Neurology-Genetics最新文献

{"title":"Clinicoradiologic Criteria for the Diagnosis of Stroke-like Episodes in MELAS.","authors":"Vadim Khasminsky,&nbsp;Eitan Auriel,&nbsp;Judith Luckman,&nbsp;Ruth Eliahou,&nbsp;Edna Inbar,&nbsp;Keshet Pardo,&nbsp;Yuval Landau,&nbsp;Rani Barnea,&nbsp;Maor Mermelstein,&nbsp;Shahar Shelly,&nbsp;Jonathan Naftali,&nbsp;Shlomi Peretz","doi":"10.1212/NXG.0000000000200082","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200082","url":null,"abstract":"<p><strong>Background and objectives: </strong>Stroke-like episodes (SLEs) in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome are often misdiagnosed as acute ischemic stroke (AIS). We aimed to determine unique clinical and neuroimaging features for SLEs and formulate diagnostic criteria.</p><p><strong>Methods: </strong>We retrospectively identified patients with MELAS admitted for SLEs between January 2012 and December 2021. Clinical features and imaging findings were compared with a cohort of patients who presented with AIS and similar lesion topography. A set of criteria was formulated and then tested by a blinded rater to evaluate diagnostic performance.</p><p><strong>Results: </strong>Eleven MELAS patients with 17 SLE and 21 AISs were included. Patients with SLEs were younger (median 45 [37-60] vs 77 [68-82] years, <i>p</i> < 0.01) and had a lower body mass index (18 ± 2.6 vs 29 ± 4, <i>p</i> < 0.01), more commonly reported hearing loss (91% vs 5%, <i>p</i> < 0.01), and more commonly presented with headache and/or seizures (41% vs 0%, <i>p</i> < 0.01). The earliest neuroimaging test performed at presentation was uniformly a noncontrast CT. Two main patterns of lesion topography with a stereotypical spatiotemporal evolution were identified-an anterior pattern (7/21, 41%) starting at the temporal operculum and spreading to the peripheral frontal cortex and a posterior pattern (10/21, 59%) starting at the cuneus/precuneus and spreading to the lateral occipital and parietal cortex. Other distinguishing features for SLEs vs AIS were cerebellar atrophy (91% vs 19%, <i>p</i> < 0.01), previous cortical lesions with typical SLE distribution (46% vs 9%, <i>p</i> = 0.03), acute lesion tissue hyperemia and venous engorgement on CT angiography (CTA) (45% vs 0%, <i>p</i> < 0.01), and no large vessel occlusion on CTA (0% vs 100%, <i>p</i> < 0.01). Based on these clinicoradiologic features, a set of diagnostic criteria were constructed for possible SLE (sensitivity 100%, specificity 81%, AUC 0.905) and probable SLE (sensitivity 88%, specificity 95%, AUC 0.917).</p><p><strong>Discussion: </strong>Clinicoradiologic criteria based on simple anamnesis and a CT scan at presentation can accurately diagnose SLE and lead to early administration of appropriate therapy.</p><p><strong>Classification of evidence: </strong>This study provides Class III evidence that an algorithm using clinical and imaging features can differentiate stroke-like episodes due to MELAS from acute ischemic strokes.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 4","pages":"e200082"},"PeriodicalIF":3.1,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5d/96/NXG-2023-000024.PMC10323819.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9814123","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 Analysis of Respiratory Function of Different Types of Limb Girdle Muscular Dystrophies Reveals Independent Trajectories.","authors":"Robert Muni-Lofra,&nbsp;Eduard Juanola-Mayos,&nbsp;Marianela Schiava,&nbsp;Dionne Moat,&nbsp;Maha Elseed,&nbsp;Jassi Michel-Sodhi,&nbsp;Elizabeth Harris,&nbsp;Michelle McCallum,&nbsp;Ursula Moore,&nbsp;Mark Richardson,&nbsp;Christina Trainor,&nbsp;Karen Wong,&nbsp;Monika Malinova,&nbsp;Carla Bolano-Diaz,&nbsp;Michael John Keogh,&nbsp;Elisabetta Ghimenton,&nbsp;Jose Verdu-Diaz,&nbsp;Anna Mayhew,&nbsp;Michela Guglieri,&nbsp;Volker Straub,&nbsp;Meredith K James,&nbsp;Chiara Marini-Bettolo,&nbsp;Jordi Diaz-Manera","doi":"10.1212/NXG.0000000000200084","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200084","url":null,"abstract":"<p><strong>Background and objectives: </strong>The prevalence and progression of respiratory muscle dysfunction in patients with limb girdle muscular dystrophies (LGMDs) has been only partially described to date. Most reports include cross-sectional data on a limited number of patients making it difficult to gain a wider perspective on respiratory involvement throughout the course of the disease and to compare the most prevalent LGMD subtypes.