# Spastic Ataxia Composite (SPAXCOM): A Scale to Evaluate the Progression of Subjects with Spasticity and Ataxia

Cécile Di Folco, Charlotte Dubec-fleury, Andreas Traschütz, Christoph Kessler, Selina Reich, Cynthia Gagnon, Isabelle Lessard, Xavier Rodrigue,

Sirio Cocozza, Sara Satolli, et al.

► To cite this version:

Cécile Di Folco, Charlotte Dubec-fleury, Andreas Traschütz, Christoph Kessler, Selina Reich, et al.  
Spastic Ataxia Composite (SPAXCOM): A Scale to Evaluate the Progression of Subjects with  
Spasticity and Ataxia. Movement Disorders, 2025, 10.1002/mds.70006. hal-05229818

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RESEARCH ARTICLE

# Spastic Ataxia Composite (SPAXCOM): A Scale to Evaluate the Progression of Subjects with Spasticity and Ataxia

Cécile Di Folco, MsC,¹ Charlotte Dubec-Fleury, MsC,¹ Andreas Traschütz, MD, PhD,² Christoph Kessler, MD,²

Selina Reich, MsC,² Cynthia Gagnon, PhD,³,⁴ Isabelle Lessard, MsC,³,⁵ Xavier Rodrigue, MD,⁶

Sirio Cocozza, MD, PhD,⁷ Sara Satolli, MD,⁷ Filippo M. Santorelli, MD,⁷ Alexandra Durr, MD, PhD,¹

Anna Heinzmann, MD,¹ Bart P. van de Warrenburg, MD,⁸ Ilse H.J. Willemse, MsC,⁸ A. Nazli Başak, MD,⁹

Atay Vural, MD,¹⁰ Bernard Brais, MD,¹¹ Stephan Klebe, MD,¹²,¹³ Rita Horvath, MD, PhD,¹⁴ PROSPAX Consortium,

Rebecca Schüle, MD,²,¹⁵ Matthis Synofzik, MD, PhD,² and Sophie Tezenas du Montcel, MD, PhD¹*

**ABSTRACT:** **Background:** Current clinical scales that track disease progression are more tailored to spasticity or ataxia, with limited sensitivity to change.

**Objectives:** The aim was to develop a sensitive and valid scale specifically geared towards optimized sensitivity to change and adapted to patients presenting with both spasticity and ataxia.

**Methods:** Longitudinal data from 127 spastic paraplegia type 7 (SPG7) and 112 autosomal recessive spastic

ataxia Charlevoix-Saguenay (ARSACS) patients were collected within the multicenter PROSPAX study. Sensitivity to change over 2 years of 30 items from the Scale for the Rating and Assessment of Ataxias (SARA), Spastic Paraplegia Rating Scale (SPRS), and the Activities of Daily Living subscale of the Friedreich's Ataxia Rating Scale (FARS-ADL) was evaluated. Items that demonstrated the highest sensitivity to change were used to build the Spastic Ataxia Composite scale (SPAXCOM).

¹Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, CNRS, Inria, Inserm, AP-HP, Groupe Hospitalier Sorbonne Université, Paris, France; ²Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; ³Groupe de Recherche Interdisciplinaire Sur Les Maladies Neuromusculaires (GRIMN), Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay-Lac-St-Jean, Saguenay, Quebec, Canada; ⁴Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada; ⁵Centre ÉCOBES-Recherche et Transfert, Cégep de Jonquière, Saguenay, Quebec, Canada; ⁶Centre Intégré Universitaire de Santé et de Services Sociaux de la Capitale Nationale, Québec City, Quebec, Canada; ⁷IRCCS Fondazione Stella Maris, Pisa, Italy; ⁸Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands; ⁹Koç University, School of Medicine, Research Center for Translational Medicine, Istanbul, Turkey; ¹⁰Department of Neurology, Koç University, School of Medicine, Istanbul, Turkey; ¹¹Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada; ¹²Department of Neurology, University Hospital Essen, Essen, Germany; ¹³Department of Neurology, Knappschaftkrankenhaus Recklinghausen, Recklinghausen, Germany; ¹⁴Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; ¹⁵Division of Neurodegenerative Diseases and Movement Disorders, Department of Neurology, Heidelberg University Hospital and Faculty of Medicine, Heidelberg, Germany

