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

Year: 2026

Type: article

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.

Source: Movement Disorders

DOI: 10.1002/mds.70337

Institutions: Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Antoine, Pitié-Salpêtrière Hospital, Institut du Cerveau, Royal College of Surgeons in Ireland, Beaumont Hospital, Fondation de Rothschild, UCL Queen Square Institute of Neurology, University College London, Azienda Sanitaria Unità Locale di Reggio Emilia, University of Padua, University Hospital Schleswig-Holstein, University of Lübeck, Vall d'Hebron Hospital Universitari, Hôpital Armand-Trousseau, Paris-Sorbonne University, Institut de génétique et de biologie moléculaire et cellulaire, Hôpitaux Universitaires de Strasbourg, Hôpital d'Hautepierre, Université de Strasbourg, Centre Hospitalier Universitaire de Nantes, Centre Hospitalier Universitaire de Montpellier, Institute for Neurosciences of Montpellier

Language: English

Topic: Neurological disorders and treatments

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,480

Funders: Biogen, Teva Pharmaceutical Industries, Amadys, European Commission, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, Merz Pharmaceuticals, Italfarmaco, Institut du Cerveau et de la Moelle Epinière

Awards: Alterations of motor networks in primary dystonia, G5420063140, G7100189111

OpenAlex ID: W7159687026