Neurology-Genetics最新文献

{"title":"Neurologic, Neuropsychologic, and Neuroradiologic Features of <i>EBF3</i>-Related Syndrome.","authors":"Claudia Ciaccio,&nbsp;Chiara Pantaleoni,&nbsp;Marco Moscatelli,&nbsp;Luisa Chiapparini,&nbsp;Vincenzo Nigro,&nbsp;Enza Maria Valente,&nbsp;Francesca Sciacca,&nbsp;Laura Canafoglia,&nbsp;Sara Bulgheroni,&nbsp;Stefano D'Arrigo","doi":"10.1212/NXG.0000000000200049","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200049","url":null,"abstract":"<p><strong>Background and objectives: </strong>Heterozygous mutations or deletions of the <i>EBF3</i> gene are known to cause a syndrome characterized by intellectual disability, neurodevelopmental disorders, facial dysmorphisms, hypotonia, and ataxia; the latter is quite common despite in most patients brain MRI is reported to be normal. Despite the predominant neurologic involvement of <i>EBF3</i>-related syndrome, a systematic definition of neurologic, cognitive/behavioral, and neuroradiologic features is lacking.</p><p><strong>Methods: </strong>We report on 6 patients (2 females and 4 males, age range 2-12 years), of whom 4 carrying a heterozygous point mutation of the <i>EBF3</i> gene and 2 with 10q26 deletion encompassing the gene, diagnosed at Carlo Besta Neurologic Institute of Milan, Italy. Clinical evaluation was performed by a pediatric neurologist and pediatric dysmorphologist; ataxia severity was rated by Scale for the Assessment and Rating of Ataxia (SARA); brain MRIs were reviewed by expert neuroradiologists; general quotient levels were obtained through standardized Griffiths Mental Development Scales. Patients carrying a 10q26.3 deletion were diagnosed by array-CGH, whereas <i>EBF3</i> variants were detected by whole exome sequencing.</p><p><strong>Results: </strong>Phenotype was consistent in all patients, but with wide variability in severity. Developmental milestones were invariably delayed and resulted in an extremely variable cognitive impairment. All patients showed ataxic signs, as confirmed by SARA scores, often associated with hypotonia. Brain MRI revealed in all children a cerebellar malformation with vermis hypoplasia and a peculiar foliation anomaly characterized by a radial disposition of cerebellar folia (dandelion sign). Neurophysiologic examinations were unremarkable.</p><p><strong>Discussion: </strong><i>EBF3</i>-related syndrome has been so far described as a neurodevelopmental condition with dysmorphic traits, with limited emphasis on the neurologic features; we highlight the predominant neurologic involvement of these patients, which can be explained at least in part by the underlying cerebellar malformation. We therefore propose that <i>EBF3</i>-related syndrome should be classified and treated as a congenital, nonprogressive ataxia.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 2","pages":"e200049"},"PeriodicalIF":3.1,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/98/da/NXG-2022-200052.PMC10117703.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9387728","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: Expanding the Allelic Heterogeneity of ANO10-Associated Autosomal Recessive Cerebellar Ataxia.","authors":"","doi":"10.1212/NXG.0000000000200065","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200065","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1212/NXG.0000000000200051.].</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 2","pages":"e200065"},"PeriodicalIF":3.1,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10117702/pdf/NXG-2023-000008.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9387717","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":"New-Onset Refractory Status Epilepticus Due to a Novel MT-TF Variant: Time for Acute Genetic Testing Before Treatment?","authors":"Elisabetta Indelicato,&nbsp;Johannes Pfeilstetter,&nbsp;Michael Zech,&nbsp;Iris Unterberger,&nbsp;Julia Wanschitz,&nbsp;Steffen Berweck,&nbsp;Sylvia Boesch","doi":"10.1212/NXG.0000000000200063","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200063","url":null,"abstract":"<p><strong>Objective: </strong>The gene MT-TF encodes the mitochondrial tRNA of phenylalanine (tRNA^phe). Its variations have been described as extremely rare etiologies of a variety of mitochondrial phenotypes.