Siddharth Srivastava MD, Jordan J. Cole MD, Julie S. Cohen ScM, Maya Chopra MBBS, FRACP, Hadley Stevens Smith PhD, MPSA, Matthew A. Deardorff MD, PhD, Ernest Pedapati MD, MS, FAAP, Brian Corner MS, Julia S. Anixt MD, Shafali Jeste MD, Mustafa Sahin MD, PhD, Christina A. Gurnett MD, PhD, Colleen A. Campbell PhD, MS, the Intellectual and Developmental Disabilities Research Center (IDDRC) Workgroup on Advocating for Access to Genomic Testing
Genetic testing of patients with neurodevelopmental disabilities (NDDs) is critical for diagnosis, medical management, and access to precision therapies. Because genetic testing approaches evolve rapidly, professional society practice guidelines serve an essential role in guiding clinical care; however, several challenges exist regarding the creation and equitable implementation of these guidelines. In this scoping review, we assessed the current state of United States professional societies' guidelines pertaining to genetic testing for unexplained global developmental delay, intellectual disability, autism spectrum disorder, and cerebral palsy. We describe several identified shortcomings and argue the need for a unified, frequently updated, and easily-accessible cross-specialty society guideline. ANN NEUROL 2024;96:900–913
{"title":"Survey of the Landscape of Society Practice Guidelines for Genetic Testing of Neurodevelopmental Disorders","authors":"Siddharth Srivastava MD, Jordan J. Cole MD, Julie S. Cohen ScM, Maya Chopra MBBS, FRACP, Hadley Stevens Smith PhD, MPSA, Matthew A. Deardorff MD, PhD, Ernest Pedapati MD, MS, FAAP, Brian Corner MS, Julia S. Anixt MD, Shafali Jeste MD, Mustafa Sahin MD, PhD, Christina A. Gurnett MD, PhD, Colleen A. Campbell PhD, MS, the Intellectual and Developmental Disabilities Research Center (IDDRC) Workgroup on Advocating for Access to Genomic Testing","doi":"10.1002/ana.27045","DOIUrl":"10.1002/ana.27045","url":null,"abstract":"<p>Genetic testing of patients with neurodevelopmental disabilities (NDDs) is critical for diagnosis, medical management, and access to precision therapies. Because genetic testing approaches evolve rapidly, professional society practice guidelines serve an essential role in guiding clinical care; however, several challenges exist regarding the creation and equitable implementation of these guidelines. In this scoping review, we assessed the current state of United States professional societies' guidelines pertaining to genetic testing for unexplained global developmental delay, intellectual disability, autism spectrum disorder, and cerebral palsy. We describe several identified shortcomings and argue the need for a unified, frequently updated, and easily-accessible cross-specialty society guideline. ANN NEUROL 2024;96:900–913</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Patrick R Blackburn, Frédéric Ebstein, Tzung-Chien Hsieh, Marialetizia Motta, Francesca Clementina Radio, Johanna C Herkert, Tuula Rinne, Isabelle Thiffault, Michele Rapp, Mariel Alders, Saskia Maas, Bénédicte Gerard, Thomas Smol, Catherine Vincent-Delorme, Benjamin Cogné, Bertrand Isidor, Marie Vincent, Ruxandra Bachmann-Gagescu, Anita Rauch, Pascal Joset, Giovanni Battista Ferrero, Andrea Ciolfi, Thomas Husson, Anne-Marie Guerrot, Carlos Bacino, Colleen Macmurdo, Stephanie S Thompson, Jill A Rosenfeld, Laurence Faivre, Frederic Tran Mau-Them, Wallid Deb, Virginie Vignard, Pankaj B Agrawal, Jill A Madden, Alice Goldenberg, François Lecoquierre, Michael Zech, Holger Prokisch, Ján Necpál, Robert Jech, Juliane Winkelmann, Monika Turčanová Koprušáková, Vassiliki Konstantopoulou, John R Younce, Marwan Shinawi, Chloe Mighton, Charlotte Fung, Chantal F Morel, Jordan Lerner-Ellis, Stephanie DiTroia, Magalie Barth, Dominique Bonneau, Ingrid Krapels, Alexander P A Stegmann, Vyne van der Schoot, Theresa Brunet, Cornelia Bußmann, Cyril Mignot, Giuseppe Zampino, Saskia B Wortmann, Johannes A Mayr, René G Feichtinger, Thomas Courtin, Claudia Ravelli, Boris Keren, Alban Ziegler, Linda Hasadsri, Pavel N Pichurin, Eric W Klee, Katheryn Grand, Pedro A Sanchez-Lara, Elke Krüger, Stéphane Bézieau, Hannah Klinkhammer, Peter Michael Krawitz, Evan E Eichler, Marco Tartaglia, Sébastien Küry, Tianyun Wang
Objective: De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.
