Neurology-Genetics最新文献

{"title":"Post-Traumatic Headache in Children and Genetic Risk of Migraine: An Observational Cohort Study.","authors":"Serena L Orr, Andrew D Hershey, Brad G Kurowski, Lisa Marie Langevin, Lisa J Martin, Valentina Pilipenko, Ken Tang, Miriam H Beauchamp, William R Craig, Quynh Doan, Roger Zemek, Keith O Yeates","doi":"10.1212/NXG.0000000000200371","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200371","url":null,"abstract":"<p><strong>Background and objectives: </strong>To examine the association between genetic risk of migraine and post-traumatic headache (PTH) in children.</p><p><strong>Methods: </strong>This is a secondary analysis of a cohort study that recruited children aged 8-17 years within 48 hours of concussion or orthopedic injury (OI) from 5 pediatric emergency departments and followed them for 6 months. Genetic risk of migraine was estimated through (1) family history of migraine, (2) polygenic risk scores (PRSs), and (3) forty individual single-nucleotide polymorphisms (SNPs). PTH was categorized as: no PTH (no PTH), PTH nonmigraine phenotype (PTH-NM), or PTH migraine phenotype. Ordinal regression models with cluster-adjusted standard errors and restricted cubic splines were used to estimate associations between genetic risk of migraine and increasing severity of PTH (no PTH vs PTH-NM vs PTH migraine phenotype), adjusting for injury type (concussion vs OI), age, sex, time since injury, first principal component, deprivation indices, concussion history, and preinjury headache history.</p><p><strong>Results: </strong>The sample included 646 children (median [interquartile range] age = 12.38 [10.52-14.41] years, including 436 (67.5%) with concussion. Family history of migraine was associated with increasing severity of PTH in 2/5 models (rs7684253 model: χ² = 3.99, df = 1, <i>p</i> = 0.046; rs75002882 model: χ² = 4.02, df = 1, <i>p</i> = 0.045), while migraine PRS was not (χ² = 12.95, df = 12, <i>p</i> = 0.373). Four SNPs were associated with increasing severity of PTH (rs13078967: χ² = 103.87, df = 6, <i>p</i> < 0.001; rs7684253: χ² = 12.90, df = 6, <i>p</i> = 0.045; rs2160875: χ² = 17.35, df = 6, <i>p</i> = 0.008; and rs75002882: χ² = 291.79, df = 6, <i>p</i> < 0.001) and 2 remained significant after Bonferroni correction (rs13078967 and rs75002882).</p><p><strong>Discussion: </strong>Four migraine susceptibility genetic variants were associated with PTH, as was family history of migraine in some models, but a migraine PRS was not.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"12 2","pages":"e200371"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147624359","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":"Quantitative Measurement of Glycosylated ⍺-Dystroglycan as a Biomarker for Disease Severity in Limb-Girdle Muscular Dystrophy Type 2I/R9.","authors":"John Vissing, Tahseen Mozaffar, Nicholas E Johnson, Katherine D Mathews, Matthew P Wicklund, Conrad Weihl, Doris G Leung, Jeffrey M Statland, Peter B Kang, Carla D Zingariello, Linda Pax Lowes, Urvi Desai, Kameron Bates, Lindsay N Alfano, Han Xie, Jessica St Romain, Tricia Blankenbiller, George McLendon, Thulashitha Rajasingham, Marjet Heitzer, Alyssa X Wu-Zhang, Kenneth Tripp, Hector M Rodriguez, Douglas Sproule","doi":"10.1212/NXG.0000000000200370","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200370","url":null,"abstract":"<p><strong>Background and objectives: </strong>Limb-girdle muscular dystrophy type 2I (LGMD2I/R9) is caused by biallelic variants in the gene for Fukutin-related protein (FKRP), an enzyme required for proper glycosylation of α-dystroglycan (⍺DG), a critical structural protein of the dystrophin glycoprotein complex. Hypoglycosylation of αDG results in impaired function of αDG, which in turn leads to chronic myocyte injury and muscular dystrophy. The \"Biomarker Development in LGMD2I/R9\" (MLB-01-001) natural history study explored glycosylated ⍺DG as a muscle biomarker for LGMD2I/R9 to support clinical trial design for the development of potential therapeutics.</p><p><strong>Methods: </strong>MLB-01-001 was a prospective, 12-month observational study of clinically affected participants 10-65 years of age with genetically confirmed LGMD2I/R9 at 11 academic centers in the United States and Denmark. Tibialis anterior (TA) muscle biopsies were obtained at baseline, month 6, month 9, and/or month 12 and measured for glycosylated ⍺DG levels relative to that of an unaffected human control using a validated, quantitative western blot assay.