Neurology-Genetics最新文献

{"title":"Spectrum of Phenotypes in SMA Patients With 4 <i>SMN2</i> Copies in the French Population: Registre SMA France.","authors":"Lorène Gerin, Juliette Ropars, Rocío Garcia-Uzquiano, Marta Gómez-García De la Banda, Pascale Saugier-Veber, Isabelle Desguerre, Emmanuelle Salort-Campana, Caroline Espil, Christine Barnerias, Vincent Laugel, Claude Cances, Frederique Audic, Pascal Cintas, Laure Le Goff, Martial Mallaret, Marie-Christine Nouguès, Séverine Drunat, Céline Tard, Lamiae Grimaldi, Susana Quijano-Roy","doi":"10.1212/NXG.0000000000200222","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200222","url":null,"abstract":"<p><strong>Background and objectives: </strong>Clinical phenotype and course of individuals with 4 copies of the <i>SMN2</i> gene are insufficiently described, and presymptomatic treatment remains controversial.</p><p><strong>Methods: </strong>This is a cohort study that analyzed data from SMA patients with zero SMN1 and 4 SMN2 copies collected in the \"Registre SMA France\" to describe epidemiology, clinical presentation, and course.</p><p><strong>Results: </strong>A total of 140 of 1,112 patients with SMA carried 4 <i>SMN2</i> copies (16% of those with available <i>SMN2</i> copy number). The median age at onset was 3.5 years (6 months-20 years), and the median follow-up was 32 years. Twelve patients (8.6%) did not walk independently (SMA2). Of them, most were able to stand or walk with support (72%). Independent walking was acquired in 91% (123 SMA3, 5 SMA4), and one-third of them lost this ability (median 16 years). Loss of ambulation was significantly earlier in children with onset before 3 years (SMA3a). There was a significant predominance of male participants in the whole cohort (63%) and in subcohorts (SMA2, 83%; SMA3, 61%; adult population, 68%). There was a significant lower risk for female participants to lose ambulation (<i>p</i> = 0.01). Sixty-five percent of patients used a wheelchair. Scoliosis surgery and ventilation were required in less than 15%.</p><p><strong>Discussion: </strong>Most SMA patients with 4 <i>SMN2</i> copies in the French population show an onset during childhood and a progressive course with absence or loss of ambulation before adulthood. Presymptomatic treatment seems an acceptable option to consider, although identification of individual pejorative markers of early or severe phenotypes would allow more targeted approaches. Our results and literature suggest a gender effect in this population.</p><p><strong>Trial registration information: </strong>NCT04177134.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 2","pages":"e200222"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051335","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 and Neuropsychological Phenotyping of Individuals With Somatic Variants in Neurodevelopmental Disorders.","authors":"Alisa Mo, Christopher A Walsh","doi":"10.1212/NXG.0000000000200254","DOIUrl":"10.1212/NXG.0000000000200254","url":null,"abstract":"<p><strong>Background and objectives: </strong>Somatic variants in brain-related genes can cause neurodevelopmental disorders, but detailed characterizations of their clinical phenotypes, neurobehavioral profiles, and comparisons with individuals with germline variants are limited.</p><p><strong>Methods: </strong>Using data from the Simons Searchlight natural history cohort, which uses standardized parent-report data collection methods, we identified individuals with neurodevelopmental disorders caused by pathogenic somatic variants and examined their phenotypic data. We further used results from standardized measurements of adaptive functioning, social behavior, and emotional and behavioral problems to compare individuals with somatic variants with those with germline variants.</p><p><strong>Results: </strong>We identified 15 probands with pathogenic or likely pathogenic somatic variants in the Simons Searchlight cohort. For 8 individuals with detailed phenotype information, symptoms included developmental delay or language delay (n = 8), hypotonia (n = 5), autism spectrum disorder (n = 4), and epilepsy (n = 3). Individuals with mosaic variants showed a range of severity in their scores on standardized measurements of adaptive functioning, social behavior, and emotional and behavioral problems. In particular, some individuals with mosaic variants showed impairments that were similar in severity or more severe compared with individuals with germline variants in the same gene.</p><p><strong>Discussion: </strong>This study improves our understanding of the clinical phenotypes and neuropsychological profiles of individuals with mosaic pathogenic variants in neurodevelopmental disorders.