Objective: To gain insight in the natural history of sporadic adult-onset ataxia (SAOA), identify unrecognized genetic underpinnings and improve early differentiation from other causes of gait instability in the elderly, including multiple system atrophy of cerebellar type (MSA-C).

Background: SAOA are rare neurodegenerative disorders characterized by progressive coordination deficits resulting from damage to the cerebellum and its pathways. Recent discoveries, specifically RFC1– and GAA-FGF14-related ataxia, reveal a substantial monogenic contribution in the etiology of SAOA. However, 70% of SAOA cases remain genetically unsolved. Frequent age-related comorbidities, like cerebrovascular disease, and the phenotypical overlap with MSA-C are among the challenges that hamper the identification of genetic etiologies. Pathogenic RFC1 and FGF14 expansions have also been found in patients with clinical diagnosis of MSA-C, likely reflecting both phenotypic mimicry as well as instances of true dual pathology. To enhance diagnostic yield in genetic testing, highlighting phenotypical characteristics to improve accurate clinical differentiation is imperative.

Method: We aim to recruit 100 patients with late-onset ataxia, including cases classified as SAOA, genetically confirmed GAA-FGF14- and RFC1-related ataxias and cases fulfilling the current MSA-C clinical diagnostic criteria. Each patient will be clinically examined at a baseline visit and at a one-year follow-up. Retrospective data from yearly visits will also be collected. We will perform deep-phenotyping covering brain MRI, autonomic function, sleep disturbances, and peripheral nerve involvement. Clinical outcome measures including ataxia rating scales, autonomic questionnaires and candidate patient reported outcomes will be collected.

Results: At the time of abstract submission, 93 patients fulfilling the inclusion criteria were retrieved in the Innsbruck database and 15 patients have been prospectively recruited. By combining long-term retrospective with prospectively collected data, we expect to highlight early clinical red flags in non-motor features in monogenic SAOA as compared to MSA-C and other causes of gait disorders in the elderly.

Conclusion: We will pinpoint candidate outcome measures for future multicentric studies and interventional trials and define clinically actionable pathways to enhance early diagnosis and optimize patient care in SAOA.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinicogenetic-characterization-of-sporadic-adult-onset-ataxias-in-austria/