</p><p><strong>Results: </strong>Of 96 participants enrolled, 71 participants underwent at least 1 TA biopsy (54 homozygous for the c.826C>A variant and 17 with other <i>FKRP</i> genotypes). Participants who were homozygous for the c.826C>A variant tended to be older, to be composed of a higher percentage of females, to have had less time since diagnosis, and to be composed of a greater percentage of ambulatory participants than those who had other <i>FKRP</i> genotypes. Glycosylated ⍺DG levels were consistently lower in LGMD2I/R9 participants than in the control at baseline (median 8.5% of control, interquartile range [IQR] 10.8%) and reflected disease severity by genotype, with c.826C>A homozygotes showing higher median glycosylated ⍺DG levels (10.5% of control, IQR 10.9%, n = 54) than participants with other <i>FKRP</i> genotypes (4.6% of control, IQR 4.3%, n = 17). Glycosylated αDG levels remained stable over 6-12 months.</p><p><strong>Discussion: </strong>Glycosylated ⍺DG was consistently lower in participants with LGMD2I/R9 than in the unaffected control, reflected disease severity by genotype, and remained stable over 6-12 months, suggesting that it may be an appropriate biomarker for assessing the effect of potential therapies for LGMD2I/R9.</p><p><strong>Trial registration information: </strong>ClinicalTrials.gov ID NCT04202627, first posted 17 Dec 2019.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"12 2","pages":"e200370"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147624371","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":"Neurogenetics and <i>Neurology® Genetics</i>: Worlds Ever-Expanding.","authors":"Peter B Kang","doi":"10.1212/NXG.0000000000200355","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200355","url":null,"abstract":"","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"12 2","pages":"e200355"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13049554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147624268","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":"Toward Trial Readiness in Congenital Myotonic Dystrophy: A Longitudinal Cohort Study of Predictors of Motor Function in Childhood.","authors":"Michael Kiefer, Julia M Hartman, Kiera N Berggren, Amanda Butler, Aileen S Jones, Melissa McIntyre, Man Hung, Samuel Carrell, Melissa A Hale, Craig Campbell, Valeria Ada Sansone, Nicholas E Johnson","doi":"10.1212/NXG.0000000000200363","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200363","url":null,"abstract":"<p><strong>Background and objectives: </strong>Congenital myotonic dystrophy (CDM) is a life-limiting genetic disorder present at birth, marked by profound motor and cognitive impairments. CDM is the most severe form of myotonic dystrophy type 1 (DM1), both caused by a cytosine-thymine-guanine (CTG) repeat expansion in the DM1 protein kinase gene. Clinical trials targeting the shared disease mechanism in DM1 adults have shown promise. However, a lack of validated clinical end points in early childhood and a limited understanding of the variable disease progression are challenges to trial design in CDM. This longitudinal cohort study identifies predictors of motor function in children with CDM to inform future clinical trials.</p><p><strong>Methods: </strong>Children with genetically confirmed CDM participated in a longitudinal natural history study, completing annual motor assessments, including the 10-m walk/run (10MWRT), 6-minute walk test, supine to stand, and grip strength. Perinatal clinical features and early childhood motor milestone achievement were captured through caregiver proxy report. Linear mixed-effects models were used to evaluate predictors of concurrent motor performance and 1-year change. The relationship between [MBNL]_inferred, a biomarker of splicing dysregulation, and the achievement of motor milestones was evaluated in a subset of participants who provided muscle biopsy samples.</p><p><strong>Results: </strong>A total of 138 visits from 42 children with CDM aged 3.0-15.3 years were included in the analysis. Motor performance on all motor outcomes improved with age. In age-adjusted models, age at independent walking explained more variance in 10MWRT times (<i>R</i> ² = 0.31, β = 0.2, <i>p</i> = 0.003) than CTG repeats_per100 (<i>R</i> ² = 0.25, β = 0.2, <i>p</i> = 0.018). Baseline motor function was the strongest predictor of 1-year change across all outcomes, with lower baseline performance associated with greater improvement. More severe splicing dysregulation during adolescence was associated with later age at independent walking (rho = -0.708, <i>p</i> = 0.001).