</p><p><strong>Methods: </strong>By means of whole-exome sequencing (WES), we detected a novel likely causative MT-TF variant (m.610T>C) in a family presenting with a combined movement disorder and epilepsy phenotype. The variant was present at 97% heteroplasmy in the peripheral blood and in a homoplasmic state in skin fibroblast-derived DNA.</p><p><strong>Results: </strong>The inaugural manifestation in the index patient was new-onset refractory myoclonic status epilepticus (NORSE) at the age of 29 years. Her son presented later with developmental regression and myoclonic epilepsy. On the beginning of valproate because of ongoing myoclonic seizures, the index patient developed a generalized brain edema requiring bilateral craniotomy. In the course of the disease, epileptic manifestations abated, and both patients developed a severe movement disorder phenotype with prominent spastic-dystonic features. Both patients did not display any further sign of mitochondrial disease.</p><p><strong>Discussion: </strong>Our report expands the clinicogenetic background of tRNA^phe disease spectrum and highlights pitfalls in the diagnostics and management of mitochondrial epilepsy. The present findings advocate the introduction of rapid genetic testing in the diagnostic flow chart of NORSE in adults.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 2","pages":"e200063"},"PeriodicalIF":3.1,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10117698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9387715","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":"Novel <i>SERAC1</i> Variant Presenting With Adult-Onset Extrapyramidal Dystonia-Parkinsonism Phenotype: A Case Report.","authors":"Catherine Ashton,&nbsp;Mark Davis,&nbsp;Nigel Laing,&nbsp;Gianina Ravenscroft,&nbsp;Philipa Lamont","doi":"10.1212/NXG.0000000000200067","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200067","url":null,"abstract":"<p><strong>Objectives: </strong>To report a novel likely pathogenic variant in the <i>SERAC1</i> gene associated with early adult-onset parkinsonism and progressive dystonia.</p><p><strong>Methods: </strong>Clinical, biochemical, and imaging assessments were performed on 2 affected adult brothers with a genetically unsolved progressive neurologic disorder followed by whole-genome sequencing.</p><p><strong>Results: </strong>A homozygous likely pathogenic variant in the <i>SERAC1</i> gene (c.[129-2A > C], p.[(?)];[(?)]) was discovered.</p><p><strong>Discussion: </strong>We describe a novel homozygous variant in the serine active site-containing protein 1 gene (<i>SERAC1</i>) in 2 brothers with a progressive extrapyramidal movement disorder of early onset parkinsonism and dystonia. Previous variants have been associated with a severe 3-methylglutaconic aciduria with dystonia, deafness, hepatopathy, encephalopathy and Leigh-like syndrome, or juvenile onset complicated spastic paraparesis. Our cases expand the phenotype of <i>SERAC1</i> variants, with an adult-onset presentation of dystonia-parkinsonism.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 2","pages":"e200067"},"PeriodicalIF":3.1,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f8/8e/NXG-2023-000010.PMC10117696.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9387721","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":"Whole-Exome Sequencing Study of Fibroblasts Derived From Patients With Cerebellar Ataxia Referred to Investigate CoQ10 Deficiency.","authors":"Edoardo Monfrini,&nbsp;Alba Pesini,&nbsp;Fabio Biella,&nbsp;Claudia F R Sobreira,&nbsp;Valentina Emmanuele,&nbsp;Gloria Brescia,&nbsp;Luis Carlos Lopez,&nbsp;Saba Tadesse,&nbsp;Michio Hirano,&nbsp;Giacomo P Comi,&nbsp;Catarina Maria Quinzii,&nbsp;Alessio Di Fonzo","doi":"10.1212/NXG.0000000000200058","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200058","url":null,"abstract":"<p><strong>Background and objectives: </strong>Coenzyme Q₁₀ (CoQ₁₀)-deficient cerebellar ataxia can be due to pathogenic variants in genes encoding for CoQ₁₀ biosynthetic proteins or associated with defects in protein unrelated to its biosynthesis. Diagnosis is crucial because patients may respond favorably to CoQ₁₀ supplementation. The aim of this study was to identify through whole-exome sequencing (WES) the pathogenic variants, and assess CoQ₁₀ levels, in fibroblasts from patients with undiagnosed cerebellar ataxia referred to investigate CoQ₁₀ deficiency.