Neurology-Genetics最新文献

{"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}

{"title":"Distinguishing Loss-of-Function and Gain-of-Function <i>SCN8A</i> Variants Using a Random Forest Classification Model Trained on Clinical Features.","authors":"Joshua B Hack,&nbsp;Kyle Horning,&nbsp;Denise M Juroske Short,&nbsp;John M Schreiber,&nbsp;Joseph C Watkins,&nbsp;Michael F Hammer","doi":"10.1212/NXG.0000000000200060","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200060","url":null,"abstract":"<p><strong>Background and objectives: </strong>Pathogenic variants at the voltage-gated sodium channel gene, <i>SCN8A</i>, are associated with a wide spectrum of clinical disease outcomes. A critical challenge for neurologists is to determine whether patients carry gain-of-function (GOF) or loss-of-function (LOF) variants to guide treatment decisions, yet in vitro studies to infer channel function are often not feasible in the clinic. In this study, we develop a predictive modeling approach to classify variants based on clinical features present at initial diagnosis.</p><p><strong>Methods: </strong>We performed an exhaustive search for individuals deemed to carry SCN8A GOF and LOF variants by means of in vitro studies in heterologous cell systems, or because the variant was classified as truncating, and recorded clinical features. This resulted in a total of 69 LOF variants: 34 missense and 35 truncating variants, including 9 nonsense, 13 frameshift, 6 splice site, 6 indels, and 1 large deletion. We then assembled a truth set of variants with known functional effects, excluding individuals carrying variants at other loci associated with epilepsy. We then trained a predictive model based on random forest using this truth set of 45 LOF variants and 45 GOF variants randomly selected from a set of variants tested by in vitro methods.</p><p><strong>Results: </strong>Phenotypic categories assigned to individuals correlated strongly with GOF or LOF variants. All patients with GOF variants experienced early-onset seizures (mean age at onset = 4.5 ± 3.1 months) while only 64.4% patients with LOF variants had seizures, most of which were late-onset absence seizures (mean age at onset = 40.0 ± 38.1 months). With high accuracy (95.4%), our model including 5 key clinical features classified individuals with GOF and LOF variants into 2 distinct cohorts differing in age at seizure onset, development of seizures, seizure type, intellectual disability, and developmental and epileptic encephalopathy.</p><p><strong>Discussion: </strong>The results support the hypothesis that patients with <i>SCN8A</i> GOF and LOF variants represent distinct clinical phenotypes. The clinical model developed in this study has great utility because it provides a rapid and highly accurate platform for predicting the functional class of patient variants during <i>SCN8A</i> diagnosis, which can aid in initial treatment decisions and improve prognosis.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 3","pages":"e200060"},"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/95/b9/NXG-2023-000002.PMC10160958.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9435997","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":"Extension of the Clinicoradiologic Spectrum of Newly Described End-Truncating <i>LAMB1</i> Variations.","authors":"Hélène Morel,&nbsp;Laurent Bailly,&nbsp;Cédric Urbanczyk,&nbsp;Dominique Hervé,&nbsp;Stéphane Berroir,&nbsp;Raphaël Le Bouc,&nbsp;Richard Levy,&nbsp;Mylène Meyer,&nbsp;Chaker Aloui,&nbsp;Elisabeth Tournier-Lasserve,&nbsp;Guillaume Mathey","doi":"10.1212/NXG.0000000000200069","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200069","url":null,"abstract":"<p><strong>Objectives: </strong>To refine the clinical spectrum of a very recently identified phenotype associated with <i>LAMB1</i> end-truncating pathogenic variations.</p><p><strong>Methods: </strong>Detailed clinical, neuropsychological, and MRI investigation of 6 patients from 2 unrelated families segregating end-truncating <i>LAMB1</i> variations.</p><p><strong>Results: </strong>All patients harbored <i>a LAMB1</i> end-truncating pathogenic variation. The specific association of a hippocampal type episodic memory dysfunction and a diffuse leukoencephalopathy was observed in all 4 patients aged older than 50 years, slightly worsening over time in 2 patients with several years of follow-up. Additional unspecific neurologic symptoms are reported, such as episodes of numbness, language troubles, or faintness in these 4 patients and the 2 younger ones.</p><p><strong>Discussion: </strong>The association of an extensive leukoencephalopathy with an episodic memory dysfunction of the hippocampal type is strongly suggestive of a <i>LAMB1</i> end-truncating variation in adults older than 50 years. Early cognitive complaints and imaging abnormalities might exist decades before. Additional transient manifestations can be observed, and this association should lead to <i>LAMB1</i> screening to avoid unnecessary invasive investigations.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 3","pages":"e200069"},"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/4a/26/NXG-2023-000012.PMC10096279.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9309029","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":"Machine Learning Approach for the Prediction of Age-Specific Probability of SCA3 and DRPLA by Survival Curve Analysis.","authors":"Yuya Hatano,&nbsp;Tomohiko Ishihara,&nbsp;Sachiko Hirokawa,&nbsp;Osamu Onodera","doi":"10.1212/NXG.0000000000200075","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200075","url":null,"abstract":"<p><strong>Background and objectives: </strong>As the number of repeats in the expansion increases, polyglutamine diseases tend to show at a younger age. From this relationship, attempts have been made to predict age at onset by parametric survival analysis. However, a method for a more accurate prediction has been desirable. In this study, we examined 2 methods for survival analysis using machine learning and 6 conventional methods for parametric survival analysis of spinocerebellar ataxia (SCA)3 and dentatorubral-pallidoluysian atrophy (DRPLA).</p><p><strong>Methods: </strong>We compared the performance of 2 machine learning methods of survival analysis (random survival forest [RSF] and DeepSurv) and 6 methods of parametric survival analysis (Weibull, exponential, Gaussian, logistic, loglogistic, and log Gaussian). Training and evaluation were performed using the leave-one-out cross-validation method, and evaluation criteria included root mean squared error (RMSE), mean absolute error (MAE), and the integrated Brier score. The latter was used as the primary end point, and the survival analysis model yielding the best result was used to predict the asymptomatic probability.</p><p><strong>Results: </strong>Among the models examined, the RSF and DeepSurv machine learning methods had a higher prediction accuracy than the parametric methods of survival analysis. For both SCA3 and DRPLA, RSF had a higher accuracy than DeepSurv for the assessment of RMSE (SCA3: 7.37, DRPLA: 10.78), MAE (SCA3: 5.52, DRPLA: 8.17), and the integrated Brier score (SCA3: 0.05, DRPLA: 0.077). Using RSF, we determined the age-specific probability distribution of age at onset based on CAG repeat size and current age.</p><p><strong>Discussion: </strong>In this study, we have demonstrated the superiority of machine learning methods for predicting age at onset of SCA3 and DRPLA using survival analysis. Such accurate prediction of onset will be useful for genetic counseling of carriers and for devising methods to verify the effects of interventions for unaffected individuals.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 3","pages":"e200075"},"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/f2/bf/NXG-2023-000018.PMC10159758.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9432057","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}