</p><p><strong>Discussion: </strong>The severity of clinical course in infancy and age of independent walking are key predictors of motor function across childhood in CDM. However, baseline motor performance is the strongest predictor of 1-year change and should be a central consideration in clinical trial design. Larger, prospective studies are needed to assess the responsiveness of early motor milestones as indicators of treatment response.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"12 2","pages":"e200363"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147624426","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":"Assessment and Treatment of Cutaneous Neurofibromas in Neurofibromatosis Type 1: A Scoping Review.","authors":"Hadiya Abdalla Elahmar, Carlos Alberto Soto Rincon, Aaron Drucker, Patricia Parkin, Carolina Barnett-Tapia","doi":"10.1212/NXG.0000000000200372","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200372","url":null,"abstract":"<p><strong>Purpose of review: </strong>Cutaneous neurofibromas (cNFs) are a hallmark feature of neurofibromatosis type 1 (NF1) and are associated with substantial physical, psychosocial, and quality-of-life burden. Progress in therapeutic development is hindered by the absence of validated, feasible, and responsive tools for quantifying cNFs and assessing their clinical effect and treatment response. This scoping review aimed to identify and summarize existing methods used to measure and quantify cNFs, evaluate their effect on health-related quality of life (HRQoL), and assess outcome measures used in cNF treatment studies.</p><p><strong>Recent findings: </strong>A comprehensive search of 6 electronic databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Clinical Trials Registry Platform) from inception to April 2025 identified 1,916 records, of which 61 articles met inclusion criteria (48 primary studies and 13 review articles). Eight studies evaluated instruments for cNF measurement, while 5 assessed HRQoL using patient-reported outcomes (PROs). A greater cNF burden, particularly an increased number, size, and facial involvement, was consistently associated with poorer HRQoL. Among identified PROs, the cNF-Skindex was the only tool specifically developed for cNFs. Twenty-three studies investigated therapeutic interventions, and 12 registered clinical trials evaluated medical or surgical treatments. Considerable heterogeneity was observed in outcome selection, with many studies lacking clearly defined end points or relying on nonvalidated or inconsistently applied measures.</p><p><strong>Summary: </strong>This scoping review highlights the availability of several methods to quantify cNFs; however, their clinical feasibility, responsiveness, and interpretability remain limited. Outcome measures used across cNF intervention studies are highly variable, impeding comparison across studies and synthesis of evidence. The cNF-Skindex represents a promising cNF-specific HRQoL instrument but requires further validation, including assessment of responsiveness and minimal important difference thresholds. Standardization of cNF measurement approaches and outcome selection is urgently needed to support robust clinical trials and enable meaningful evaluation of treatment efficacy in NF1.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"12 2","pages":"e200372"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147624320","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":"Expanding the Clinicoradiologic Phenotype of the <i>CTSA</i>-Associated Small Vessel Disease CARASAL: A Comparison With CADASIL.","authors":"Minne N Cerfontaine, Gido Gravesteijn, Remco J Hack, Benno Gesierich, Mark C Kruit, Ido R Van Den Wijngaard, Irene C Notting, Esther A R Nibbeling, Marianna Bugiani, Marjo S van der Knaap, Camiel J F Boon, Marco Duering, Julie W Rutten, Saskia A J Lesnik Oberstein","doi":"10.1212/NXG.0000000000200358","DOIUrl":"10.1212/NXG.0000000000200358","url":null,"abstract":"<p><strong>Background and objectives: </strong>Genetic small vessel diseases (SVDs) are associated with early onset of stroke and dementia. Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) is an extremely rare genetic SVD caused by a single heterozygous <i>CTSA</i> variant, which can mimic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common genetic SVD. In this study, we describe a series of patients with CARASAL and compare stroke subtypes and radiologic features with those of patients with CADASIL.