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

*Correspondence to:* Dr. Sophie Tezenas du Montcel, Département d'information médicale (DIM) Sorbonne Université-Hôpital Saint Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France; E-mail: sophie.tezenas@aphp.fr

**Relevant conflicts of interest/financial disclosures:** No conflicts of interest related to the article to declare.

**Funding agencies:** This work was supported as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme

on Rare Diseases (also to F.M.S.), under the EJP RD COFUND-EJP N° 825575 by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) No 441409627 (to M.S., R.S., F.M.S.), by the ANR No M20JAR014 (to S.T.d.M.). Moreover, the work was supported by the Bundesministerium für Bildung und Forschung (BMBF) through funding for the TreatHSP network (grant 01GM2209A to R.S.), and the Clinician Scientist program "PRECISE.net" funded by the Else Kröner-Fresenius-Stiftung (to M.S., R.S., and A.T.). The research leading to these results has received funding from the program "Investissements d'avenir" ANR-10-IAIHU-06 (to S.T.d.M). R.H. is supported by the Wellcome Discovery Award (226653/Z/22/2), the Medical Research Council (MRC) (UK) (MR/V009346/1), the Addenbrookes Charitable Trust (G100142), the Hereditary Neuropathy Foundation, the Stoneygate Trust, the Lily Foundation, Ataxia UK, Action for AT, Muscular Dystrophy UK, the LifeArc Centre to Treat Mitochondrial Diseases (LAC-TreatMito), and the UKRI/Horizon Europe Guarantee MSCA Doctoral Network Programme (Project 101120256: MMM). R.H. is also supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. B.P.v.d.W. and I.H.J.W. were supported by a grant from ZonMw (No. 463002002). F.M.S. is supported in part by the Italian Ministry of Health Ricerca Corrente 2024 and RF-2019-12370417. This study was further supported by the University of Tübingen, Medical Faculty, as part of the Clinician Scientist Program grant 439-0-0 (to A.T.). Several authors are members of the European Reference Network for Rare Neurological Diseases - Project ID 739510 (R.S., M.S., A.D., B.P.v.d.W.).

The PROSPAX Consortium collaborators members are listed in Appendix 1.

Received: 4 April 2025; Revised: 21 July 2025; Accepted: 28 July 2025

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.70006
**Results:** With seven items, the SPAXCOM showed an effect size of 0.71, higher than reference scales (SARA: 0.43, SPRS: 0.42, FARS-ADL: 0.27). The SPAXCOM had a similar sensitivity to change for both genotypes and was more sensitive in participants with a SARA lower than 10 and within the intermediate disease stage (FARS-Disease Staging: 2-3.5). The SPAXCOM showed a high correlation with disease duration ($r = 0.67$ [0.60; 0.72]) and disease stage ($r = 0.86$ [0.83; 0.89]). Perception of improvement, stagnation, and worsening were associated with a mean yearly SPAXCOM change of

0.44 (-0.14; 1.01), 0.61 (0.19; 1.03), and 1.22 (0.96; 1.49), respectively.

**Conclusion:** The SPAXCOM is more sensitive to change and homogeneous across genotypes than the reference scales, allowing a reduction of the required sample size in future clinical trials. © 2025 The Author(s). *Movement Disorders* published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

**Key Words:** ataxia; disease progression; spastic ataxia; spastic ataxia Charlevoix-Saguenay type; SPG7

Spastic ataxia (SPAX) is a clinical phenotype defined by the coexistence of cerebellar ataxia and spastic paraplegia comprising a heterogeneous group of >100 predominantly hereditary conditions.¹,² Among these, autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and spastic paraplegia type 7 (SPG7) are amongst the most common genetic forms of SPAXs worldwide.²,³ These diseases are multisystemic, neurodegenerative, and characterized by progressive cerebellar ataxia, spasticity.⁴

With continuous progress in the understanding of the molecular pathogenesis of these and related disorders, novel targeted disease-modifying therapies are on the horizon and will need to be evaluated in clinical trials. Conducting such trials in these diseases is, however, challenging due to their rarity, heterogeneity, and slow progression. Sensitive outcome measures that capture change in relatively short frames are thus crucial to successful drug development.

