BACKGROUND: Spinocerebellar ataxia 21 (SCA21) is a rare neurological disorder caused by heterozygous variants in TMEM240. A growing, yet still limited number of reports suggested that hyperkinetic movements should be considered a defining component of the disease. CASE SERIES: We describe two newly identified families harboring the recurrent pathogenic TMEM240 p.Pro170Leu variant. Both index patients and the mother of the first proband developed movement disorders, manifesting as myoclonic dystonia and action-induced dystonia without co-occurring ataxia in one case, and pancerebellar syndrome complicated by action-induced dystonia in the other. We reviewed the literature on TMEM240 variants linked to hyperkinetic disorders, comparing our cases to described phenotypes. DISCUSSION: Adding to prior preliminary observations, our series highlights the relevance of hyperkinetic movements as clinically meaningful features of SCA21. TMEM240 mutation should be included in the differential diagnosis of myoclonic dystonia and ataxia-dystonia syndromes.

2nd Department of Neurology Faculty of Medicine Comenius University Bratislava Slovakia

Clinical Genetics Unit Department of Women's and Children's Health University of Padova Padova Italy

Department of Neurology and Centre of Clinical Neuroscience General University Hospital and 1st Faculty of Medicine Charles University Kateřinská30 12 800 Prague Czech Republic

Department of Neurology Zvolen Hospital Zvolen Slovakia

DZPG Deutsches Zentrum für Psychische Gesundheit Munich Germany

Institute for Advanced Study Technical University of Munich Garching Germany

Institute of Human Genetics Technical University of Munich School of Medicine Munich Germany

Institute of Neurogenomics Helmholtz Munich Neuherberg Germany

Medical Genetics and Neurogenetics Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Munich Cluster for Systems Neurology Munich Germany

Parkinson and Movement Disorders Unit Department of Clinical Neurosciences Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

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