</p><p><strong>Methods: </strong>WES was performed on genomic DNA extracted from 16 patients. Sequencing data were filtered using a virtual panel of genes associated with CoQ₁₀ deficiency and/or cerebellar ataxia. CoQ₁₀ levels were measured by high-performance liquid chromatography in 14 patient-derived fibroblasts.</p><p><strong>Results: </strong>A definite genetic etiology was identified in 8 samples of 16 (diagnostic yield = 50%). The identified genetic causes were pathogenic variants of the genes <i>COQ8A</i> (<i>ADCK3</i>) (n = 3 samples), <i>ATP1A3</i> (n = 2), <i>PLA2G6</i> (n = 1), <i>SPG7</i> (n = 1), and <i>MFSD8</i> (n = 1). Five novel mutations were found (<i>COQ8A</i> n = 3, <i>PLA2G6</i> n = 1, and <i>MFSD8</i> n = 1). CoQ₁₀ levels were significantly decreased in 3/14 fibroblast samples (21.4%), 1 carrying compound heterozygous <i>COQ8A</i> pathogenic variants, 1 harboring a homozygous pathogenic <i>SPG7</i> variant, and 1 with an unknown molecular defect.</p><p><strong>Discussion: </strong>This work confirms the importance of <i>COQ8A</i> gene mutations as a frequent genetic cause of cerebellar ataxia and CoQ₁₀ deficiency and suggests <i>SPG7</i> mutations as a novel cause of secondary CoQ₁₀ deficiency.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 2","pages":"e200058"},"PeriodicalIF":3.1,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/10/bf/NXG-2023-000001.PMC10117701.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9387725","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":"A Phase 1 Study of Oral Vitamin D₃ in Boys and Young Men With X-Linked Adrenoleukodystrophy.","authors":"Keith P Van Haren, Kristen Cunanan, Avni Awani, Meng Gu, Dalia Peña, Lindsay C Chromik, Michal Považan, Nicole C Rossi, Jordan Goodman, Vandana Sundaram, Jennifer Winterbottom, Gerald V Raymond, Tina Cowan, Gregory M Enns, Emmanuelle Waubant, Lawrence Steinman, Peter B Barker, Daniel Spielman, Ali Fatemi","doi":"10.1212/NXG.0000000000200061","DOIUrl":"10.1212/NXG.0000000000200061","url":null,"abstract":"<p><strong>Background and objectives: </strong>There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD.</p><p><strong>Methods: </strong>In this open-label, multicenter, phase 1 study, we recruited boys and young men with ALD without brain lesions to a 12-month study of daily oral vitamin D₃ supplementation. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80 ng/mL) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in the brain, measured with magnetic resonance spectroscopy, and blood, measured via mass spectrometry. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. After a midstudy safety assessment, we modified the dosing regimen, so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily.</p><p><strong>Results: </strong>Between October 2016 and June 2019, we enrolled 21 participants (n = 12, fixed-dose regimen; n = 9, weight-stratified regimen) with a median age of 6.7 years (range: 1.9-22 years) and median weight of 20 kg (range: 11.7-85.5 kg). The number of participants achieving target vitamin D levels was similar in both groups at 6 months (fixed dose: 92%; weight stratified: 78%) and 12 months (fixed dose: 67%; weight stratified: 67%). Among the 12 participants in the fixed-dose regimen, half had asymptomatic elevations in either urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels in the brain, but not the blood, increased significantly between baseline and 12 months.</p><p><strong>Discussion: </strong>Our vitamin D dosing regimens were well tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels warrant further study as a biomarker for vitamin D and ALD.