Several scales have been published to measure ataxia⁵ and spasticity.⁶ Among those, spasticity and ataxia are often measured by two different scales, the Spastic Paraplegia Rating Scale (SPRS)⁷ and the Scale for the Assessment and Rating of Ataxia (SARA).⁸ As a result, none of the scales are designed for the conditions in which both symptoms are present in combination. SARA showed a low sensitivity to change in SPG7,³,⁹,¹⁰ other hereditary spastic paraplegias,¹¹ and ARSACS.³,⁹,¹²,¹³ SPRS likewise showed a slow sensitivity to change in hereditary spastic paraplegia type 3A, 4, and 5, the latter with prominent ataxia.¹⁴⁻¹⁶ However, their sensitivity to change has not been systematically assessed and compared against each other in genotypes such as SPG7 and ARSACS. The last scale used to monitor disease progression is Friedreich's Ataxia Rating Scale (FARS), comprising, among others, a functional disability staging (FARS-DS) and a scale evaluating activities of daily living (FARS-ADL).¹⁷ The latter was shown to have a similar sensitivity to change to SARA in patients of various genotypes with ataxia.¹⁸

To address these limitations, our study aimed to build a composite score (the Spastic Ataxia Composite scale [SPAXCOM]) capturing the progression of individuals

with spastic ataxia that is sufficiently sensitive to change to serve as an endpoint, using items from the three reference scales assessed in a large longitudinal cohort.

## Patients and Methods

This study was conducted using data acquired within the PROSPAX project (*ClinicalTrials.gov* No. NCT04297891) approved by the local ethics committee of each center following the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. Written informed consent was obtained from each patient before enrollment.

## Survey Design and Participants

Participants were enrolled in the PROSPAX study (an integrated, multimodal, progression chart in spastic ataxias)—a 2-year prospective, international, longitudinal, multicenter, natural progression study in spastic ataxias. Participants were included from nine sites in seven countries (Germany, Italy, Canada, Turkey, the Netherlands, France, and the UK). Inclusion criteria were confirmed pathogenic biallelic mutations in SACS or SPG7, clinically manifest disease, age above 10 years, and informed consent (by the patient or by both legal representatives for minors). Participants already enrolled in an interventional study at baseline or with a history of the presence of another neurological disorder were excluded. Healthy controls with no neurological or psychiatric disease history, no family history of neurodegenerative disease, and no neurological signs upon clinical examination were also recruited. Participants underwent clinical evaluation at baseline, 1 year, and 2 years after baseline.

## Outcomes

Of the multiple variables measured during the study, this analysis focused on SPRS,⁷ SARA,⁸ and FARS-ADL.¹⁷ Items included in each scale are detailed
in Table S1. The disease stage was evaluated using the Functional Staging for Ataxia (FARS-Disease Staging, FARS-DS).<sup>17</sup> Based on clinical expertise, the following classification was used: Mild stage for scores from 0 (Normal) to 1.5, Intermediate stage for scores from 2 to 3.5, and Advanced stage for those from 4 to 6 (confined to wheelchair or bed). Age at onset refers to age at motor symptoms onset. Disease duration was computed as the difference between age at baseline visit and age at onset.

## Statistical Analysis

Our methodology was designed to construct a composite score capturing the progression of individuals with spastic ataxia geared towards optimizing sensitivity to change (Fig. 1). In the first step, we built the SPAXCOM as the combination of items that yielded

the highest effect size. Then, we assessed the SPAXCOM sensitivity to change in different subgroups and compared it with those of the reference scales. We further assessed a pathological threshold derived from controls values, structure, internal consistency, and concurrent validity of our composite score.

