Early and Extensive Degeneration of Sensory Neurons in Spinocerebellar Ataxia Type 3
Milou Baarsma, Bart P.C. van de Warrenburg, Nens van Alfen, Roderick P.P.W.M. MaasAbstract
Background
Postmortem studies have shown significant degeneration of the peripheral nervous system (PNS) in spinocerebellar ataxia type 3 (SCA3). Although PNS involvement accelerates overall ataxia progression, PNS biomarkers for therapeutic trials are lacking and our mechanistic understanding of related clinical manifestations remains incomplete.
Objective
We employed a multimodal approach to characterize and quantify peripheral sensory nervous system degeneration throughout the course of SCA3.
Methods
Forty SCA3 mutation carriers, including 10 preataxic individuals, were enrolled in this study. Detailed clinical assessments of ataxia and neuropathy severity were combined with high‐resolution nerve ultrasound and electrophysiological examinations to evaluate cross‐sectional areas (CSAs) and sensory action potential amplitudes of upper and lower limb nerves.
Results
Sensory axonal loss in at least one nerve was found in 97% of ataxic and 50% of preataxic individuals. Ultrasound examinations showed CSA reductions at one or more measurement sites in at least two nerves in all participants. Upper limb nerves were more commonly affected than the sural nerve, which supports a widespread, non–length‐dependent pattern of axonal damage. The degree of sensory axonal loss was associated with ataxia severity, estimated disease duration, and patient‐reported ability to perform activities of daily living.
Conclusions
Abnormalities of the peripheral sensory nervous system are highly prevalent in SCA3, emerge before ataxia onset, and reflect disease severity. The combination of electrophysiological and ultrasound profiles suggests early involvement of the dorsal root ganglia, highlighting an underestimated source of (sensory) ataxia in SCA3. Longitudinal studies are warranted to validate the biomarker potential of these measures. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.