</p><p><strong>Methods: </strong>Twenty-one patients with CARASAL were included from 3 pedigrees; 7 participated in a prospective genetic SVD cohort study, and for 14, data were collected retrospectively. Clinical characteristics were assessed, and 2 analyses of neuroimaging outcomes were performed: (1) a comparison between patients with CARASAL (n = 7) and age- and sex-matched patients with CADASIL (n = 28) and (2) a comparison between patients with CARASAL and normalized white matter hyperintensity volume (nWMHv)-matched patients with CADASIL (n = 28). Enophthalmos in patients with CARASAL was investigated and quantified on MRI.</p><p><strong>Results: </strong>Stroke patients with CARASAL (n = 9) had variable stroke subtypes, including subcortical stroke (n = 3/9), cortical stroke (n = 4/9), and (fatal) intracerebral hemorrhage (n = 4/9). Total nWMHv was higher in patients with CARASAL than in those with CADASIL (mean difference: 5.0% of intracranial volume, 95% CI [2.0-8.0], <i>p</i> = 0.0007). Compared with nWMHv-matched patients with CADASIL, patients with CARASAL had higher pontine nWMHv (mean rank difference: 25.5, <i>p</i> = 0.0019), but fewer lacunes and a higher brain parenchymal fraction (both <i>p</i> < 0.05). Overall, 13 of 14 patients with CARASAL had an enophthalmos, with reduced volumes of the extraocular rectus muscles and intraorbital fat, and an \"orbital check-mark sign\" on MRI.</p><p><strong>Discussion: </strong>Stroke in CARASAL is heterogeneous, suggesting that CARASAL-specific guidelines for stroke management are warranted. The high white matter hyperintensity lesion load, including the pons, in combination with the orbital check-mark sign, can serve as radiologic clues for the diagnosis of CARASAL.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"12 2","pages":"e200358"},"PeriodicalIF":3.7,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13020558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576041","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":"Clinical Trial Designs for Rare Disorders: A Scoping Review of the Effectiveness of Pharmacologic Interventions in Fragile X Syndrome.","authors":"Adam Van Steenbergen, Manpreet Kaur, Keneizha Rubanarayana, Francois Bolduc","doi":"10.1212/NXG.0000000000200373","DOIUrl":"10.1212/NXG.0000000000200373","url":null,"abstract":"<p><strong>Purpose of review: </strong>Rare disorders (RDs) collectively affect a substantial proportion of the population, yet most lack clinically approved, mechanistically targeted therapies. Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and a major genetic contributor to autism spectrum disorder, exemplifies this gap. Despite more than 3 decades of preclinical research and numerous pharmacologic clinical trials informed by disease mechanisms, no targeted therapy for FXS has received regulatory approval. This scoping review aims to evaluate the design characteristics, outcome measures, and reported effect sizes of pharmacologic clinical trials in FXS to highlight methodological limitations that may have hindered the accurate assessment of therapeutic efficacy in FXS and to inform future trials in RDs.</p><p><strong>Recent findings: </strong>We conducted a scoping review of published interventional studies involving individuals with FXS, identified through searches of PubMed, Excerpta Medica Database (EMBASE), PsycINFO, and CENTRAL. Eligible studies were pharmacologic trials that reported sufficient statistical information to calculate effect sizes for recurrent behavioral outcome measures. 23 trials met inclusion criteria, comprising 14 placebo-controlled randomized controlled trials (RCTs) and 9 open-label studies, with a total of 1,469 participants. Recurrent outcome measures included the Aberrant Behavior Checklist (the FXS-specific ABC-Cfx), the Clinical Global Impressions-Improvement scale, the Vineland Adaptive Behavior Scales-Second Edition (VABS-II), and the Visual Analog Scale (VAS) for Anxiety (VAS Anxiety). The median absolute effect sizes were small among RCTs (|d| = 0.22) and moderate among open-label studies (|d| = 0.70). Across studies, substantial heterogeneity was observed in trial design, sample size, participant characteristics, and outcome measures, complicating cross-trial comparisons and interpretation of efficacy signals.</p><p><strong>Summary: </strong>Collectively, existing pharmacologic trials in FXS have demonstrated limited and inconsistent treatment effects, with interpretation constrained by small sample sizes, heterogeneity in designs and outcome measures, and differences in participant characteristics. Greater standardization of trial design and outcome assessment, improved alignment between outcome measures and treatment mechanisms, and careful consideration of participant stratification are critical to improving signal detection in future trials. These insights have broader relevance for RD research, where methodological rigor is essential to translating promising mechanisms into effective therapies.