## Item Selection

From the 30 items composing SARA, SPRS, and FARS-ADL, we aimed to build a combination of items that optimized sensitivity to change. From the complete dataset, we generated 1000 resamples with a stratified random sampling on genotype and FARS Stage. Each resample was composed of a “training” set (60% of the resample participants without replacement) and a “test” set (the remaining 40% of the data). The training set was used to select the item combination yielding the

<figure><img src="image_2.png" /><figcaption>**FIG. 1.** Graphical summary of the methodology to build and assess the Spastic Ataxia Composite scale (SPAXCOM). ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; SARA, Scale for the Rating and Assessment of Ataxias; SPRS, Spastic Paraplegia Rating Scale; FARS-ADL, Friedreich's Ataxia Rating Scale-Activities of Daily Living; CI, confidence interval; IRT, item response theory. [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>
19.0 ± 10.3 years. Most participants (60%) had intermediate disease (Table 1). ARSACS participants had a mean age of 35.3 ± 12.7 years and a disease duration of 29.5 ± 11.6 years. Most ARSACS participants (53%) had advanced disease. Healthy controls were on average aged 46.6 ± 14.7 years. All controls had a SARA score below 5, SPRS below 6, and FARS-ADL below 4 points.

## SPAXCOM

### Item Selection

All longitudinal data from 127 SPG7 participants and 112 ARSACS participants were used for item selection. Effect sizes of the items ranged from -0.2 to 0.51 for ARSACS and SPG7 participants combined, with 12 items displaying an effect size superior to 0.2 (Fig. 2).

Over the 1000 data resamples on which the stepwise item selection was performed, 161 different optimized combinations of items were obtained, of the 2^30 theoretically possible combinations of 30 items. These combinations reached an average effect size of 0.77 (2.5th and 97.5th percentiles: [0.66; 0.90]) on training data and (0.55 [0.36; 0.74]) on test data (Fig. S2).

The most frequent optimized combination occurred 216 times (including 205 times in association with other items, and 11 times alone) (Fig. S3). It was composed of seven items: three items from SARA (gait, sitting, and fast alternating hand movements), three items from SPRS (walking distance without pause, climbing stairs, and weakness of foot dorsiflexion), and one from

FARS-ADL (personal hygiene). These items were also among the most frequently selected items over the 1000 iterations: four of them (SARA gait, SARA fast alternating hand movements, SPRS walking distance without pause, FARS-ADL personal hygiene) were selected more than 90% of the times, two (SPRS climbing stairs and SPRS weakness of foot dorsiflexion) were selected more than 65% of the time, and one (SARA sitting) was selected 49% of the time (Fig. S4). The SPAXCOM score was obtained by summing these seven items, with a range from 0 (no disability) to 32 (maximum disability) (Data S1).

### Sensitivity to Change

The SPAXCOM score achieved a mean effect size of 0.71 (95% bootstrapped CI: 0.58; 0.85) for ARSACS and SPG7 participants combined (Fig. 3A, Table S2). This corresponds to ARSACS participants increasing on average by 1.10 (0.82; 1.34) points of SPAXCOM per year, and SPG7 participants increasing on average by 1.00 (0.73; 1.27) points of SPAXCOM per year. By comparison, SARA reached a mean effect size of 0.43 (0.31; 0.59), SPRS of 0.42 (0.3; 0.56), and FARS-ADL of 0.27 (0.14; 0.43). The mean (95%) change in SPAXCOM score was 0.44 (-0.14; 1.01) for subjects reporting an improvement over the last year, 0.61 (0.19; 1.03) for subjects reporting being stable, and 1.22 (0.96; 1.49) for those reporting a worsening condition. Among the 76 controls with a stable PGI-C, the mean SPAXCOM evolution was -0.01 (-0.1; 0.08) (95% CI) (Table S3).