Methods: Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells.
Results: We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells.
Interpretation: Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024.
目的:cullin-3泛素连接酶(CUL3)的新变异与神经发育障碍(NDDs)密切相关,但迄今为止尚未有大规模的病例报道。在此,我们旨在收集携带CUL3罕见变异的散发性病例,描述基因型与表型的相关性,并研究其潜在的致病机制:方法:通过多中心合作收集遗传数据和详细的临床记录。方法:通过多中心合作收集遗传数据和详细的临床记录,使用 GestaltMatcher 分析畸形面部特征。使用患者衍生 T 细胞评估变异对 CUL3 蛋白稳定性的影响:我们收集了37名具有杂合子CUL3变异的个体,这些个体表现为以智力障碍为特征的综合型NDD,伴有或不伴有自闭症特征。其中,35 例为功能缺失(LoF)变异,2 例为错义变异。患者体内的 CUL3 LoF 变异可能会影响蛋白质的稳定性,导致蛋白质平衡紊乱,体外泛素-蛋白质共轭物的减少就是证明。值得注意的是,我们发现在患者衍生细胞中,CUL3的主要底物4E-BP1(EIF4EBP1)未能成为蛋白酶体降解的靶标:我们的研究进一步完善了CUL3相关神经精神疾病的临床和突变谱,扩展了cullin RING E3连接酶相关神经精神疾病的谱系,并提示通过LoF变体导致的单倍体功能缺失是主要的致病机制。ann neurol 2024.
{"title":"Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder.","authors":"Patrick R Blackburn, Frédéric Ebstein, Tzung-Chien Hsieh, Marialetizia Motta, Francesca Clementina Radio, Johanna C Herkert, Tuula Rinne, Isabelle Thiffault, Michele Rapp, Mariel Alders, Saskia Maas, Bénédicte Gerard, Thomas Smol, Catherine Vincent-Delorme, Benjamin Cogné, Bertrand Isidor, Marie Vincent, Ruxandra Bachmann-Gagescu, Anita Rauch, Pascal Joset, Giovanni Battista Ferrero, Andrea Ciolfi, Thomas Husson, Anne-Marie Guerrot, Carlos Bacino, Colleen Macmurdo, Stephanie S Thompson, Jill A Rosenfeld, Laurence Faivre, Frederic Tran Mau-Them, Wallid Deb, Virginie Vignard, Pankaj B Agrawal, Jill A Madden, Alice Goldenberg, François Lecoquierre, Michael Zech, Holger Prokisch, Ján Necpál, Robert Jech, Juliane Winkelmann, Monika Turčanová Koprušáková, Vassiliki Konstantopoulou, John R Younce, Marwan Shinawi, Chloe Mighton, Charlotte Fung, Chantal F Morel, Jordan Lerner-Ellis, Stephanie DiTroia, Magalie Barth, Dominique Bonneau, Ingrid Krapels, Alexander P A Stegmann, Vyne van der Schoot, Theresa Brunet, Cornelia Bußmann, Cyril Mignot, Giuseppe Zampino, Saskia B Wortmann, Johannes A Mayr, René G Feichtinger, Thomas Courtin, Claudia Ravelli, Boris Keren, Alban Ziegler, Linda Hasadsri, Pavel N Pichurin, Eric W Klee, Katheryn Grand, Pedro A Sanchez-Lara, Elke Krüger, Stéphane Bézieau, Hannah Klinkhammer, Peter Michael Krawitz, Evan E Eichler, Marco Tartaglia, Sébastien Küry, Tianyun Wang","doi":"10.1002/ana.27077","DOIUrl":"10.1002/ana.27077","url":null,"abstract":"<p><strong>Objective: </strong>De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.</p><p><strong>Methods: </strong>Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells.</p><p><strong>Results: </strong>We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells.</p><p><strong>Interpretation: </strong>Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryan M. McCormack, Arjun S. Chandran, Samden D. Lhatoo, Sandipan Pati, Zhouxuan Li, Katherine Harris, Nuria Lacuey, Giridhar Kalamangalam, Stephen Thompson, Nitin Tandon
Periventricular nodular heterotopia (PVNH) is the most common neuronal heterotopia, frequently resulting in pharmaco-resistant epilepsy. Here, we characterize variables that predict good epilepsy outcomes following surgical intervention using stereo-electroencephalography (SEEG) -informed magnetic resonance-guided laser interstitial thermal therapy (MRgLITT).
