Hereditary Ataxias: From Pathogenesis and Clinical Features to Neuroimaging, Fluid, and Digital Biomarkers—A Scoping Review

TL;DR

This review maps biomarkers for hereditary ataxias, highlighting subtype-specific signatures and the need for standardized validation to improve diagnosis and therapies.

Contribution

The study provides a comprehensive scoping review of biomarkers across multiple hereditary ataxia subtypes, emphasizing multimodal frameworks and gaps in current evidence.

Findings

MRI volumetry, DTI, and FDG-PET reveal subtype-specific neurodegeneration patterns in hereditary ataxias.

Fluid biomarkers like neurofilament light chain and frataxin are informative across multiple ataxia subtypes.

Wearable technologies and electrophysiological measures offer scalable tools for early detection and longitudinal monitoring.

Abstract

Hereditary ataxias are a heterogeneous group of disorders with overlapping clinical presentations but diverse genetic and molecular etiologies. Biomarkers are increasingly essential to improve diagnosis, refine prognosis, and accelerate the development of targeted therapies. Following PRISMA-ScR guidelines, we conducted a scoping review of PubMed and complementary sources (2010–2025) to map and describe the current landscape of genetic, imaging, fluid, electrophysiological, and digital biomarkers across the most prevalent hereditary ataxias, including SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, SCA27B, dentatorubral–pallidoluysian atrophy (DRPLA), Friedreich’s ataxia (FRDA), RFC1-related ataxia (CANVAS), SPG7, and fragile X-associated tremor/ataxia syndrome (FXTAS). Eligible evidence encompassed observational cohorts, clinical trials, case series, and case reports providing primary biomarker data, with the objective of characterizing evidence breadth and identifying knowledge gaps rather than assessing comparative effectiveness. Across modalities, converging evidence highlights subtype-specific biomarker signatures. MRI volumetry, DTI, and FDG-PET map characteristic neurodegeneration patterns. Fluid biomarkers such as neurofilament light chain are informative across several SCAs and FRDA, while frataxin levels constitute robust endpoints in FRDA trials. Pathology-specific biomarkers such as ataxin-3 are advancing as tools for target engagement and may generalize to future gene-lowering strategies. Electrophysiological and oculographic measures show sensitivity for early disease detection, and wearable technologies are emerging as scalable tools for longitudinal monitoring. This scoping review synthesizes the heterogeneous evidence on hereditary ataxia biomarkers, highlighting multimodal frameworks that link molecular mechanisms with clinical endpoints. Mapping current approaches also reveals substantial variability and gaps across diseases and modalities, underscoring the need for harmonized validation in international multicenter cohorts and systematic integration into future clinical trials to advance precision medicine in hereditary ataxias.

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