<table><caption>TABLE 1 Characteristics of participants at baseline</caption><thead><tr><th>Characteristic</th><th>SPG7 (N = 127)</th><th>ARSACS (N = 112)</th><th>HC (N = 58)</th></tr></thead><tbody><tr><td>Sex (female)</td><td>48 (37.8)</td><td>52 (46.4)</td><td>32 (55.2)</td></tr><tr><td>Age at baseline (years)</td><td>55.4 ± 10.2</td><td>35.3 ± 12.7</td><td>46.6 ± 14.7</td></tr><tr><td>Age at onset (years)</td><td>36.4 ± 12.6</td><td>6.3 ± 9.0</td><td></td></tr><tr><td>Disease duration (years)</td><td>19.0 ± 10.3</td><td>29.5 ± 11.6</td><td></td></tr><tr><td>FARS Stage</td><td></td><td></td><td></td></tr><tr><td>Advanced</td><td>40 (31.5)</td><td>59 (52.7)</td><td></td></tr><tr><td>Intermediate</td><td>76 (59.8)</td><td>39 (34.8)</td><td></td></tr><tr><td>Mild</td><td>11 (8.7)</td><td>14 (12.5)</td><td>58 (100.0)</td></tr><tr><td>SARA total (/40)</td><td>11.71 ± 5.52</td><td>17.93 ± 7.54</td><td>0.47 ± 0.81</td></tr><tr><td>SPRS total (/52)</td><td>18.29 ± 8.20</td><td>22.27 ± 10.79</td><td>0.93 ± 1.36</td></tr><tr><td>FARS-ADL (/36)</td><td>11.07 ± 5.25</td><td>13.16 ± 6.63</td><td>0.17 ± 0.56</td></tr><tr><td>SPAXCOM (/32)</td><td>10.24 ± 5.29</td><td>14.32 ± 7.13</td><td>0.31 ± 0.78</td></tr></tbody></table>

Disease duration: age at baseline–age at symptom onset. Mild disease stage: FARS Stage scores 0 to 1.5, Intermediate: scores 2 to 3.5, Advanced: scores 4 to 6. Data are expressed as mean ± standard deviation or frequency (percent).

Abbreviations: ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; FARS, Friedreich's Ataxia Rating Scale; FARS-ADL, Friedreich's Ataxia Rating Scale-Activities of Daily Living; HC, healthy controls; SARA, Scale for the Rating and Assessment of Ataxias; SPRS, Spastic Paraplegia Rating Scale; SPAXCOM, Spastic Ataxia Composite scale; SPG7, spastic paraplegia type 7.
<figure><img src="image_3.png" /><figcaption>**FIG. 2.** Effect sizes of the 30 items for the Scale for the Rating and Assessment of Ataxias (SARA), Spastic Paraplegia Rating Scale (SPRS), and Friedrich's Ataxia Rating Scale-Activities of Daily Living (FARS-ADL) scales. Effect sizes are reported for spastic paraplegia type 7 (SPG7) + autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) participants (all) and for each genotype separately. Items are sorted by their effect size on all participants. The effect size is the mean standardized annual change in score, calculated using linear regression for each patient separately. [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>

## Subgroup Analysis

On patients with a SARA score below 10 at baseline, the SPAXCOM had an average effect size of 0.77 (0.59; 0.99), similar to that of patients with a baseline SARA score over 10 (0.68 [0.53; 0.89]) (Fig. 3B). When we used the FARS Stage to separate the patients, the average effect size was 0.86 (0.7; 1.05) in participants at the Intermediate stage, and 0.60 (0.43; 0.85) in participants at the Advanced stage (Fig. 3C). The effect size of the SPAXCOM was similar in both genotypes: 0.75 (0.58; 0.93) and 0.69 (0.51; 0.95) in ARSACS and SPG7 participants, respectively (Fig. 3D). SPRS and FARS-ADL also had similar effect sizes for both genotypes and disease stages (Table S2). SARA, however, showed a higher sensitivity to change in SPG7 than in ARSACS, and in Intermediate-stage participants than in Advanced-stage ones. Compared with the SPAXCOM, all scores had a lower sensitivity to change in all subgroups, except SARA, which reached a similar

effect size to that of the SPAXCOM on SPG7 patients and patients with milder ataxia (SARA below 10). Finally, the SPAXCOM of healthy controls remained stable, with a mean effect size of -0.12 (-0.29; 0.19).

## Threshold for Non-Healthy Functioning

For healthy controls, the SPAXCOM values ranged from 0 to 5, with a mean value of 0.31 ± 0.78; 95% of them had a SPAXCOM value below 1. A threshold value of 1 can thus be chosen to characterize a healthy state. At baseline, the average SPAXCOM total score was 10.24 ± 5.29 in SPG7 participants and 14.32 ± 7.13 in ARSACS participants, none being below the score value of 2 points (Fig. 4).