</p><p><strong>Methods: </strong>We reviewed the results of spirometry studies collected longitudinally in our cohort of patients in routine clinical visits from 2002 to 2020 along with additional clinical and genetic data. A linear mixed model was used to investigate the factors associated with the progression of respiratory dysfunction.</p><p><strong>Results: </strong>We followed up 156 patients with 5 different forms of LGMDs for a median of 8 years (range 1-25 years). Of them, 53 patients had pathogenic variants in the <i>Capn3</i> gene, 47 patients in the <i>Dysf</i> gene, 24 patients in the <i>Fkrp</i> gene, 19 in the <i>Ano5</i> gene, and 13 in one of the sarcoglycan genes (SCG). At baseline, 58 patients (37.1%) had a forced vital capacity percentage predicted (FVCpp) below 80%, while 14 patients (8.9%) had peak cough flow (PCF) values below 270 L/min. As a subgroup, <i>FKRP</i> was the group with a higher number of patients having FVC <80% and/or PCF <270 L/min at initial assessment (66%). We observed a progressive decline in FVCpp and PCF measurements over time, being age, use of wheelchair, and LGMD subtype independent factors associated with this decline. <i>Fkrp</i> and sarcoglycan patients had a quicker decline in their FVC (Kaplan-Meier curve, F test, <i>p</i> < 0.001 and <i>p</i> = 0.02, respectively). Only 7 of the 58 patients with low FVCpp values reported symptoms of respiratory dysfunction, which are commonly reported by patients with FVCpp below 50%-60%. The number of patients ventilated increased from 2 to 8 during follow-up.</p><p><strong>Discussion: </strong>Respiratory dysfunction is a frequent complication of patients with LGMDs that needs to be carefully studied and has direct implications in the care offered in daily clinics. Respiratory dysfunction is associated with disease progression because it is especially seen in patients who are full-time wheelchair users, being more frequent in patients with mutations in the <i>Fkrp</i> and sarcoglycan genes.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 4","pages":"e200084"},"PeriodicalIF":3.1,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10335843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10174320","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":"Identification of an 85-kb Heterozygous 4p Microdeletion With Full Genome Analysis in Autosomal Dominant Charcot-Marie-Tooth Disease.","authors":"Hsueh Wen Hsueh,&nbsp;Hsiao-Jung Kao,&nbsp;Chi-Chao Chao,&nbsp;Sung-Ju Hsueh,&nbsp;Yu-Ning Huang,&nbsp;Wan-Jia Lin,&nbsp;Jen-Ping Su,&nbsp;Horng-Tzer Shy,&nbsp;Ti-Yen Yeh,&nbsp;Cheng-Chen Lin,&nbsp;Pui-Yan Kwok,&nbsp;Ni-Chung Lee,&nbsp;Sung-Tsang Hsieh","doi":"10.1212/NXG.0000000000200078","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200078","url":null,"abstract":"<p><strong>Background and objectives: </strong>Charcot-Marie-Tooth disease (CMT) is a syndrome of a hereditary neurodegenerative condition affecting the peripheral nervous system and is a single gene disorder. Deep phenotyping coupled with advanced genetic techniques is critical in discovering new genetic defects of rare genetic disorders such as CMT.</p><p><strong>Methods: </strong>We applied multidisciplinary investigations to examine the neurophysiology and nerve pathology in a family that fulfilled the diagnosis of CMT2. When phenotype-guided first-tier genetic tests and whole-exome sequencing did not yield a molecular diagnosis, we conducted full genome analysis by examining phased whole-genome sequencing and whole-genome optical mapping data to search for the causal variation. We then performed a systematic review to compare the reported patients with interstitial microdeletion in the short arm of chromosome 4.</p><p><strong>Results: </strong>In this family with CMT2, we reported the discovery of a heterozygous 85-kb microdeletion in the short arm of chromosome 4 (4p16.3)[NC_000004.12:g.1733926_1819031del] spanning 3 genes [<i>TACC3</i> (intron 6-exon 16), <i>FGFR3</i> (total deletion), and <i>LETM1</i> (intron 10-exon14)] that cosegregated with disease phenotypes in family members. The clinical features of peripheral nerve degeneration in our family are distinct from the well-known 4p microdeletion syndrome of Wolf-Hirschhorn syndrome, in which brain involvement is the major phenotype.