The genetic landscape of sporadic adult-onset degenerative ataxia: a multi-modal genetic study of 377 consecutive patients from the longitudinal multi-centre SPORTAX cohort

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.

Keywords: Adult-onset ataxia; CANVAS; Disease trajectories; Genetic testing; Genomics; Multiple system atrophy; Prospective cohort; SCA27B; Sporadic ataxia.

Fig. 1

Genetic landscape of sporadic adult-onset degenerative ataxia. (a) 377 individuals with sporadic adult-onset ataxia from the SPORTAX cohort underwent genetic testing (229 SAOA patients and 148 MSA-C_cp patients). FGF14 (GAA)_≥250 repeat alleles were identified in 45 individuals (blue); biallelic RFC1 (AAGGG) repeat expansions were identified in 17 individuals (orange); 25 different definitive, probably or unclear genetic diagnoses through SNVs were identified in 24 individuals (green); one individual has two relevant SNV findings. Two individuals had multiple relevant genetic findings for the ataxia phenotype demonstrated by split pictographs (P25 and P40). (b) number and percentage of SNV findings divided by phenotypic subtype and SNV interpretation (definitive/probable/unclear). (c, d) Number of individuals with a relevant genetic finding of SNVs (n = 25, definitive, probable and unclear) in respective autosomal-dominant (n = 14) (c) or autosomal-recessive (n = 11) (d) genes. Only genetic SNVs of the definitive, probably and unclear categories are shown here as based on the interpretation of the link between variants and phenotype, separated by gene in MSA-C_cp individuals (dark green) and SAOA individuals (light green). Patients with MSA-C_cp and meeting the criteria of clinically probable multiple system atrophy cerebellar type; SAOA, sporadic adult-onset ataxia of unknown aetiology.

Fig. 2

Progression of disease severity (SARA), and cross-sectional NfL assessments in different ataxia disease groups. (a, c) Progression of disease severity as calculated by a linear mixed effect model (LMEM) combining cross-sectional and longitudinal SARA scores, plotted against time from onset, estimated trajectories per disease group with 95% CIs, GAA-FGF14 (a) (FGF14 MSA-Ccp n = 9, non-genetic MSA-Ccp n = 72, FGF14 SAOA n = 36), RFC1 (c) (RFC1 MSA-Ccp n = 3, non-genetic MSA-Ccp n = 72, RFC1 SAOA n = 14). (b, d) Cross-sectional plasma NfL levels at first visit per disease group, GAA-FGF14 (b) (FGF14 MSA-Ccp n = 4, non-genetic MSA-Ccp n = 58, FGF14 SAOA n = 14), RFC1 (d) (RFC1 MSA-Ccp n = 2, non-genetic MSA-Ccp n = 58, RFC1 SAOA n = 8). Patients with MSA-C_cp patients meeting the criteria of clinically probable multiple system atrophy cerebellar type; SAOA, sporadic adult-onset ataxia of unknown aetiology. Each point represents an individual subject and means ± SEM are indicated. Differences between groups were assessed Kruskal Wallis H test followed by Dunn's post hoc test, ∗p < 0.05, ∗∗∗p < 0.001, ns is non-significant.