyloid cardiomyopathy (ATTRv-CM), although frequent concurrent peripheral nerve involvement has been reported (94%). We aimed to characterize the polyneuropathy in p.V142I ATTR amyloidosis (ATTRv-PN) from the UK amyloidosis cohort.</p><p><strong>Methods: </strong>We performed a retrospective cohort study of all confirmed p.V142I Variant Transthyretin Amyloidosis (ATTRv) individuals in the National Hospital for Neurology and Neurosurgery Inherited Neuropathy Clinic between January 2019 and October 2024. Because presence of ATTRv-PN was required to access disease-modifying therapy for amyloidosis during this time, all individuals with p.V142I ATTRv were evaluated for neuropathy, providing an unselected cohort.</p><p><strong>Results: </strong>We identified 52 individuals with p.V142I ATTRv among whom the clinical presentation was cardiac in 47 (90%) and neuropathic in 5 (10%). Age at diagnosis was 71.3 ± 12.2 years. Twenty of the 52 individuals (38%) had symptoms suggestive of neuropathy with an average duration of symptoms of 4.9 ± 3.5 years 20/52 (38%) had signs suggestive of neuropathy with average Neuropathy Impairment Score being 9.0 ± 10.5. After investigations, 21/52 (40%) individuals had clinical features, neurophysiology, and/or skin biopsies consistent with ATTRv-PN (8 large-fiber/13 small-fiber). Six of the 52 individuals (12%) had neuropathies because of alternative etiologies (e.g., diabetes).</p><p><strong>Discussion: </strong>Real-world experience from the UK national cohort of p.V142I ATTRv indicates that peripheral neuropathy is of a mild severity and less frequent than previously reported.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 5","pages":"e200304"},"PeriodicalIF":3.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling of Dysferlinopathy (LGMDR2) Progression: A Longitudinal Fat Fraction Analysis.","authors":"Carla Florencia Bolano-Diaz, Harmen Reyngoudt, Ian J Wilson, Meredith K James, Fiona Elizabeth Smith, Ericky Caldas de Almeida Araujo, Heather Gordish-Dressman, Heather Hilsden, Laura E Rufibach, Dorothy Wallace, Louise Ward, Roberto Stramare, Alessandro Rampado, Mark Smith, Jean-Marc Boisserie, Julien Le Louer, Sheryl Foster, Anthony Peduto, Noriko Sato, Takeshi Tamaru, Anne Marie Sawyer, John W Day, Kristi J Jones, Maggie Christine Walter, Tanya Stojkovic, Madoka Mori-Yoshimura, Jerry R Mendell, Elena Pegoraro, Volker Straub, Andrew M Blamire, Pierre Carlier, Jordi Diaz-Manera","doi":"10.1212/NXG.0000000000200283","DOIUrl":"10.1212/NXG.0000000000200283","url":null,"abstract":"<p><strong>Background and objectives: </strong>Limb-girdle muscular dystrophy R2 (LGMDR2) is characterized by progressive muscle weakness usually leading to severe disability. The rate of progression and disease severity is variable among patients, although factors influencing this variability are not completely understood. The Dysferlinopathy Clinical Outcome Study is a natural history study that followed patients with LGMDR2 for 3 consecutive years using functional outcome measures and skeletal muscle MRI.The aim of our study was to develop statistical models able to describe fat fraction (FF) progression of the lower limbs in patients with LGMDR2 using clinical and radiologic variables to better understand which factors influence disease progression and improve the design of future clinical trials.</p><p><strong>Methods: </strong>We used linear-mixed modeling to analyze changes in FF over time according to patients' age. We calculated the average FF trajectory for each muscle of the lower limbs. We built 2 multivariate models for each segment adding other clinical factors and using likelihood ratio test and residuals' analysis to determine whether they better fitted observed FF values.</p><p><strong>Results: </strong>Muscles that participated in the same joint movement progressed similarly over time. FF was expected to be higher the older patients were and the earlier the age at symptom onset. Women had absolute FF values 8.8% higher than men in the lower leg. No differences in FF trajectory were seen based on ethnic groups (White, Asian, Black, or Hispanic), genetic variants, or residual dysferlin expression. Although multivariate models showed a better global fit to the data, there was no improvement in representing individual patient variability.</p><p><strong>Discussion: </strong>In conclusion, this study provides a better understanding of skeletal muscle fat replacement progression in the lower limb muscles of patients with LGMDR2, highlighting the influence of age at symptom onset, sex, and baseline motor function, which should be considered in the design and analysis of clinical trials. Although complex models improved the overall data fit, they did not improve the accuracy in identifying changes at a patient level, underlying the need for further research and validation and the fact that other variables we have not measured are probably influencing progression.