Ilaria Giordano, MD, Florian Harmuth, MSc, Heike Jacobi, MD, Brigitte Paap, PhD, Stefan Vielhaber, MD, Judith Machts, MSc, Ludger Schöls, MD, Matthis Synofzik, MD, Marc Sturm, PhD, Chantal Tallaksen, MD, Iselin M. Wedding, MD, Sylvia Boesch, MD, Andreas Eigentler, MD, Bart van de Warrenburg, MD, Judith van Gaalen, MD, Christoph Kamm, MD, Ales Dudesek, MD, Jun-Suk Kang, MD, Dagmar Timmann, MD, Gabriella Silvestri, MD, Marcella Masciullo, MD, Thomas Klopstock, MD, Christiane Neuhofer, MD, Christos Ganos, MD, Alessandro Filla, MD, Peter Bauer, MD, Sophie Tezenas du Montcel, MD, PhD and Thomas Klockgether, MD
Journal of Neurology,
Objective: To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations.
Methods: The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing.
Results: The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p < 0.0001) and disease duration (0.22 ± 0.06 per additional year, p = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made.
Conclusions: Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort.
ClinicalTrials.gov registration: NCT02701036.