</p><p><strong>Discussion: </strong>In summary, we used the full genome analysis approach to discover a new microdeletion in a family with CMT2. The deleted segment contains 3 genes (<i>TACC3</i>, <i>FGFR3</i>, and <i>LETM1</i>) that likely play a role in the pathogenesis of nerve degeneration.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 4","pages":"e200078"},"PeriodicalIF":3.1,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d6/03/NXG-2023-000021.PMC10281236.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9709345","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":"Analysis of Structural Variants Previously Associated With ALS in Europeans Highlights Genomic Architectural Differences in Africans.","authors":"Nomakhosazana R Monnakgotla,&nbsp;Amokelani C Mahungu,&nbsp;Jeannine M Heckmann,&nbsp;Gerrit Botha,&nbsp;Nicola J Mulder,&nbsp;Gang Wu,&nbsp;Evadnie Rampersaud,&nbsp;Jason Myers,&nbsp;Marka Van Blitterswijk,&nbsp;Rosa Rademakers,&nbsp;J Paul Taylor,&nbsp;Joanne Wuu,&nbsp;Michael Benatar,&nbsp;Melissa Nel","doi":"10.1212/NXG.0000000000200077","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200077","url":null,"abstract":"<p><strong>Background and objectives: </strong>Amyotrophic lateral sclerosis (ALS) is a degenerative condition of the brain and spinal cord in which protein-coding variants in known ALS disease genes explain a minority of sporadic cases. There is a growing interest in the role of noncoding structural variants (SVs) as ALS risk variants or genetic modifiers of ALS phenotype. In small European samples, specific short SV alleles in noncoding regulatory regions of <i>SCAF4</i>, <i>SQSTM1</i>, and <i>STMN2</i> have been reported to be associated with ALS, and several groups have investigated the possible role of <i>SMN1</i>/<i>SMN2</i> gene copy numbers in ALS susceptibility and clinical severity.</p><p><strong>Methods: </strong>Using short-read whole genome sequencing (WGS) data, we investigated putative ALS-susceptibility <i>SCAF4</i> (3'UTR poly-T repeat), <i>SQSTM1</i> (intron 5 AAAC insertion)<i>,</i> and <i>STMN2</i> (intron 3 CA repeat) alleles in African ancestry patients with ALS and described the architecture of the <i>SMN1</i>/<i>SMN2</i> gene region. South African cases with ALS (n = 114) were compared with ancestry-matched controls (n = 150), 1000 Genomes Project samples (n = 2,336), and H3Africa Genotyping Chip Project samples (n = 347).</p><p><strong>Results: </strong>There was no association with previously reported <i>SCAF4</i> poly-T repeat, <i>SQSTM1</i> AAAC insertion, and long <i>STMN2</i> CA alleles with ALS risk in South Africans (<i>p</i> > 0.2). Similarly, <i>SMN1</i> and <i>SMN2</i> gene copy numbers did not differ between South Africans with ALS and matched population controls (<i>p</i> > 0.9). Notably, 20% of the African samples in this study had no <i>SMN2</i> gene copies, which is a higher frequency than that reported in Europeans (approximately 7%).</p><p><strong>Discussion: </strong>We did not replicate the reported association of <i>SCAF4</i>, <i>SQSTM1</i>, and <i>STMN2</i> short SVs with ALS in a small South African sample. In addition, we found no link between <i>SMN1</i> and <i>SMN2</i> copy numbers and susceptibility to ALS in this South African sample, which is similar to the conclusion of a recent meta-analysis of European studies. However, the <i>SMN</i> gene region findings in Africans replicate previous results from East and West Africa and highlight the importance of including diverse population groups in disease gene discovery efforts. The clinically relevant differences in the <i>SMN</i> gene architecture between African and non-African populations may affect the effectiveness of targeted <i>SMN2</i> gene therapy for related diseases such as spinal muscular atrophy.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 4","pages":"e200077"},"PeriodicalIF":3.1,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/24/90/NXG-2023-000020.PMC10281237.