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 2","pages":"e200254"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781636","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 Second Decade of <i>Neurology® Genetics</i> Beckons.","authors":"Peter B Kang","doi":"10.1212/NXG.0000000000200247","DOIUrl":"10.1212/NXG.0000000000200247","url":null,"abstract":"","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 1","pages":"e200247"},"PeriodicalIF":3.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11820806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411236","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":"Women With Genetic Epilepsies.","authors":"Paula T Marques, Nagham Kaka, Quratulain Zulfiqar Ali, Marlene Rong, Esther Bui, Danielle M Andrade","doi":"10.1212/NXG.0000000000200233","DOIUrl":"10.1212/NXG.0000000000200233","url":null,"abstract":"<p><p>Some epilepsy syndromes are more common in female individuals. Often, these syndromes have an underlying genetic variant involving the X chromosome that is typically lethal in male individuals, resulting in a higher female prevalence. However, some of the idiopathic generalized epilepsies such as juvenile myoclonic epilepsy are conditions with complex inheritance, with thousands of variants in genes throughout the genome. But they can also have a predominance in female individuals. In this study, we performed a narrative review of PubMed and Scopus using the following entries: \"epilepsy in women,\" \"genetic epilepsy in female individuals,\" \"epilepsy genetics in women,\" \"female-specific epilepsy genetics,\" \"epilepsy and genetic mutations in female individuals.\" The findings were synthesized and described according to clinical characteristics, underlying genetic mechanisms, and treatment considerations for these epilepsy syndromes manifesting largely in female individuals. The epilepsy syndromes reviewed here include Rett syndrome, <i>CDKL5</i> deficiency disorder, <i>PCDH19</i>-related epilepsy, subcortical band heterotopia, periventricular heterotopia, Aicardi syndrome, and juvenile myoclonic epilepsy. Recognizing these epilepsy syndromes and understanding their underlying genetic etiology helps provide a tailored treatment approach early in the course of the disease. It can also assist with genetic counselling for family members who plan to have children.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 1","pages":"e200233"},"PeriodicalIF":3.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11820811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411237","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":"Ten Years of <i>Neurology</i>® <i>Genetics</i>: Reflecting on the Past, Inspiring the Future.","authors":"Stefan M Pulst","doi":"10.1212/NXG.0000000000200252","DOIUrl":"10.1212/NXG.0000000000200252","url":null,"abstract":"","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 1","pages":"e200252"},"PeriodicalIF":3.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123913","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":"Mild Malformation of Cortical Development With Oligodendroglial Hyperplasia and Epilepsy: A Systematic Review.","authors":"Yixin Zhan, Shijia Chen, Zhenghan Jin, Jiping Zhou, Yin-Xi Zhang, Qun Hou, Yi Wang, Guoqing Zheng, Yang Zheng","doi":"10.1212/NXG.0000000000200240","DOIUrl":"10.1212/NXG.0000000000200240","url":null,"abstract":"<p><strong>Background and objectives: </strong>Mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE) is a newly described rare entity of drug-resistant epilepsy, with a wide spectrum of presentations. We aim to describe the diagnostic features and prognosis of MOGHE in a large cohort.</p><p><strong>Methods: </strong>We performed a systematic review preregistered on PROSPERO (CRD42023472978), in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We searched PubMed, Embase, Scopus, and ScienceDirect between database inception and November 30, 2023, for all published studies on MOGHE. Inclusion criteria were a histopathologic diagnosis of MOGHE. The risk of bias was analyzed with a standardized tool specifically for case reports and case series. The demographic, clinical, EEG, neuroimaging, genetic, and neuropathologic features; treatments; and prognosis were extracted and analyzed. Subgroup analysis was performed with the age at onset and <i>SLC35A2</i> variant status.</p><p><strong>Results: </strong>A total of 163 patients with MOGHE from 18 studies were included in the analysis. The median age at seizure onset was 1.2 years, and 103 were male. Ninety-five patients presented with unilobed lesions. Ninety-nine had lesions in the frontal lobe. A total of 101 patients achieved a favorable surgical outcome. Patients with an onset before 10 years were more likely to present with epileptic spasms, the West syndrome, a circumscribed pattern of interictal EEG, intellectual disabilities, and a better seizure outcome, compared with those with an onset age 10 years and older. Forty-five patients (72.6%) were <i>SLC35A2</i>-positive. Patients harboring the <i>SLC35A2</i> variants were more likely to present as Lennox-Gastaut syndrome, when compared with those who were <i>SLC35A2</i>-negative.