Sarah M. Brooker MD, PhD, Maria Novelli MD, Robert Coukos PhD, Neha Prakash MBBS, Walaa A. Kamel MD, Marta Amengual-Gual MD, Mathieu Anheim MD, PhD, Giulia Barcia MD, PhD, Tanya Bardakjian MS, Franciska Baur MD, Steffen Berweck MD, Bigna K. Bölsterli MD, Melanie Brugger MD, Thomas Cassini MD, Nicolas Chatron MD, Brian Corner MS, Hormos Salimi Dafsari MD, Jean-Madeleine de Sainte Agathe MD, Colin A. Ellis MD, Kimberly M. Ezell APRN, FNP, Cendrine Foucard MD, Steven J. Frucht MD, Maria C. Garcia MBBS, Deepak Gill MBBS, FRACP, Anne Guimier MD, Rizwan Hamid MD, PhD, Damià Heine-Suñer PhD, Peter Herkenrath MD, Marie Hully MD, Ioannis U. Isaias MD, PhD, Louis Januel MD, Chloe Laurencin MD, Taylor Laut MS, Alinoe Lavillaureix MD, Gaetan Lesca MD, PhD, Marion Lesieur-Sebellin MD, Luca Magistrelli MD, PhD, Cecilia Marelli MD, PhD, Heather C. Mefford MD, PhD, Bryce A. Mendelsohn MD, Saadet Mercimek-Andrews MD, PhD, Claire Miller MD, PhD, Shekeeb S. Mohammad MBBS, PhD, FRACP, Francesca Morgante MD, PhD, Sirisha Nandipati MD, Thomas Opladen MD, Mahesh Padmanaban MD, Micaela Pauni MD, Gianni Pezzoli MD, Amelie Piton PhD, Francis Ramond MD, PhD, Giulietta M. Riboldi MD, PhD, Christelle Rougeot-Jung MD, Fernando Santos-Simarro MD, PhD, Ingrid E. Scheffer MBBS, PhD, Naoual Serari M2, Christine M. Stahl MD, Ann Stembridge Kung MS, Susana Tarongí Sanchez MD, Christel Thauvin-Robinet MD, PhD, Marianne Till MD, Christine Tranchant MD, PhD, Christopher Troedson MBBS, FRACP, Thomas F. Tropea DO, MPH, Olivier Vanakker MD, PhD, Patricia Vega MD, Maxi Leona Wiese MD, Udo Wieshmann MD, PhD, FRCP, Laura J. Williams MB BCh BAO, MD, Thomas Wirth MD, Michael Zech MD, Hans Zempel MD, PhD, Emmanuel Roze MD, PhD, Vincenzo Leuzzi MD, Serena Galosi MD, PhD, Victor S. C. Fung PhD, FRACP, Gemma Carvill PhD, Dimitri Krainc MD, PhD, Elizabeth Gerard MD, Niccolò E. Mencacci MD, PhD
{"title":"The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series","authors":"Sarah M. Brooker MD, PhD, Maria Novelli MD, Robert Coukos PhD, Neha Prakash MBBS, Walaa A. Kamel MD, Marta Amengual-Gual MD, Mathieu Anheim MD, PhD, Giulia Barcia MD, PhD, Tanya Bardakjian MS, Franciska Baur MD, Steffen Berweck MD, Bigna K. Bölsterli MD, Melanie Brugger MD, Thomas Cassini MD, Nicolas Chatron MD, Brian Corner MS, Hormos Salimi Dafsari MD, Jean-Madeleine de Sainte Agathe MD, Colin A. Ellis MD, Kimberly M. Ezell APRN, FNP, Cendrine Foucard MD, Steven J. Frucht MD, Maria C. Garcia MBBS, Deepak Gill MBBS, FRACP, Anne Guimier MD, Rizwan Hamid MD, PhD, Damià Heine-Suñer PhD, Peter Herkenrath MD, Marie Hully MD, Ioannis U. Isaias MD, PhD, Louis Januel MD, Chloe Laurencin MD, Taylor Laut MS, Alinoe Lavillaureix MD, Gaetan Lesca MD, PhD, Marion Lesieur-Sebellin MD, Luca Magistrelli MD, PhD, Cecilia Marelli MD, PhD, Heather C. Mefford MD, PhD, Bryce A. Mendelsohn MD, Saadet Mercimek-Andrews MD, PhD, Claire Miller MD, PhD, Shekeeb S. Mohammad MBBS, PhD, FRACP, Francesca Morgante MD, PhD, Sirisha Nandipati MD, Thomas Opladen MD, Mahesh Padmanaban MD, Micaela Pauni MD, Gianni Pezzoli MD, Amelie Piton PhD, Francis Ramond MD, PhD, Giulietta M. Riboldi MD, PhD, Christelle Rougeot-Jung MD, Fernando Santos-Simarro MD, PhD, Ingrid E. Scheffer MBBS, PhD, Naoual Serari M2, Christine M. Stahl MD, Ann Stembridge Kung MS, Susana Tarongí Sanchez MD, Christel Thauvin-Robinet MD, PhD, Marianne Till MD, Christine Tranchant MD, PhD, Christopher Troedson MBBS, FRACP, Thomas F. Tropea DO, MPH, Olivier Vanakker MD, PhD, Patricia Vega MD, Maxi Leona Wiese MD, Udo Wieshmann MD, PhD, FRCP, Laura J. Williams MB BCh BAO, MD, Thomas Wirth MD, Michael Zech MD, Hans Zempel MD, PhD, Emmanuel Roze MD, PhD, Vincenzo Leuzzi MD, Serena Galosi MD, PhD, Victor S. C. Fung PhD, FRACP, Gemma Carvill PhD, Dimitri Krainc MD, PhD, Elizabeth Gerard MD, Niccolò E. Mencacci MD, PhD","doi":"10.1002/ana.27272","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss-of-function variants in <i>NUS1</i> have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic <i>NUS1</i> variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Cases with <i>NUS1</i>-related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform. Clinical data were acquired through retrospective case-note review.