Clinical, Imaging, and Laboratory Markers of Premanifest Spinocerebellar Ataxia 1, 2, 3, and 6: A Systematic Review

Abstract

Background and Purpose Premanifest mutation carriers with spinocerebellar ataxia (SCA) can exhibit subtle abnormalities before developing ataxia. We summarized the preataxic manifestations of SCA1, -2, -3, and -6, and their associations with ataxia onset. Methods We included studies of the premanifest carriers of SCA published between January 1998 and December 2019 identified in Scopus and PubMed by searching for terms including ‘spinocerebellar ataxia’ and several synonyms of ‘preataxic manifestation’. We systematically reviewed the results obtained in studies categorized based on clinical, imaging, and laboratory markers. Results We finally performed a qualitative analysis of 48 papers. Common preataxic manifestations appearing in multiple SCA subtypes were muscle cramps, abnormal muscle reflexes, instability in gait and posture, lower Composite Cerebellar Functional Severity scores, abnormalities in video-oculography and transcranial magnetic stimulation, and gray-matter loss and volume reduction in the brainstem and cerebellar structures. Also, decreased sensory amplitudes in nerve conduction studies were observed in SCA2. Eotaxin and neurofilament light-chain levels were revealed as sensitive blood biomarkers in SCA3. Concerning potential predictive markers, hyporeflexia and abnormalities of somatosensory evoked potentials showed correlations with the time to ataxia onset in SCA2 carriers. However, no longitudinal data were found for the other SCA gene carriers. Conclusions Our results suggest that preataxic manifestations vary among SCA1, -2, -3, and -6, with some subtypes sharing specific features. Combining various markers into a standardized index for premanifest carriers may be useful for early screening and assessing the risk of disease progression in SCA carriers.

Blood Neurofilament Light Chain in Genetic Ataxia: A Meta‐Analysis

“…Data interpretations in transformed scale (ie, of log scale) is another solution. [49][50][51] Although previous systematic reviews have reviewed the NfL levels in genetic ataxia, 37,38 there are clear differences between our study and these reviews. First, we applied a different method (ie, meta-analysis) and statistically integrated the results of included studies, which could increase the validity and reliability of results by increasing the number of observations and statistical power, [52][53][54] even though some of these results have been found in original studies.…”

“…In genetic ataxia, recent studies have found that CSF and blood NfL concentrations were significantly elevated in the early stage of disease, and were closely correlated with disease progression and severity, suggesting that NfL may serve as a biomarker of genetic ataxia 26‐36 . However, no comprehensive meta‐analysis has ever been conducted to evaluate the potential role of NfL as a biomarker in predicting disease or symptom onset, measuring disease severity, tracking progression, as well as monitoring therapeutic response in genetic ataxia 27,37,38 . Therefore, we firstly performed a meta‐analysis to summarize the current scientific literature on cNfL and bNfL including plasma NfL (pNfL) or serum NfL (sNfL) in genetic ataxia.…”

“…[26][27][28][29][30][31][32][33][34][35][36] However, no comprehensive meta-analysis has ever been conducted to evaluate the potential role of NfL as a biomarker in predicting disease or symptom onset, measuring disease severity, tracking progression, as well as monitoring therapeutic response in genetic ataxia. 27,37,38 Therefore, we firstly performed a meta-analysis to summarize the current scientific literature on cNfL and bNfL including plasma NfL (pNfL) or serum NfL (sNfL) in genetic ataxia. This meta-analysis can provide clinical application value when using NfL levels as a biomarker of genetic ataxia.…”

Levels of Neurofilament Light at the Preataxic and Ataxic Stages of Spinocerebellar Ataxia Type 1

“…The use of sNfL levels as an outcome variable might thus help to reduce trial sample sizes compared to clinical and other surrogate outcome measures. 14,18,19,30 For instance, our estimates suggest that a total sample size of 14 individuals would suffice to detect therapeutic effect sizes of 50% at the ataxic stage of SCA1.…”

Serum NfL in spinocerebellar ataxia type 1 is increased already at the preataxic stage, correlating with proximity to clinical onset

“…Our longitudinal assessment of sNfL levels shows that intra-individual biological variation of sNfL levels is likely only a minimal source of noise in observation and intervention trials of SCA1. The use of sNfL levels as outcome parameter might thus help to reduce trial sample sizes in comparison to clinical and other surrogate outcome measures 14, 18, 19, 30 . For instance, our estimates suggest that a total sample size of 14 subjects would suffice to detect therapeutic effect sizes of 50% at the ataxic stage of SCA1.…”