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 4","pages":"e200283"},"PeriodicalIF":3.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Untangling Complexity in Dysferlinopathy With MRI Modeling of Disease Trajectory.","authors":"Jasper M Morrow","doi":"10.1212/NXG.0000000000200295","DOIUrl":"10.1212/NXG.0000000000200295","url":null,"abstract":"","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 4","pages":"e200295"},"PeriodicalIF":3.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Changes of Motor Function in Becker Muscular Dystrophy.","authors":"Luca Bello, Pietro Riguzzi, Giuliana Capece, Martina Penzo, Angela Petrosino, Elena Sogus, Sara Mastellaro, Michela Caroli, Matteo Villa, Daniele Sabbatini, Domenico Gorgoglione, Sara Vianello, Gianni Sorarù, Elena Pegoraro","doi":"10.1212/NXG.0000000000200285","DOIUrl":"10.1212/NXG.0000000000200285","url":null,"abstract":"<p><strong>Background and objectives: </strong>Becker muscular dystrophy (BMD) is due to <i>Duchenne muscular dystrophy</i> gene variants allowing partial expression of dystrophin. A detailed description of disease trajectories in different genetic subgroups, and the identification of factors predicting progressive vs stable disease, are indispensable for designing and interpreting current and future clinical trials.</p><p><strong>Methods: </strong>We recruited male participants with a molecularly confirmed diagnosis of BMD at our Institution, and followed them up with an observational longitudinal design with functional evaluations, including North Star Ambulatory Assessment (NSAA), 6-minute walk test, and timed function tests.</p><p><strong>Results: </strong>We recruited 107 participants. Time-to-event analyses of age at loss of ambulation estimated that only 25% of individuals with BMD lose ambulation by age 60 years. Functional measures, over a follow-up of a mean ± SD of 6.4 ± 3.5 evaluations per participant, and a time of 6.1 ± 3.6 years, showed a poor performance in the common deletions del 45-47 and del 45-48, and preserved muscle function with del 48 and deletions ending on exon 51. In the overall cohort, all measures declined significantly over time, but this decrease was more evident in genetic groups with more marked weakness, and in participants with baseline values of NSAA of 32/34 or lower.</p><p><strong>Discussion: </strong>These data refine genotype-phenotype correlations in BMD; quantify the decline in several practical and reliable motor outcome measures, which can be directly applied to power calculations for clinical trials; and point to useful inclusion/exclusion criteria for trials. Long-term outcomes will serve as a comparator for \"real-world\" efficacy data of upcoming therapeutics.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 4","pages":"e200285"},"PeriodicalIF":3.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144745541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition: Beyond <i>APOE</i>.","authors":"Vijay K Ramanan, Michael G Heckman, Ekaterina I Hofrenning, Scott A Przybelski, Jonathan Graff-Radford, Val J Lowe, Mary M Machulda, Melissa E Murray, Alicia Algeciras-Schimnich, Daniel J Figdore, David A Bennett, David S Knopman, Clifford R Jack, Ronald C Petersen, Owen A Ross, Prashanthi Vemuri","doi":"10.1212/NXG.0000000000200266","DOIUrl":"10.1212/NXG.0000000000200266","url":null,"abstract":"<p><strong>Background and objectives: </strong>The <i>APOE</i> (apolipoprotein E) ε4 allele is the strongest known genetic risk factor for sporadic Alzheimer disease (AD) and for brain amyloidosis, an early marker of disease pathophysiology. However, <i>APOE</i> ε4 is present in only 25% of the general population and is by itself inadequate for explaining susceptibility to amyloid accumulation or AD diagnosis. Existing studies have been limited by potential confounding due to inclusion of individuals carrying <i>APOE</i> ε4 or ε2 (which has a modest protective association). We hypothesized that genome-wide association study (GWAS) and genetic risk score (GRS) analyses in <i>APOE</i> ε3/ε3 individuals would uniquely identify novel predictors of β-amyloid pathology in older adults.</p><p><strong>Methods: </strong>We analyzed data from the Mayo Clinic Study of Aging (MCSA), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Rush Religious Orders Study and Memory and Aging Project. Frequency of <i>APOE</i> ε3/ε3 in those samples ranged from 48% to 61%. A GWAS was performed across 1,496 individuals with amyloid PET to identify candidate variants for GRS generation. Postmortem neuropathologic data (N = 710) were used to refine the variant list to capture high-likelihood true associations. An independent sample (N = 641) with plasma p-tau₁₈₁ data was used for validation.