{"title":"Laser Ablation of Periventricular Nodular Heterotopia for Medically Refractory Epilepsy","authors":"Ryan M. McCormack, Arjun S. Chandran, Samden D. Lhatoo, Sandipan Pati, Zhouxuan Li, Katherine Harris, Nuria Lacuey, Giridhar Kalamangalam, Stephen Thompson, Nitin Tandon","doi":"10.1002/ana.27059","DOIUrl":"https://doi.org/10.1002/ana.27059","url":null,"abstract":"Periventricular nodular heterotopia (PVNH) is the most common neuronal heterotopia, frequently resulting in pharmaco-resistant epilepsy. Here, we characterize variables that predict good epilepsy outcomes following surgical intervention using stereo-electroencephalography (SEEG) -informed magnetic resonance-guided laser interstitial thermal therapy (MRgLITT).","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Widad Abou Chaar, Anirudh N. Eranki, Hannah A. Stevens, Sonya L. Watson, Darice Y. Wong, Veronica S. Avila, Megan Delfeld, Alexander J. Gary, Sanjukta Tawde, Malia Triebold, Marcello Cherchi, Tao Xie, Paul J. Lockhart, Melanie Bahlo, David Pellerin, Marie‐Josée Dicaire, Matt Danzi, Stephan Zuchner, Bernard C. Brais, Susan Perlman, Margit Burmeister, Henry Paulson, Sharan Srinivasan, Lawrence Schut, Matthew Bower, Khalaf Bushara, Chuanhong Liao, Vikram G. Shakkottai, John Collins, H. Brent Clark, Soma Das, Brent L. Fogel, Christopher M. Gomez
ObjectivesSpinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late‐onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4‐aminopyridine in a cohort of 102 patients bearing GAA repeat expansions.MethodsWe compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post‐mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B.ResultsIn our cohort of 102 patients with SCA27B, we found that SCA27B was a late‐onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post‐mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4‐aminopyridine.InterpretationOur study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024
{"title":"Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B)","authors":"Widad Abou Chaar, Anirudh N. Eranki, Hannah A. Stevens, Sonya L. Watson, Darice Y. Wong, Veronica S. Avila, Megan Delfeld, Alexander J. Gary, Sanjukta Tawde, Malia Triebold, Marcello Cherchi, Tao Xie, Paul J. Lockhart, Melanie Bahlo, David Pellerin, Marie‐Josée Dicaire, Matt Danzi, Stephan Zuchner, Bernard C. Brais, Susan Perlman, Margit Burmeister, Henry Paulson, Sharan Srinivasan, Lawrence Schut, Matthew Bower, Khalaf Bushara, Chuanhong Liao, Vikram G. Shakkottai, John Collins, H. Brent Clark, Soma Das, Brent L. Fogel, Christopher M. Gomez","doi":"10.1002/ana.27060","DOIUrl":"https://doi.org/10.1002/ana.27060","url":null,"abstract":"ObjectivesSpinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (<jats:italic>FGF14</jats:italic>) gene has recently been recognized as a common cause of late‐onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4‐aminopyridine in a cohort of 102 patients bearing GAA repeat expansions.MethodsWe compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post‐mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B.ResultsIn our cohort of 102 patients with SCA27B, we found that SCA27B was a late‐onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post‐mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4‐aminopyridine.InterpretationOur study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}