A case report of late-onset cerebellar ataxia associated with a rare p.R342W TGM6 (SCA35) mutation
Arianna Manini,
Tommaso Bocci,
Alice Migazzi,
Edoardo Monfrini,
Dario Ronchi,
Giulia Franco,
Anna De Rosa,
Ferdinando Sartucci,
Alberto Priori,
Stefania Corti,
Giacomo Pietro Comi,
Nereo Bresolin,
Manuela Basso,
Alessio Di Fonzo
Affiliations
Arianna Manini
Neurology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan
Tommaso Bocci
”Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan and ASST Santi Paolo e Carlo
Alice Migazzi
Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento
Edoardo Monfrini
Neurology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan
Dario Ronchi
Neurology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan
Giulia Franco
Neurology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan
Anna De Rosa
Department of Clinical and Experimental Medicine, Unit of Neurology, Pisa University Medical School
Ferdinando Sartucci
Department of Clinical and Experimental Medicine, Unit of Neurology, Pisa University Medical School
Alberto Priori
”Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan and ASST Santi Paolo e Carlo
Stefania Corti
Neurology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan
Giacomo Pietro Comi
Neurology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan
Nereo Bresolin
Neurology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan
Manuela Basso
Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento
Alessio Di Fonzo
Neurology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan
Abstract Background Mutations in TGM6 gene, encoding for transglutaminase 6 (TG6), have been implicated in the pathogenesis of spinocerebellar ataxia type 35 (SCA35), a rare autosomal dominant disease marked by cerebellar degeneration and characterized by postural instability, incoordination of gait, features of cerebellar dysfunction and pyramidal signs. Case presentation Here we report the case of an Italian patient with late-onset, slowly progressive cerebellar features, including gait ataxia, scanning speech and ocular dysmetria and pyramidal tract signs. Whole exome sequencing revealed the rare heterozygous c.1024C > T (p.R342W) variant of TGM6, located at a highly evolutionary conserved position and predicted as pathogenic by in silico tools. Expression of TG6-R342W mutant in HEK293T cells led to a significant reduction of transamidase activity compared to wild-type TG6. Conclusion This finding extends SCA35 genetic landscape, highlighting the importance of TGM6 screening in undiagnosed late-onset and slowly progressive cerebellar ataxias.