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9710786","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":"<i>LAMA2</i>-Related Muscular Dystrophy Across the Life Span: A Cross-sectional Study.","authors":"Karlijn Bouman,&nbsp;Jan T Groothuis,&nbsp;Jonne Doorduin,&nbsp;Nens van Alfen,&nbsp;Floris E A Udink Ten Cate,&nbsp;Frederik M A van den Heuvel,&nbsp;Robin Nijveldt,&nbsp;Erik-Jan Kamsteeg,&nbsp;Anne T M Dittrich,&nbsp;Jos M T Draaisma,&nbsp;Mirian C H Janssen,&nbsp;Baziel G M van Engelen,&nbsp;Corrie E Erasmus,&nbsp;Nicol C Voermans","doi":"10.1212/NXG.0000000000200089","DOIUrl":"10.1212/NXG.0000000000200089","url":null,"abstract":"<p><strong>Background and objectives: </strong><i>LAMA2</i>-related muscular dystrophy (<i>LAMA2</i>-MD) is a rare neuromuscular disease characterized by proximal and axial muscle weakness, rigidity of the spine, scoliosis, and respiratory impairment. No curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data, and appropriate clinical and functional outcome measures are needed. We aim for deep clinical phenotyping, establishment of a well-characterized baseline cohort for prospective follow-up and recruitment for future clinical trials, improvement of clinical care, and selection of outcome measures for reaching trial readiness.</p><p><strong>Methods: </strong>We performed a cross-sectional, single-center, observational study. This study included neurologic examination and functional measurements among others the Motor Function Measure 20/32 (MFM-20/32) as primary outcome measure, accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electrocardiography and echocardiography, and dual-energy X-ray absorptiometry.</p><p><strong>Results: </strong>Twenty-seven patients with genetically confirmed <i>LAMA2</i>-MD were included (21 ± 13 years; M = 9; ambulant = 7). Axial and proximal muscle weakness was most pronounced. The mean MFM-20/32 score was 42.0% ± 29.4%, with domain 1 (standing and transfers) being severely affected and domain 3 (distal muscle function) relatively spared. Physical activity as measured through accelerometry showed very strong correlations to MFM-20/32 (Pearson correlation, -0.928, <i>p</i> < 0.01). Muscle ultrasound showed symmetrically increased echogenicity, with the sternocleidomastoid muscle most affected. Respiratory function was impaired in 85% of patients without prominent diaphragm dysfunction and was independent of age. Ten patients (37%) needed (non)invasive ventilatory support. Cardiac assessment revealed QRS fragmentation in 62%, abnormal left ventricular global longitudinal strain in 25%, and decreased left ventricular ejection fraction in 14% of patients. Decreased bone quality leading to fragility fractures was seen in most of the patients.</p><p><strong>Discussion: </strong><i>LAMA2</i>-MD has a widely variable phenotype. Based on the results of this cross-sectional study and current standards of care for congenital muscular dystrophies, we advise routine cardiorespiratory follow-up and optimization of bone quality. We propose MFM-20/32, accelerometry, and muscle ultrasound for assessing disease severity and progression. For definitive clinical recommendations and outcome measures, natural history data are needed.</p><p><strong>Clinical trials registration: </strong>This study was registered at clinicaltrials.gov (NCT04478981, 21 July 2020). The first patient was enrolled in September 2020.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 5","pages":"e200089"},"PeriodicalIF":3.1,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/01/98/NXG-2023-000029.PMC10356133.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10226540","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":"Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy.","authors":"Gorka Fernández-Eulate, Julian Theuriet, Christopher J Record, Giorgia Querin, Marion Masingue, Sarah Leonard-Louis, Anthony Behin, Nadine Le Forestier, Antoine Pegat, Maud Michaud, Jean-Baptiste Chanson, Aleksandra Nadaj-Pakleza, Celine Tard, Anne-Laure Bedat-Millet, Guilhem Sole, Marco Spinazzi, Emmanuelle Salort-Campana, Andoni Echaniz-Laguna, Vianney Poinsignon, Philippe Latour, Mary M Reilly, Francoise Bouhour, Tanya Stojkovic","doi":"10.1212/NXG.0000000000200087","DOIUrl":"10.1212/NXG.0000000000200087","url":null,"abstract":"<p><strong>Background and objectives: </strong>Spinal muscular atrophy (SMA) is mainly caused by homozygous <i>SMN1</i> gene deletions on 5q13. Non-5q SMA patients' series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders.</p><p><strong>Methods: </strong>Description of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel.</p><p><strong>Results: </strong>Seventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis: <i>BICD2</i> (n = 9), <i>DYNC1H1</i> (n = 7), <i>TRPV4</i> (n = 4), <i>VCP</i>, <i>HSBP1</i>, <i>AR</i> (n = 2), <i>VRK1</i>, <i>DNAJB2</i>, <i>MORC2</i>, <i>ASAH1</i>, <i>HEXB</i>, and unexpectedly, <i>COL6A3</i> (n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS.</p><p><strong>Discussion: </strong>Non-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 4","pages":"e200087"},"PeriodicalIF":3.1,"publicationDate":"2023-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3b/83/NXG-2023-000027.PMC10352921.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9848237","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":"Ataxia and Diplopia: A New <i>SCN8A</i>-Related Phenotype.","authors":"Alexandra Laliberté, Kenneth A Myers","doi":"10.1212/NXG.0000000000200085","DOIUrl":"10.1212/NXG.0000000000200085","url":null,"abstract":"<p><strong>Objectives: </strong>The objective of this study was to describe the first patient with recurrent ataxia and diplopia in association with a pathogenic variant in <i>SCN8A</i>.</p><p><strong>Methods: </strong>We identified a girl with a heterozygous <i>SCN8A</i> pathogenic variant and performed thorough phenotyping.</p><p><strong>Results: </strong>A 10-year-old girl was previously well with normal intelligence. She had recurrent diplopia, dysmetria, and unsteady gait, which occurred only in the context of febrile illnesses. EEG during her initial acute episode showed multifocal epileptiform discharges, with similar findings seen on a follow-up study 3 months later when she was well. Brain MRI finding was normal. A gene panel identified a de novo <i>SCN8A</i> variant, p.Arg847Gln, classified as likely pathogenic. One year after her initial presentation, the girl is well and developmentally normal and has never had an event concerning for seizure.</p><p><strong>Discussion: </strong>This case presentation demonstrates that <i>SCN8A</i> pathogenic variants should be considered in children with transient ataxia, dysmetria, and diplopia in the context of viral febrile illnesses, even if there is no history of seizures. While there are clinical and molecular data suggesting that SCN8A dysfunction can cause temperature-sensitive phenotypes, further research is necessary to determine how the functional changes caused by our patient's <i>SCN8A</i> variant result in her unique phenotype.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 4","pages":"e200085"},"PeriodicalIF":3.0,"publicationDate":"2023-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/37/44/NXG-2023-000144.PMC10335842.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10174319","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":"Systemic Capillary Leak Syndrome With Cerebral Involvement in a <i>C9orf72</i> Expansion Carrier: Case Report and Review of the Literature.","authors":"Stefan Sennfält, Oskar Aspegren, Martin Engvall, Tobias Granberg, Fredrik Piehl","doi":"10.1212/NXG.0000000000200081","DOIUrl":"10.1212/NXG.0000000000200081","url":null,"abstract":"<p><strong>Objective: </strong>Systemic capillary leak syndrome (SCLS) is a rare condition associated with episodes of hypotension, hemoconcentration, hypoalbuminemia, and rhabdomyolysis. We describe a middle-aged man presenting with several distinct SCLS-like episodes, the last being fatal. In addition, in the year before the final event, he developed rapid cognitive decline with contrast-enhancing lesions on MRI and highly elevated neurofilament light protein levels in CSF.</p><p><strong>Methods: </strong>Data and imaging were obtained from patient medical records.</p><p><strong>Results: </strong>At the time, the SCLS-like episodes were interpreted as myositis secondary to viral infection. A thorough workup for other causes, including genetic testing, was negative. As for the rapid cognitive decline, despite an extensive workup for infectious and inflammatory causes, no definitive diagnosis was made. Whole genome sequencing however identified a <i>C9orf72</i> hexanucleotide expansion.</p><p><strong>Discussion: </strong>The <i>C9orf72</i> expansion is associated with frontotemporal dementia and amyotrophic lateral sclerosis but has also been shown to increase susceptibility to neuroinflammation. Recent findings also suggest <i>C9orf72</i> to exert functions in the immune system, in particular regulation of type I interferon responses, in turn shown to be associated with SCLS. This case suggests a possible link between SCLS, cerebral inflammation, dysregulated type I interferon signaling, and expansions in <i>C9orf72</i>.