The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series.
The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Rome, IT · Author affiliation
Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.Location evidence
EG · Author affiliation · country only
Department of Neurology, Beni Suef University, Beni Suef, Egypt.Location evidence
Palma, ES · Author affiliation
Department of Pediatrics, Pediatric Neurology, Hospital Universitario Son Espases, Palma, Spain.Location evidence
Strasbourg, FR · Author affiliation
Department of Neurology, The University Hospitals of Strasbourg, Strasbourg, France.Location evidence
Paris, FR · Author affiliation
Universite Paris Cite, Department of Genomic Medicine of Rare Disorders, Necker Hospital, Paris, France.Location evidence
Köln, DE · Author affiliation
Department of Pediatrics, University of Cologne, Köln, Germany.Location evidence
DE · Author affiliation · country only
Schon Klinik Vogtareuth, Specialist Centre for Paediatric Neurology, Neurorehabilitation, and Epileptology, Vogtareuth, Germany.Location evidence
Zürich, CH · Author affiliation
Department of Pediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.Location evidence
Munich, DE · Author affiliation
Technical University of Munich School of Medicine and Health, Institute of Human Genetics, München, Germany.Location evidence
Lyon, FR · Author affiliation
Department of Genetics, University Hospital Centre Lyon, Lyon, France.Location evidence
Westmead, AU · Author affiliation
Department of Neurology, Movement Disorders Unit, Westmead Hospital, Westmead, New South Wales, Australia.Location evidence
GB · Author affiliation · country only
Department of Neurology, Movement Disorders Unit, Westmead Hospital, Westmead, New South Wales, Australia.Location evidence
Sydney, AU · Author affiliation
The University of Sydney, Sydney Medical School, Sydney, New South Wales, Australia.Location evidence
Nelson, GB · Author affiliation
TY Nelson Department of Neurology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.Location evidence
Milan, IT · Author affiliation
Gaetano Pini-CTO, Parkinson Institute, Milan, Italy.Location evidence
Würzburg, DE · Author affiliation
Department of Neurology, University Hospital Wurzburg, Wurzburg, Germany.Location evidence
Edmonton, CA · Author affiliation
Department of Medical Genetics, University of Alberta, Faculty of Medicine and Dentistry, Edmonton, Alberta, Canada.Location evidence
Rennes, FR · Author affiliation
CHU de Rennes, Service de Génétique Médicale, Rennes, France.Location evidence
Montpellier, FR · Author affiliation
Montpellier University, Expert Center for Neurogenetic Diseases, Montpellier, France.Location evidence
London, GB · Author affiliation
City St. George's University of London, Neuroscience and Cell Biology Institute, London, UK.Location evidence
Heidelberg, DE · Author affiliation
Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Heidelberg, Germany.Location evidence
Buenos Aires, AR · Author affiliation
Department of Pediatrics, Neuropediatric Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.Location evidence
Saint-Étienne, FR · Author affiliation
Department of Medical Genetics, Saint Etienne University Hospital, Saint-Etienne, France.Location evidence
Melbourne, AU · Author affiliation
University of Melbourne, Austin Health and Royal Children's Hospital and Florey Neuroscience Institutes, Melbourne, Victoria, Australia.Location evidence
ES · Author affiliation · country only
CHU Dijon, Centre de Genetique, Dijon, Spain.Location evidence
BE · Author affiliation · country only
Ghent University Hospital, Center for Medical Genetics, Ghent, Belgium.Location evidence
Richmond, GB · Author affiliation
Kingston and Richmond NHS Foundation Trust, Kingston upon Thames, UK.Location evidence
Garching, DE · Author affiliation
Technical University of Munich, Institute for Advanced Study Garching, Munich, Germany.Location evidence
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Original abstract
ObjectiveA 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.MethodsCases 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.ResultsWe 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.InterpretationHeterozygous 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.