</p><p><strong>Classification of evidence: </strong>This study provides Class IV evidence that fixed or weight-stratified vitamin D supplementation achieved target levels of 25-hydroxyvitamin D in boys and young men with X-ALD without brain lesions.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 2","pages":"e200061"},"PeriodicalIF":3.0,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7c/fb/NXG-2023-000003.PMC10117697.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9387716","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":"Transcriptome and Genome Analysis Uncovers a <i>DMD</i> Structural Variant: A Case Report.","authors":"Chiara Folland, Vijay Ganesh, Ben Weisburd, Catriona McLean, Andrew J Kornberg, Anne O'Donnell-Luria, Heidi L Rehm, Igor Stevanovski, Sanjog R Chintalaphani, Paul Kennedy, Ira W Deveson, Gianina Ravenscroft","doi":"10.1212/NXG.0000000000200064","DOIUrl":"10.1212/NXG.0000000000200064","url":null,"abstract":"<p><strong>Objective: </strong>Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the dystrophin gene (<i>DMD</i>). Hypermethylated CGG expansions within <i>DIP2B</i> 5' UTR are associated with an intellectual development disorder. Here, we demonstrate the diagnostic utility of genomic short-read sequencing (SRS) and transcriptome sequencing to identify a novel <i>DMD</i> structural variant (SV) and a <i>DIP2B</i> CGG expansion in a patient with DMD for whom conventional diagnostic testing failed to yield a genetic diagnosis.</p><p><strong>Methods: </strong>We performed genomic SRS, skeletal muscle transcriptome sequencing, and targeted programmable long-read sequencing (LRS).</p><p><strong>Results: </strong>The proband had a typical DMD clinical presentation, autism spectrum disorder (ASD), and dystrophinopathy on muscle biopsy. Transcriptome analysis identified 6 aberrantly expressed genes; <i>DMD</i> and <i>DIP2B</i> were the strongest underexpression and overexpression outliers, respectively. Genomic SRS identified a 216 kb paracentric inversion (NC_000023.11: g.33162217-33378800) overlapping 2 <i>DMD</i> promoters. ExpansionHunter indicated an expansion of 109 CGG repeats within the 5' UTR of <i>DIP2B</i>. Targeted genomic LRS confirmed the SV and genotyped the <i>DIP2B</i> repeat expansion as 270 CGG repeats.</p><p><strong>Discussion: </strong>Here, transcriptome data heavily guided genomic analysis to resolve a complex <i>DMD</i> inversion and a <i>DIP2B</i> repeat expansion. Longitudinal follow-up will be important for clarifying the clinical significance of the <i>DIP2B</i> genotype.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 2","pages":"e200064"},"PeriodicalIF":3.1,"publicationDate":"2023-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/23/42/NXG-2023-000007.PMC10117699.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10187227","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 Manifestation of Nebulin-Associated Nemaline Myopathy.","authors":"Cristiane Araujo Martins Moreno,&nbsp;Mariana Cunha Artilheiro,&nbsp;Alulin Tacio Quadros Santos Monteiro Fonseca,&nbsp;Clara Gontijo Camelo,&nbsp;Gisele Chagas de Medeiros,&nbsp;Fernanda Chiarion Sassi,&nbsp;Claudia Regina Furquim de Andrade,&nbsp;Sandra Donkervoort,&nbsp;Andre Macedo Serafim Silva,&nbsp;Luiz Dalfior-Junior,&nbsp;Osorio Lopes Abath-Neto,&nbsp;Umbertina Conti Reed,&nbsp;Carsten Bönnemann,&nbsp;Edmar Zanoteli","doi":"10.1212/NXG.0000000000200056","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200056","url":null,"abstract":"<p><strong>Background and objectives: </strong>Nemaline myopathy (NM) is a genetically heterogeneous inherited myopathy related with at least 12 genes, whereas pathogenic variants in <i>NEB</i> gene are the most common genetic cause. The clinical spectrum of NM caused by NEB pathogenic variants (NM-<i>NEB</i>) is very broad, ranging from mild to severe presentations manifesting with generalized weakness, as well as respiratory and bulbar involvement. There is currently not enough data regarding the progression of the disease. In this study, we present a genotypic and phenotypic spectrum of 33 patients with NM caused by NEB variants (NM-<i>NEB</i>) classified according to age groups and the use of ventilatory support. We focused on interventional support, genotype-phenotype correlation, and association between respiratory, bulbar, and motor systems in groups of patients stratified by age and by the use of ventilatory support (VS).