Distinct Brain Drivers and Shared Cerebello–Cortical Input in <scp> <i>ADCY5</i> </scp> and <scp> <i>SGCE</i> </scp> Hyperkinetic Movements

BACKGROUND: Hyperkinetic movement disorders arise from dysfunction within cortico-basal ganglia-cerebellar loops. They frequently involve psychiatric and cognitive symptoms, reflecting impairment of both motor and non-motor domains within these loops. ADCY5 (MxMD-ADCY5) and SGCE (MYC/DYT-SGCE) related movement disorders are childhood-onset monogenic hyperkinetic conditions, both characterized by myoclonus, dystonia, and frequent psychiatric manifestations. Previous evidence suggests predominant basal ganglia involvement in MxMD-ADCY5 and cerebellar involvement in MYC/DYT-SGCE. OBJECTIVES: The aim was to determine how basal ganglia and cerebellar dysfunction drives cortical dysregulation in hyperkinetic movement disorders. METHODS: Resting-state functional magnetic resonance imaging (fMRI) was used to examine effective connectivity in motor and non-motor cortico-basal ganglia-cerebellar loops. Findings were validated using leave-one-out cross-validation. Microstructural properties of regions within these loops were assessed with diffusion-weighted imaging, using neurite orientation dispersion and density measures. RESULTS: We enrolled 21 patients with MxMD-ADCY5, 24 with MYC/DYT-SGCE, and matched healthy controls. Both patient groups exhibited elevated rates of psychiatric comorbidities. In MxMD-ADCY5, abnormal basal ganglia connectivity influenced the cerebellum, which in turn modulated cortical activity across motor and non-motor loops. Reduced neurite density was observed in the subthalamic nucleus, a relay between basal ganglia and cerebellum. In MYC/DYT-SGCE, the cerebellum showed predominant influence on cortical activity, with downstream modulation of basal ganglia activity, but no microstructural alterations were detected. Cross-validation largely confirmed the connectivity patterns' reliability. CONCLUSION: Abnormal cortical modulation in both disorders converges on a shared cerebellar-cortical pathway, with basal ganglia influences in MxMD-ADCY5 transmitted via the cerebellum to the cortex, and cerebellar contributions in MYC/DYT-SGCE directly influencing the cortex. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Journal
Movement Disorders
Published
2026-04-30
DOI
https://doi.org/10.1002/mds.70337
Primary Topic
Neurological and metabolic disorders
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article
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article

Distinct Brain Drivers and Shared Cerebello–Cortical Input in ADCY5 and SGCE Hyperkinetic Movements

M Vidailhet, Eavan M. McGovern, Quentin Salardaine, Oriane Trouillard et al.
Movement Disorders
Neurological and metabolic disorders
article

Distinct Brain Drivers and Shared Cerebello–Cortical Input in ADCY5 and SGCE Hyperkinetic Movements

M Vidailhet, Eavan M. McGovern, Quentin Salardaine, Oriane Trouillard, Mohamed Doulazmi, Asya Ekmen, Benoît Béranger, Miryam Carecchio, Lina Daghsen, Cécile Delorme, Diane Doummar, Sabine Meunier, Aurélie Méneret, Victoria González, Florence Riant, Caroline Dubacq, Mélanie Didier, Clément Tarrano, Alexander Münchau, Cecile Gallea, Carlo Fusco, Vanessa Brochard, Kailash P Bhatia, Agathe Roubertie, Norbert Brüggemann, Mathieu Anheim, Pierre Pouget, Manon Gomes, Christine Tranchant, Philippe Damier, Eoin Mulroy, Emmanuel Roze, Romain Valabregue, Yulia Worbe
article en

Abstract

BACKGROUND: Hyperkinetic movement disorders arise from dysfunction within cortico-basal ganglia-cerebellar loops. They frequently involve psychiatric and cognitive symptoms, reflecting impairment of both motor and non-motor domains within these loops. ADCY5 (MxMD-ADCY5) and SGCE (MYC/DYT-SGCE) related movement disorders are childhood-onset monogenic hyperkinetic conditions, both characterized by myoclonus, dystonia, and frequent psychiatric manifestations. Previous evidence suggests predominant basal ganglia involvement in MxMD-ADCY5 and cerebellar involvement in MYC/DYT-SGCE. OBJECTIVES: The aim was to determine how basal ganglia and cerebellar dysfunction drives cortical dysregulation in hyperkinetic movement disorders. METHODS: Resting-state functional magnetic resonance imaging (fMRI) was used to examine effective connectivity in motor and non-motor cortico-basal ganglia-cerebellar loops. Findings were validated using leave-one-out cross-validation. Microstructural properties of regions within these loops were assessed with diffusion-weighted imaging, using neurite orientation dispersion and density measures. RESULTS: We enrolled 21 patients with MxMD-ADCY5, 24 with MYC/DYT-SGCE, and matched healthy controls. Both patient groups exhibited elevated rates of psychiatric comorbidities. In MxMD-ADCY5, abnormal basal ganglia connectivity influenced the cerebellum, which in turn modulated cortical activity across motor and non-motor loops. Reduced neurite density was observed in the subthalamic nucleus, a relay between basal ganglia and cerebellum. In MYC/DYT-SGCE, the cerebellum showed predominant influence on cortical activity, with downstream modulation of basal ganglia activity, but no microstructural alterations were detected. Cross-validation largely confirmed the connectivity patterns' reliability. CONCLUSION: Abnormal cortical modulation in both disorders converges on a shared cerebellar-cortical pathway, with basal ganglia influences in MxMD-ADCY5 transmitted via the cerebellum to the cortex, and cerebellar contributions in MYC/DYT-SGCE directly influencing the cortex. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Movement Disorders
Hebron University (PS), Centre National de la Recherche Scientifique (FR), University of Padua (IT), Royal College of Surgeons in Ireland (IE), Inserm (FR), Université de Montpellier (FR), Beaumont Hospital (IE), Centre Hospitalier Universitaire de Nantes (FR), Sorbonne Université (FR), Institut de génétique et de biologie moléculaire et cellulaire (FR), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), Centre Hospitalier Universitaire de Montpellier (FR), Assistance Publique – Hôpitaux de Paris (FR), Hôpital Saint-Antoine (FR), University Hospital Schleswig-Holstein (DE), Pitié-Salpêtrière Hospital (FR), Fondation Ophtalmologique Adolphe de Rothschild (FR), Fondation de Rothschild (FR), Vall d'Hebron Hospital Universitari (ES), Institute for Neurosciences of Montpellier (FR), National Hospital for Neurology and Neurosurgery (GB), Institut du Cerveau (FR), Hôpital d'Hautepierre (FR), University College London (GB), Université Paris 1 Panthéon-Sorbonne (FR), Université de Strasbourg (FR), University of Lübeck (DE), Nantes Université (FR)
Amadys, European Commission, Fondation pour la Recherche Médicale, Merz Pharmaceuticals, Institut du Cerveau et de la Moelle Epinière
Good health and well-being
Openalex Percentile: Top 11%
Neurological and metabolic disorders
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