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"12 2","pages":"e200373"},"PeriodicalIF":3.7,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13016380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147522560","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":"Expanding the <i>AFG3L2</i> Spectrum: A Link to Axonal Neuropathy.","authors":"Alessandra Rocco, Christian Laurini, Yuri Matteo Falzone, Silvia Calzavara, Ubaldo Del Carro, Stefano Carlo Previtali, Francesca Maltecca","doi":"10.1212/NXG.0000000000200368","DOIUrl":"10.1212/NXG.0000000000200368","url":null,"abstract":"<p><strong>Objectives: </strong>The <i>AFG3L2</i> gene encodes a mitochondrial AAA-protease involved in inner mitochondrial membrane (IMM) proteostasis. Heterozygous variants in the AFG3L2 proteolytic domain cause Spinocerebellar Ataxia type 28, heterozygous variants in the AFG3L2 ATPase domain cause Optic Atrophy type 12, while biallelic variants lead to recessive Spastic Ataxia type 5. In this study, we aimed to investigate the link between <i>AFG3L2</i> haploinsufficiency and Charcot-Marie-Tooth (CMT) phenotypes.</p><p><strong>Methods: </strong>We performed clinical evaluation, genetic analyses, electrophysiology, and functional studies in 1 patient's fibroblasts.</p><p><strong>Results: </strong>In this study, we report a patient presenting with progressive symmetric distal muscle atrophy, weakness, <i>pes cavus</i>, and sensory deficits at lower limbs, in the absence of cerebellar or pyramidal signs. Electrophysiologic studies confirmed axonal sensorimotor neuropathy. After excluding common CMT-related genes, clinical exome sequencing revealed a heterozygous truncating variant in <i>AFG3L2</i> [NM_006793.3:c.121C > T; p.(Arg41*)]. In patient's fibroblasts, we observed ∼50% reduction in AFG3L2 protein levels, which is sufficient to hyperactivate the stress-sensitive IMM protease OMA1. Consequently, we detected increased OPA1 processing, mitochondrial shortening, and activation of the integrated stress response.</p><p><strong>Discussion: </strong>These findings suggest that <i>AFG3L2</i> haploinsufficiency can underlie axonal CMT, expanding the clinical spectrum of <i>AFG3L2</i>-related diseases and emphasizing its potential inclusion in CMT diagnostic panels.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"12 2","pages":"e200368"},"PeriodicalIF":3.7,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13010279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147516026","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":"The Genetics of TDP-43 Type C Neurodegeneration: A Whole-Genome Sequencing Study and Literature Review.","authors":"Malik Nassan, Ivan Ayala, Jennifer Sloan, Anna Bonfitto, Bobbi Stark, Serena Song, Marcus Naymik, Changiz Geula, Tamar Gefen, Elena Barbieri, Ignazio Piras, M-Marsel Mesulam, Matthew Huentelman","doi":"10.1212/NXG.0000000000200369","DOIUrl":"10.1212/NXG.0000000000200369","url":null,"abstract":"<p><strong>Background and objectives: </strong>Frontotemporal lobar degeneration TDP43 type C (TDP-C) is a rare and unique neurodegenerative disease that attacks the anterior temporal lobe. Recently, it was shown that Annexin-A11 and TDP-43 coaggregate specifically in TDP-C. Current literature on the genetic associations with TDP-C, reviewed here, lacks a discernible corpus of robust or replicated findings. In this study, using blood tissue, we completed whole genome sequencing to investigate <i>ANXA11</i> and <i>TARDBP</i> genetic variants for their association with TDP-C. Then, we completed genome-wide hypothesis-free analyses using artificial intelligence to identify rare pathogenic variants associated with TDP-C.</p><p><strong>Methods: </strong>(1) We tested common variants in <i>ANXA11</i> and <i>TARDBP</i> for their association with 37 TDP-C cases vs 290 controls. We attempted to replicate our findings in a different cohort of 467 TDP-C cases vs 3,153 controls and contrasted them with cohorts of TDP-A and TDP-B. (2) AI-guided analyses were completed to prioritize pathogenic rare variants associated with TDP-C in our cohort.