</p><p><strong>Methods: </strong>Clinical and genetic data from patients with NM-NEB followed up in one specialized center were collected through regular consultations. Patients were evaluated regarding motor, bulbar, and respiratory functions.</p><p><strong>Results: </strong>Thirty-three patients with NM-NEB were evaluated consisting of 15 females and 18 males with an average age of 18 (±12) years and a median of 17 (±11) years. 32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS. Scoliosis and dysphagia were more common among patients who used VS. Described for the first time, half of the patients presented tongue atrophy in a triple furrow pattern, and the presence of the atrophy was associated with dysphagia. Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains. In addition to that, we showed that VS use was associated with scoliosis and dysphagia.</p><p><strong>Discussion: </strong>NM-NEB is a very debilitating disease. There is an association between scoliosis and respiratory dysfunction while patients using VS have more often scoliosis than the no-VS group. Triple furrow tongue atrophy is a novel and frequent finding, which is directly associated with dysphagia. Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities. All observations are relevant in the management care of patients with NM.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 1","pages":"e200056"},"PeriodicalIF":3.1,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/26/40/NXG-2022-200059.PMC9879277.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10584267","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":"Genetic Risk for Alzheimer Disease and Plasma Tau Are Associated With Accelerated Parietal Cortex Thickness Change in Middle-Aged Adults.","authors":"Jasmeet Pannu Hayes, Meghan E Pierce, Emma Brown, David Salat, Mark W Logue, Julie Constantinescu, Kate Valerio, Mark W Miller, Richard Sherva, Bertrand Russell Huber, William Milberg, Regina McGlinchey","doi":"10.1212/NXG.0000000000200053","DOIUrl":"10.1212/NXG.0000000000200053","url":null,"abstract":"<p><strong>Background and objectives: </strong>Neuroimaging and biomarker studies in Alzheimer disease (AD) have shown well-characterized patterns of cortical thinning and altered biomarker concentrations of tau and β-amyloid (Aβ). However, earlier identification of AD has great potential to advance clinical care and determine candidates for drug trials. The extent to which AD risk markers relate to cortical thinning patterns in midlife is unknown. The first objective of this study was to examine cortical thickness change associated with genetic risk for AD among middle-aged military veterans. The second objective was to determine the relationship between plasma tau and Aβ and change in brain cortical thickness among veterans stratified by genetic risk for AD.</p><p><strong>Methods: </strong>Participants consisted of post-9/11 veterans (N = 155) who were consecutively enrolled in the Translational Research Center for TBI and Stress Disorders prospective longitudinal cohort and were assessed for mild traumatic brain injury (TBI) and posttraumatic disorder (PTSD). Genome-wide polygenic risk scores (PRSs) for AD were calculated using summary results from the International Genomics of Alzheimer's Disease Project. T-tau and Aβ40 and Aβ42 plasma assays were run using Simoa technology. Whole-brain MRI cortical thickness change estimates were obtained using the longitudinal stream of FreeSurfer. Follow-up moderation analyses examined the AD PRS × plasma interaction on change in cortical thickness in AD-vulnerable regions.