</p><p><strong>Results: </strong>The GWAS identified previously implicated (e.g., <i>PICALM</i> and <i>RBFOX1</i>) and novel potential associations with amyloid PET burden. A non-<i>APOE</i> GRS of top variants was strongly associated with amyloid PET levels in the MCSA (<i>p</i> = 4.34 × 10^-9, β = 5.88) and ADNI (<i>p</i> = 1.87 × 10^-8, β = 12.1) cohorts. In both cohorts, this non-<i>APOE</i> amyloid GRS outperformed a comparator GRS (based on variants associated with clinically diagnosed AD dementia risk) in explaining phenotypic variation. The non-<i>APOE</i> amyloid GRS was also associated with postmortem neuropathologic β-amyloid and neurofibrillary tangle burden and in an independent sample was associated with plasma p-tau₁₈₁ concentrations (a robust indicator of cerebral amyloidosis).</p><p><strong>Discussion: </strong>Our non-<i>APOE</i> amyloid GRS, which appropriately includes variants associated with amyloid deposition in <i>APOE</i> ɛ4/ɛ2 noncarriers, may advance personalized prediction of genetic susceptibility to β-amyloid accumulation within the large segment of the population that is <i>APOE</i> ε3/ε3. This may have future implications for risk modification, trial enrollment, and treatment selection.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 4","pages":"e200266"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Valosin-Containing Protein Multisystem Proteinopathy and Myopathology.","authors":"Werner Stenzel, Hans H Goebel","doi":"10.1212/NXG.0000000000200290","DOIUrl":"10.1212/NXG.0000000000200290","url":null,"abstract":"","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 4","pages":"e200290"},"PeriodicalIF":3.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12270490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscle Biopsy Findings in Valosin-Containing Protein Multisystem Proteinopathy.","authors":"Marianela Schiava, Yolande Parkhurst, Matthew Henderson, Tuomo Polvikoski, Manouela V Valtcheva, Ichizo Nishino, Michio Inoue, Yukako Nishimori, Yoshihiko Saito, Tanya Stojkovic, Rocio N Villar-Quiles, Norma Beatriz Romero, Teresinha Evangelista, Edoardo Malfatti, Sarah Souvannanorath, Elena Pegoraro, Pietro Riguzzi, Mauro Monforte, Sara Bortolani, Eleonora Torchia, Mario Sabatelli, Giorgio Tasca, Volker Straub, Chiara Marini-Bettolo, Michela Guglieri, Hakan Cetin, Ellen Gelpi, Sigrid Klotz, Jan L De Bleecker, Alicia Alonso-Jimenez, Jonathan Baets, Willem De Ridder, Peter De Jonghe, Kristl G Claeys, Dietmar Rudolf Thal, Jorge A Bevilacqua, Sushan Luo, Wenhua Zhu, Jie Lin, George Papadimas, Constantinos Papadopoulos, Eleni Zamba-Papanicolaou, Sophia Xirou, Endre Pal, Carmelo Rodolico, Anna Kostera-Pruszczyk, Biruta Kierdaszuk, Anna Kaminska, Nuria Muelas, Juan Jesus Vilchez, Cristina Domínguez-González, Aurelio Hernandez-Lain, Jorge Alonso-Perez, Velina Nedkova-Hristova, Carlos Aledo, Anders Oldfors, Umesh A Badrising, Hani Kushlaf, Thomas E Lloyd, Chiseko Ikenaga, Lindsay N Alfano, Colin C Quinn, David Walk, Matthias Vorgerd, Conrad Weihl, Montse Olivé, Jordi Diaz-Manera","doi":"10.1212/NXG.0000000000200265","DOIUrl":"10.1212/NXG.0000000000200265","url":null,"abstract":"<p><strong>Background and objectives: </strong>Valosin Containing Protein-associated multisystem proteinopathy (VCP-MSP) is a progressive, autosomal dominant disorder caused by pathogenic variants in the VCP gene, resulting in a heterogeneous clinical presentation. Muscle biopsy findings are characteristic but not pathognomonic. This study aimed to comprehensively analyse VCP-related myopathology and explore correlations with clinical phenotypes, genetic variants, and disease progression.</p><p><strong>Methods: </strong>Muscle biopsy images and data were collected retrospectively from adults (≥18 years) with pathogenic or likely pathogenic VCP variants enrolled in the VCP Multicentre International Study. Biopsy data were standardized using the \"Common Data Elements for Muscle Biopsy Reporting.\" Variations in biopsy findings were analysed by biopsy site, time from disease onset, the four most common VCP variants, and clinical phenotypes.