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 4","pages":"e200081"},"PeriodicalIF":3.0,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/15/3a/NXG-2023-000139.PMC10275405.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9661521","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":"Cerebellar Ataxia and Peripheral Neuropathy in a Family With <i>PNPLA8</i>-Associated Disease.","authors":"Birute Burnyte,&nbsp;Ramune Vilimiene,&nbsp;Kristina Grigalioniene,&nbsp;Irina Adomaitiene,&nbsp;Algirdas Utkus","doi":"10.1212/NXG.0000000000200068","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200068","url":null,"abstract":"<p><strong>Objectives: </strong>To describe clinical and genetic findings in 2 siblings with slowly progressive ataxia.</p><p><strong>Methods: </strong>We studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause.</p><p><strong>Results: </strong>Both siblings presented with adolescence-onset ataxia, progressive sensorimotor polyneuropathy, and preserved cognition over time. The onset of symptoms was between 10 and 14 years of age. A brain MRI demonstrated mild cerebellar atrophy in the older brother at age 45 years. Exome sequencing revealed compound heterozygous loss-of-function variants c.2269del (p.(Thr757GlnfsTer10)) and c.2275_2276del (p.(Leu759AlafsTer4)) in <i>PNPLA8</i>. The novel variant c.2269del results in frameshift with a premature stop codon p.(Thr757GlnfsTer10) and loss of normal enzyme function.</p><p><strong>Discussion: </strong>Our findings support the theory that biallelic loss-of-function <i>PNPLA8</i> variants are involved in neurodegenerative mitochondrial disease. Compared with patients previously described, these patients' phenotype may be interpreted as a milder phenotype associated with a slight progression of ataxia throughout adulthood.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 3","pages":"e200068"},"PeriodicalIF":3.1,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0e/9f/NXG-2023-000011.PMC10088641.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9305349","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":"CircPDS5B Reduction Improves Angiogenesis Following Ischemic Stroke by Regulating MicroRNA-223-3p/NOTCH2 Axis.","authors":"Ling Kui,&nbsp;Zongyu Li,&nbsp;Guoyun Wang,&nbsp;Xuzhen Li,&nbsp;Feng Zhao,&nbsp;Yinming Jiao","doi":"10.1212/NXG.0000000000200074","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200074","url":null,"abstract":"<p><strong>Background and objectives: </strong>Ischemic stroke (IS) is responsible for major causes of global death and disability, for which promoting angiogenesis is a promising therapeutic strategy. This study analyzed circular RNA PDS5B (circPDS5B) and its related mechanisms in angiogenesis in IS.</p><p><strong>Methods: </strong>In the permanent middle cerebral artery occlusion (pMCAO) mouse model, circPDS5B, microRNA (miR)-223-3p, and NOTCH2 levels were checked. By testing neurologic function, neuronal apoptosis, and expression of angiogenesis-related proteins in pMCAO mice, the protective effects of circPDS5B knockdown were probed. In human brain microvascular endothelial cells (HBMECs) under oxygen-glucose deprivation (OGD) conditions, the effects of circPDS5B, miR-223-3p, and NOTCH2 on angiogenesis were studied by measuring cellular activities.</p><p><strong>Results: </strong>The increase of circPDS5B and NOTCH2 expression and the decrease of miR-223-3p expression were examined in pMCAO mice. Reducing circPDS5B expression indicated protection against neurologic dysfunction, apoptosis, and angiogenesis impairment. For circPDS5B-depleted or miR-223-3p-restored HBMECs under OGD treatment, angiogenesis was promoted. MiR-223-3p inhibition-associated reduction of angiogenesis could be counteracted by knocking down NOTCH2. CircPDS5B depletion-induced angiogenesis in OGD-conditioned HBMECs was repressed after overexpressing NOTCH2.</p><p><strong>Discussion: </strong>In IS, the expression of circPDS5B was upregulated, and miR-223-3p inhibited HBMECs activity and promoted NOTCH2 expression, thus promoting IS. CircPDS5B reduction improves angiogenesis following ischemic stroke by regulating microRNA-223-3p/NOTCH2 axis.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 3","pages":"e200074"},"PeriodicalIF":3.1,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fa/9b/NXG-2023-000017.PMC10162703.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9430745","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}