</p><p><strong>Discussion: </strong>MOGHE is a distinct entity of drug-resistant epilepsy associated with <i>SLC35A2</i> variants, characterized by age-dependent phenotypes. The study emphasizes the clinical pearls indicative of the rare disease, which may facilitate early recognition and appropriate selection of treatments. The included studies were case reports or series, which were mainly limited by selection and reporting biases.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 1","pages":"e200240"},"PeriodicalIF":3.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123912","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 Spectrum of Genetic Risk in Alzheimer Disease.","authors":"Nicholas Karagas, Jessica E Young, Elizabeth E Blue, Suman Jayadev","doi":"10.1212/NXG.0000000000200224","DOIUrl":"10.1212/NXG.0000000000200224","url":null,"abstract":"<p><p>Alzheimer disease (AD), the most common dementing syndrome in the United States, is currently established by the presence of amyloid-β and tau protein biomarkers in the setting of clinical cognitive impairment. These straightforward diagnostic parameters belie an immense complexity of genetic architecture underlying risk and presentation in AD. In this review, we provide a focused overview of the current state of AD genetics. We discuss the discovery of familial autosomal dominant genes, the identification of candidate genes associated with AD, and genetic variants conferring higher risk of developing AD compared with the general population. In particular, we discuss important features of AD risk due to the <i>APOE</i> ε4 allele. In addition to risk, we describe how the field has made headway understanding genetic factors that may protect from AD. The biological implications and practical limitations of information gleaned from genome-wide association studies in AD over the years are also discussed. The readers will have an up-to-date understanding of where we are in our efforts to understand the layers of genetic complexity in AD.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 1","pages":"e200224"},"PeriodicalIF":3.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068947","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":"Spinocerebellar Ataxia Type 2: A Review and Personal Perspective.","authors":"Stefan M Pulst","doi":"10.1212/NXG.0000000000200225","DOIUrl":"10.1212/NXG.0000000000200225","url":null,"abstract":"<p><p>Spinocerebellar ataxias (SCAs) are dominantly inherited diseases that lead to neurodegeneration in the cerebellum and other parts of the nervous system. This review examines the progress that has been made in SCA2 from its initial clinical description to discovery of DNA CAG-repeat expansions in the <i>ATXN2</i> gene. <i>ATXN2</i> repeat alleles cover the range from recessive and dominant mendelian alleles to risk alleles for amyotrophic lateral sclerosis. We review studies aimed at defining the normal function of ATXN2 and mutant ATXN2 using cellular and mouse models. Progress in testing small compounds and antisense oligonucleotides in preclinical studies is described as well including our recent focus on staufen-1 (STAU1) and mRNA metabolism and control of autophagy.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 1","pages":"e200225"},"PeriodicalIF":3.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053956","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":"UK Biobank-A Unique Resource for Discovery and Translation Research on Genetics and Neurologic Disease.","authors":"Hannah Taylor, Melissa Lewins, M George B Foody, Oliver Gray, Jelena Bešević, Megan C Conroy, Rory Collins, Ben Lacey, Naomi Allen, Lucy Burkitt-Gray","doi":"10.1212/NXG.0000000000200226","DOIUrl":"10.1212/NXG.0000000000200226","url":null,"abstract":"<p><p>UK Biobank is a large-scale prospective study with extensive genetic and phenotypic data from half a million adults. Participants, aged 40 to 69, were recruited from the general UK population between 2006 and 2010. During recruitment, participants completed questionnaires covering lifestyle and medical history, underwent physical measurements, and provided biological samples for long-term storage. Whole-cohort assays have been conducted, including biochemical markers, genotyping, whole-exome and whole-genome sequencing, as well as proteomics and metabolomics in large