</p><p><strong>Result: </strong>A total of 112 muscle biopsies were included. Most individuals were male (66.0%). The mean age at biopsy was 53.3 years (SD 10.0), with a mean disease duration of 6.5 years (SD 4.5). The most frequent VCP variant was c.464G>A (p.Arg155His) (18.8%). The top clinical phenotypes were isolated myopathy (37.5%), myopathy with Paget disease of bone (17.9%), and myopathy with motor neuron involvement (13.4%). The vastus lateralis was the most common biopsy site (34.8%), and 91% were open biopsies. Histopathologic findings included atrophic fibres (87.5%), rimmed vacuoles (72.3%), endomysial fibrosis (58.0%), and protein aggregates (51.8%), primarily p62 (60.3%) and VCP (36.2%). Degeneration niches with fibrofatty replacement and atrophic fibres were seen in 33.3% of biopsies without frequency differences by clinical phenotypes. There were no differences in biopsy findings among the 4 most common VCP gene variants, except for the absence of degeneration niches in muscle biopsies of 12 patients with c.277C>T (p.Arg93Cys). MRI data from 30 patients showed fat pockets corresponding to these niches and STIR hyperintensity correlated with inflammatory infiltrates in 42.9%. Concordance between clinical phenotype, biopsy, and neurophysiology was observed in only 49.4% of cases, indicating significant heterogeneity.</p><p><strong>Discussion: </strong>VCP-MSP muscle biopsies consistently show myopathic or mixed patterns with rimmed vacuoles and p62/VCP-positive inclusions, regardless of clinical phenotype, age, or progression. Some lack vacuoles, challenging diagnosis. Discrepancies between clinical, neurophysiology, and biopsy findings should prompt consideration of VCP-MSP to improve detection and management.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 4","pages":"e200265"},"PeriodicalIF":3.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12270496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype-Phenotype Association for 14 <i>GFAP</i> Variants in Alexander Disease.","authors":"Albee Messing, Amy Tara Waldman, Daniel M Bolt","doi":"10.1212/NXG.0000000000200270","DOIUrl":"10.1212/NXG.0000000000200270","url":null,"abstract":"<p><strong>Background and objectives: </strong>Alexander disease is a rare monogenic disorder caused by dominant variants in <i>GFAP</i> (glial fibrillary acidic protein). Over 180 variants have been associated with the disease, with a wide spectrum of severity and clinical manifestations. Previous attempts at genotype-phenotype correlations have been hampered by the small numbers of cases that have been published for many of the variants. We sought to determine whether genotype-phenotype correlations could be discerned from available information.</p><p><strong>Methods: </strong>We compiled a list of variants in <i>GFAP</i> for which 7 or more unrelated cases had been either published or identified through an ongoing natural history study and other sources (with a closing date of July 27, 2024). For each of these cases, we tabulated age at onset, age at death (or last contact), and sex. We used a Kruskal-Wallis test to evaluate statistical differences in age at onset in relation to variant. Differences in survival across variants were studied using Kaplan-Meier curves.</p><p><strong>Results: </strong>Fourteen variants met our criteria for detailed analysis (10 with 7 or more unrelated cases and 4 additional variants involving 2 of the most commonly affected amino acids, R79 and R239) derived from a total of 231 cases. The variants seem to fall into 3 distinct groups-some with consistent early onsets (N77S, R79C and R79L, and most of the R239s), some with consistent late onsets (R70W and N386S), and some with more variable onsets (R416W). Pairwise comparison results found that R239H was associated with significantly earlier onsets than R239C. We found similar groupings for survival. Finally, we evaluated sex as a potential modifying factor for either age at onset or survival but found no significant association.</p><p><strong>Discussion: </strong>Genotype-phenotype correlations do exist in Alexander disease, at least for a limited number of GFAP variants for which sufficient numbers of individual cases can be identified to allow valid statistical analysis.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 3","pages":"e200270"},"PeriodicalIF":3.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144303360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum: The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.","authors":"Allison A Dilliott, Maria C Costanzo, Sara Bandres-Ciga, Cornelis Blauwendraat, Bradford Casey, Quy Hoang, Hirotaka Iwaki, Dongkeun Jang, Jonggeol Jeffrey Kim, Hampton L Leonard, Kristin S Levine, Mary Makarious, Trang T Nguyen, Guy A Rouleau, Andrew B Singleton, Patrick Smadbeck, J Solle, Dan Vitale, Mike Nalls, Jason Flannick, Noël P Burtt, Sali M K Farhan","doi":"10.1212/NXG.0000000000200273","DOIUrl":"10.1212/NXG.0000000000200273","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1212/NXG.0000000000200246.].</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 3","pages":"e200273"},"PeriodicalIF":3.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}