title: The preclinical stage of spinocerebellar ataxias.
abstract: The autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of degenerative diseases of the cerebellum and connected regions. The discovery of various SCA genes and the subsequent possibility of predictive testing currently allow a genetic diagnosis to be established years or even decades before the actual appearance of ataxia symptoms. A growing body of evidence, however, indicates that this preclinical stage is subject to the earliest pathophysiologic changes. This review article comprehensively summarizes the studies conducted in preclinical carriers of a mutation in one of the SCA genes. From these data, it can indeed be concluded that the preclinical phase in SCA is already characterized by detectable central and peripheral nervous system changes, which are reflected by subtle abnormalities during a careful clinical examination, changes in structural and functional brain imaging, abnormal neurophysiologic measurements, and/or altered motor learning paradigms. As these may be compensated for a long time, ataxia symptoms probably only appear after a certain threshold of dysfunction or degeneration has been exceeded. Detailed knowledge of this disease stage is of particular relevance for a better understanding of the pathogenesis of SCAs, will allow us to determine the optimal point in time for interventions in future therapeutic trials, and points to objective, valid biomarkers to assess disease progression. Further studies will benefit from a consensus-based definition of the preclinical stage, from using one and the same validated ataxia rating scale with one fixed cutoff value, and from applying similar mathematical models to calculate time to predicted disease onset.
authors.affiliation: From the Department of Neurology & Donders Institute for Brain, Cognition, and Behaviour (R.P.P.W.M.M., J.v.G., B.P.C.v.d.W.), Radboud University Medical Center, Nijmegen, the Netherlands; and the Department of Neurology & German Center for Neurodegenerative Diseases (T.K.), University Hospital Bonn, Germany.
authors.forename: Roderick P P W M
authors.initials: RP
authors.lastname: Maas
authors.affiliation: From the Department of Neurology & Donders Institute for Brain, Cognition, and Behaviour (R.P.P.W.M.M., J.v.G., B.P.C.v.d.W.), Radboud University Medical Center, Nijmegen, the Netherlands; and the Department of Neurology & German Center for Neurodegenerative Diseases (T.K.), University Hospital Bonn, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: van Gaalen
authors.affiliation: From the Department of Neurology & Donders Institute for Brain, Cognition, and Behaviour (R.P.P.W.M.M., J.v.G., B.P.C.v.d.W.), Radboud University Medical Center, Nijmegen, the Netherlands; and the Department of Neurology & German Center for Neurodegenerative Diseases (T.K.), University Hospital Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.affiliation: From the Department of Neurology & Donders Institute for Brain, Cognition, and Behaviour (R.P.P.W.M.M., J.v.G., B.P.C.v.d.W.), Radboud University Medical Center, Nijmegen, the Netherlands; and the Department of Neurology & German Center for Neurodegenerative Diseases (T.K.), University Hospital Bonn, Germany. bart.vandewarrenburg@radboudumc.nl.
authors.forename: Bart P C
authors.initials: BP
authors.lastname: van de Warrenburg
mesh_terms: D003952:Diagnostic Imaging / Q000379:methods / Q000639:trends; D018450:Disease Progression; D006801:Humans; D009154:Mutation / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*