</p><p><strong>Results: </strong>(1) Four common variants in <i>ANXA11</i> (rs113772135, rs2789686, rs1079242, rs61860017) were significantly associated with TDP-C in the discovery cohort and replicated in the other cohort of TDP-C but not in TDP-A or TDP-B, providing evidence for <i>ANXA11</i> specific association with TDP-C. Rs1079242-A showed the most robust replication (<i>p</i> = 7.35 × 10^-05) and correlates with higher ANXA11 level in CSF (<i>p</i> = 4 × 10^-11). No associations were found between <i>TARDBP</i> and TDP-C (<i>p</i> > 0.05). Using AI-guided rare variant analyses, we identified a pathogenic variant in <i>FIG4</i>, a gene that has been implicated in amyotrophic lateral sclerosis (ALS). Because of the observed potential genetic overlap between some ALS genes and TDP-C, we leveraged mendelian randomization and found that ALS genetic load is associated with TDP-C risk (<i>p</i> = 0.0046).</p><p><strong>Discussion: </strong>This study provides replicated evidence for the association between common variants in <i>ANXA11</i> with TDP-C. Knowing rs1079242-A affects ANXA11 level in CSF, future studies may aim to investigate ANXA11 level as potential CSF biomarker for TDP-C. Moreover, <i>FIG4 and ANXA11</i> have been implicated in the inositol pathway. Our results provide novel insights into the genetic risk of TDP-C and offer new clues about its underpinning mechanisms.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"12 2","pages":"e200369"},"PeriodicalIF":3.7,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13010282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147515992","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":"Utility of 18F-FDG PET/CT in the Surveillance of Patients With Neurofibromatosis Type 1.","authors":"Maria Gabriela Tanase, Lina Djilani, Remy Lamontagne, Rahma Derbel, Mathilde Baril, Vincent Roy, Mathieu Blais, François-Alexandre Buteau, Hélène T Khuong, Francois Gros-Louis, Manon Leclerc, Nicolas Dupre","doi":"10.1212/NXG.0000000000200361","DOIUrl":"10.1212/NXG.0000000000200361","url":null,"abstract":"<p><strong>Background and objectives: </strong>Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that predisposes affected individuals to benign and malignant tumors throughout their lifetime. Early detection of those lesions is critical for effective management. PET/CT with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) has emerged as a potentially efficient modality for detecting malignant tumors in patients with NF1. The aim of this study was to investigate this hypothesis by assessing the presence of incidental findings of malignant and potentially malignant tumors using ¹⁸F-FDG PET/CT in an adult NF1 cohort.</p><p><strong>Methods: </strong>In this retrospective observational study, clinical data were collected from medical records, including sex, age, family history, clinical manifestations, and tumor diagnosis. Data on imaging and diagnostic modalities that led to the diagnosis of NF1-related tumors or other malignant and potentially malignant tumors were collected. These modalities included ¹⁸F-FDG PET/CT, MRI, CT, mammography, scintigraphy, and pathology reports.</p><p><strong>Results: </strong>A total of 79 adult patients with NF1 were included in this study, comprising 29 male and 50 female patients, all of whom had received an NF1 diagnosis. Of these, 51 patients (64.6%) underwent a ¹⁸F-FDG PET/CT scan during their follow-up. A total of 31 malignant or potentially malignant tumors were diagnosed in addition to 2 pheochromocytomas and 24 gliomas. Notably, ¹⁸F-FDG PET/CT scans incidentally detected 12 significant findings: 4 gastrointestinal stromal tumors, 3 carcinomas and premalignant tumors of the thyroid gland, 2 malignant peripheral nerve sheath tumors, 1 serous borderline ovarian tumor, 1 testicular seminoma, and 1 pheochromocytoma. Most incidental findings required surgery and could have significantly affected disease management if diagnosed at a later stage.</p><p><strong>Discussion: </strong>In this cohort of 79 adult patients with NF1, ¹⁸F-FDG PET/CT proved as a valuable complementary imaging modality to conventional imaging by enabling the detection of incidental malignant or potentially malignant tumors. Our results highlight ¹⁸F-FDG PET/CT's beneficial impact on disease management by suggesting that the incorporation of ¹⁸F-FDG PET/CT into screening protocols could improve early detection of NF1-related cancers in asymptomatic adults, potentially offering early treatment options to improve clinical outcomes.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"12 2","pages":"e200361"},"PeriodicalIF":3.7,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147516033","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}