Abstract
BACKGROUND: While most sporadic adult-onset neurodegenerative diseases have only a minor monogenic component, given several recently identified late adult-onset ataxia genes, the genetic burden may be substantial in sporadic adult-onset ataxias. We report systematic mapping of the genetic landscape of sporadic adult-onset ataxia in a well-characterised, multi-centre cohort, combining several multi-modal genetic screening techniques, plus longitudinal natural history data. METHODS: Systematic clinico-genetic analysis of a prospective longitudinal multi-centre cohort of 377 consecutive patients with sporadic adult-onset ataxia (SPORTAX cohort), including clinically defined sporadic adult-onset ataxia of unknown aetiology (SAOA) (n = 229) and 'clinically probable multiple system atrophy of cerebellar type' (MSA-C(cp)) (n = 148). Combined GAA-FGF14 (SCA27B) and RFC1 repeat expansion screening with next-generation sequencing (NGS) was complemented by natural history and plasma neurofilament light chain analysis in key subgroups. FINDINGS: 85 out of 377 (22.5%) patients with sporadic adult-onset ataxia carried a pathogenic or likely pathogenic variant, thereof 67/229 (29.3%) patients with SAOA and 18/148 (12.2%) patients meeting the MSA-C(cp) criteria. This included: 45/377 (11.9%) patients with GAA-FGF14(≥250) repeat expansions (nine with MSA-C(cp)), 17/377 (4.5%) patients with RFC1 repeat expansions (three with MSA-C(cp)), and 24/377 (6.4%) patients with single nucleotide variants (SNVs) identified by NGS (six with MSA-C(cp)). Five patients (1.3%) were found to have two relevant genetic variants simultaneously (dual diagnosis). INTERPRETATION: In this cohort of sporadic adult-onset ataxia, a cohort less likely to have a monogenic cause, a substantial burden of monogenic variants was identified, particularly GAA-FGF14 and RFC1 repeat expansions. This included a substantial share of patients meeting the MSA-C(cp) criteria, suggesting a reduced specificity of this clinical diagnosis and potential co-occurrence of MSA-C plus a second, independent genetic condition. These findings have important implications for the genetic work-up and counselling of patients with sporadic ataxia, even when presenting with MSA-like features. With targeted treatments for genetic ataxias now on the horizon, these findings highlight their potential utility for these patients. FUNDING: This work was supported by the Clinician Scientist programme "PRECISE.net" funded by the Else Kröner-Fresenius-Stiftung (to DM, AT, CW, OR, and MS), by the Deutsche Forschungsgemeinschaft (as part of the PROSPAX project), and by the Canadian Institutes of Health Research and the Fondation Groupe Monaco. Support was also provided by Humboldt Research Fellowship for Postdocs and the Hertie-Network of Excellence in Clinical Neuroscience and a Fellowship award from the Canadian Institutes of Health Research.