</p><p><strong>Results: </strong>Higher AD PRS, signifying greater genetic risk for AD, was associated with accelerated cortical thickness change in a right hemisphere inferior parietal cortex cluster that included the supramarginal gyrus, angular gyrus, and intraparietal sulcus. Higher tau, but not Aβ42/40 ratio, was associated with greater cortical thickness change among those with higher AD PRS. Mild TBI and PTSD were not associated with cortical thickness change.</p><p><strong>Discussion: </strong>Plasma tau, particularly when combined with genetic stratification for AD risk, can be a useful indicator of brain change in midlife. Accelerated inferior parietal cortex changes in midlife may be an important factor to consider as a marker of AD-related brain alterations.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 1","pages":"e200053"},"PeriodicalIF":3.0,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3c/2c/NXG-2022-200056.PMC9893442.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10660179","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 Allelic Heterogeneity of <i>ANO10</i>-Associated Autosomal Recessive Cerebellar Ataxia.","authors":"Sean Massey,&nbsp;Yiran Guo,&nbsp;Lisa G Riley,&nbsp;Nicole J Van Bergen,&nbsp;Sarah A Sandaradura,&nbsp;Elizabeth McCusker,&nbsp;Michel Tchan,&nbsp;Christel Thauvin-Robinet,&nbsp;Quentin Thomas,&nbsp;Thibault Moreau,&nbsp;Mark Davis,&nbsp;Daphne Smits,&nbsp;Grazia M S Mancini,&nbsp;Hakon Hakonarson,&nbsp;Sandra Cooper,&nbsp;John Christodoulou","doi":"10.1212/NXG.0000000000200051","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200051","url":null,"abstract":"<p><strong>Background and objectives: </strong>The term autosomal recessive cerebellar ataxia (ARCA) encompasses a diverse group of heterogeneous degenerative disorders of the cerebellum. Spinocerebellar ataxia autosomal recessive 10 (SCAR10) is a distinct classification of cerebellar ataxia caused by variants in the <i>ANO10</i> gene. Little is known about the molecular role of ANO10 or its role in disease. There is a wide phenotypic spectrum among patients, even among those with the same or similar genetic variants. This study aimed to characterize the molecular consequences of variants in <i>ANO10</i> and determine their pathologic significance in patients diagnosed with SCAR10.</p><p><strong>Methods: </strong>We presented 4 patients from 4 families diagnosed with spinocerebellar ataxia with potential pathogenic variants in the <i>ANO10</i> gene. Patients underwent either clinical whole-exome sequencing or screening of a panel of known neuromuscular disease genes. Effects on splicing were studied using reverse transcriptase PCR to analyze complementary DNA. Western blots were used to examine protein expression.</p><p><strong>Results: </strong>One individual who presented clinically at a much earlier age than typical was homozygous for an <i>ANO10</i> variant (c.1864A > G [p.Met622Val]) that produces 2 transcription products by altering an exonic enhancer site. Two patients, both of Lebanese descent, had a homozygous intronic splicing variant in <i>ANO10</i> (c.1163-9A > G) that introduced a cryptic splice site acceptor, producing 2 alternative transcription products and no detectable wild-type protein. Both these variants have not yet been associated with SCAR10. The remaining patient was found to have compound heterozygous variants in <i>ANO10</i> previously associated with SCAR10 (c.132dupA [p.Asp45Argfs*9] and c.1537T > C [p.Cys513Arg]).</p><p><strong>Discussion: </strong>We presented rare pathogenic variants adding to the growing list of <i>ANO10</i> variants associated with SCAR10. In addition, we described an individual with a much earlier age at onset than usually associated with <i>ANO10</i> variants. This expands the phenotypic and allelic heterogeneity of <i>ANO10</i>-associated ARCA.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 1","pages":"e200051"},"PeriodicalIF":3.1,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/32/de/NXG-2022-200054.PMC9872716.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9335829","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}