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>We identified 41 subjects carrying 38 different pathogenic or likely pathogenic heterozygous <i>NUS1</i> variants. The majority of cases displayed developmental delays and intellectual disability of variable severity. Epilepsy was present in 68.3% of cases (28/41) with onset typically in early childhood. Strikingly, 87.8% of cases (36/41) presented with movement disorders and for 13 of these cases the movement disorder was not accompanied by epilepsy. The phenomenology of the movement disorders was complex with myoclonus observed in 68.3% of cases (28/41), either in isolation or in combination with dystonia, ataxia, and/or parkinsonism. Seven cases that otherwise did not have prominent movement disorders had mild incoordination and intention tremor, suggestive of cerebellar dysfunction. There was no observed genotype–phenotype correlation, suggesting that other genetic or acquired factors impact the clinical presentation.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>Heterozygous <i>NUS1</i> pathogenic variants cause a complex neurological disorder, variably featuring developmental and epileptic encephalopathies and a broad spectrum of movement disorders, which represent the major source of neurological disability for most cases. ANN NEUROL 2025;98:561–572</p>\n </section>\n </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 3","pages":"561-572"},"PeriodicalIF":7.7000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221205/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ana.27272","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Objective
A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss-of-function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders.
Methods
Cases with NUS1-related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform. Clinical data were acquired through retrospective case-note review.
Results
We identified 41 subjects carrying 38 different pathogenic or likely pathogenic heterozygous NUS1 variants. The majority of cases displayed developmental delays and intellectual disability of variable severity. Epilepsy was present in 68.3% of cases (28/41) with onset typically in early childhood. Strikingly, 87.8% of cases (36/41) presented with movement disorders and for 13 of these cases the movement disorder was not accompanied by epilepsy. The phenomenology of the movement disorders was complex with myoclonus observed in 68.3% of cases (28/41), either in isolation or in combination with dystonia, ataxia, and/or parkinsonism. Seven cases that otherwise did not have prominent movement disorders had mild incoordination and intention tremor, suggestive of cerebellar dysfunction. There was no observed genotype–phenotype correlation, suggesting that other genetic or acquired factors impact the clinical presentation.
Interpretation
Heterozygous NUS1 pathogenic variants cause a complex neurological disorder, variably featuring developmental and epileptic encephalopathies and a broad spectrum of movement disorders, which represent the major source of neurological disability for most cases. ANN NEUROL 2025;98:561–572
期刊介绍：
Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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