subsets of the cohort, with potential for additional assays in the future. Participants consented to link their data to electronic health records, enabling the identification of health outcomes over time. Research studies using UK Biobank data have already enhanced our understanding of the role of genetic variation in neurologic disease, offering insights into potential therapeutic approaches. The integration of genetic and imaging data has led to significant discoveries regarding the relationship between genetic variants and brain structure and function, particularly in Alzheimer disease and Parkinson disease. Genetic data have also allowed Mendelian randomization analyses to be performed, enabling further investigation into the causality of associations between behavioral and physiologic factors-such as diet and blood pressure-and neurologic outcomes. Furthermore, genetic and proteomic data have been particularly useful in identifying new drug targets for neurologic disease and in enhancing risk prediction algorithms that are increasingly applied in clinical practice to identify those at higher risk. As UK Biobank continues to be enhanced, and the cases of neurologic disease accrue over time, the study will become increasingly valuable for both discovery and translational research on genetics and neurologic disease.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"11 1","pages":"e200226"},"PeriodicalIF":3.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257034","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":"Shared Genetics of Migraine and Gastrointestinal Disorders Implicates Underlying Neurologic Mechanisms Yet Heterogeneous Etiologies.","authors":"Daniel I Chasman, Yanjun Guo, Andrew T Chan, Pamela M Rist, Kyle Staller","doi":"10.1212/NXG.0000000000200201","DOIUrl":"10.1212/NXG.0000000000200201","url":null,"abstract":"<p><strong>Background and objectives: </strong>Migraine is strongly comorbid with irritable bowel syndrome (IBS), one of several gastrointestinal (GI) conditions that are distinguished by symptomatic profiles that are partly overlapping. Potential shared mechanisms of migraine and the GI conditions were investigated by assessing shared genetics on a genome-wide basis.</p><p><strong>Methods: </strong>Analyses leveraged genome-wide summary statistics from large-scale genetic studies for migraine, including by aura status, IBS, peptic ulcer disease (PUD), gastrointestinal reflux (GERD), functional dyspepsia (FD), diverticular disease (DD), and the immune-related inflammatory bowel disease (IBD) or its constituents, ulcerative colitis (UC) and Crohn disease (CD). Genetic correlation was evaluated on a genome-wide basis and at independent local regions, including those related to therapeutic targeting of serotonin and the calcitonin gene-related peptide. Genetic correlation was assessed for enrichment at genes according to tissue specificity of gene expression. Potential causality between migraine and the GI conditions was assessed by Mendelian randomization.</p><p><strong>Results: </strong>Genetic correlation with migraine was strongly significant among the nonimmune GI disorders, maximally for IBS (rg [SE] = 0.37[0.04], <i>p</i> = 10^-21) and minimally for DD (0.18 (0.04), 7.5 × 10^-7), but null for IBD. There were distinct patterns of local genetic sharing with migraine across the GI conditions at 22 significant segments of the genome, 7 of which were novel for either migraine or GI or both. Enrichment analysis suggested involvement of the CNS in genetic overlap of GERD, IBS, and PUD with migraine. There was local genetic sharing with migraine at <i>CALCA/CALCB</i> (encoding calcitonin gene-related peptide [CGRP]) in an inverse sense for GERD and PUD, but with concordance and greater significance for DD, IBD, and UC. Mendelian randomization supported causal effects of PUD, GERD and particularly DD (OR[SE] = 1.90 (1.35-2.68, <i>p</i> = 2.2 × 10^-4) on migraine, but not of migraine on any GI condition.</p><p><strong>Discussion: </strong>Genetic sharing of migraine and non-immune-related GI disorders was extensive yet distinct across GI disorders that have overlapping symptoms, with enrichment signals that imply neurologic mechanisms. Causal effects of some GI conditions on migraine were supported. A concordant local correlation at <i>CALCA/CALCB</i> of migraine with both DD and the immune-related disorders suggests potential benefit to these conditions from repurposed migraine therapeutics targeting CGRP.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 6","pages":"e200201"},"PeriodicalIF":3.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11637577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830420","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}