## Structure

Given the small number of items of the SPAXCOM, unidimensional and two-dimensional IRT models were
<figure><img src="image_4.png" /><figcaption>**FIG. 3.** Effect sizes for the Spastic Ataxia Composite (SPAXCOM), Scale for the Rating and Assessment of Ataxias (SARA), Spastic Paraplegia Rating Scale (SPRS), and Friedreich's Ataxia Rating Scale-Activities of Daily Living (FARS-ADL) total scores, and their bootstrapped confidence intervals. (A) On all data. (B) Assessed separately according to baseline SARA scores. (C) Assessed separately on patients' FARS Stage. The boxplot corresponding to patients with Mild stage is not shown, due to insufficient data (N = 25). Whiskers correspond to 1.5 times the interquartile range. (D) Assessed separately on both genotypes. [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**FIG. 4.** Correlation between the Spastic Ataxia Composite scale (SPAXCOM), disease duration, and disease stage. (A) Scatterplot displaying the SPAXCOM score depending on disease duration, computed as the difference between age at baseline visit and age at symptoms onset (N = 232). (B) Scatterplot displaying the SPAXCOM score depending on Friedreich's Ataxia Rating Scale (FARS) Stage (N = 239). [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>
tested. The unidimensional model displaying a lower BIC was retained (1-dimension BIC: 3778, 2-dimension BIC: 3796). It explained 65% of the score variance with fair fit indices (RMSEA = 0.100 [0.068, 0.132], CFI = 0.979, TLI = 0.969, SRMSR = 0.058; Table S4).

## Internal Consistency

The SPAXCOM showed good internal consistency, with a Cronbach's alpha of 0.878 (0.844; 0.906). One item increased the Cronbach's alpha when removed (SARA alternating hand), but not out of the confidence interval (Table S4). The seven items were correlated, with correlations ranging from 0.3 to 0.8 (Fig. S5).

## Concurrent Validity

The SPAXCOM score was highly correlated with disease duration ($r = 0.67$, [0.60; 0.72], $P < 0.001$, Fig 4A), as was the SARA ($r = 0.71$ [0.65; 0.76], $P < 0.001$) and, to a lesser extent, the SPRS ($r = 0.55$ [0.47; 0.62], $P < 0.001$) and FARS-ADL scores ($r = 0.58$ [0.5; 0.65], $P < 0.001$). Of all the scores, the SPAXCOM had the highest correlation with the FARS-DS ($r = 0.86$ [0.83; 0.89], $P < 0.001$, Fig 4B). A high correlation with FARS-DS was also found for SARA ($r = 0.79$ [0.75; 0.83], $P < 0.001$), SPRS ($r = 0.79$ [0.74; 0.82], $P < 0.001$), and FARS-ADL ($r = 0.76$ [0.71; 0.8], $P < 0.001$).

## Discussion

This study aimed to develop a composite score for spastic ataxia, specifically geared towards optimized sensitivity to change and adapted to patients presenting both spasticity and ataxia. The novel SPAXCOM allows capture with a single scale of the progression of participants with spastic ataxia with higher sensitivity to change than the tested reference scales, rendering it the currently most promising clinician-reported outcome (ClinRO) in clinical trials for spastic ataxias.

To generate a common, change-optimized scale for genotypes presenting with spastic ataxia, we combined the most sensitive items of the FARS-ADL, SPRS, and SARA scores. Our primary rationale for selecting items based on sensitivity to change was to maximize the responsiveness and efficiency of the outcome measure in clinical trial settings. This intended context of use justifies, even necessitates, a more focused, composite approach as it enhances the ability to detect treatment effects by concentrating on the most dynamic and clinically relevant features. Similar approaches have been applied before, for example, just recently with the development of the SCACOMS, a composite scale for spinocebellar ataxias derived from items from the Clinical Global Impression-Global Improvement Scale (CGI-I), the Friedrich Ataxia Rating Scale (FARS)-Functional Stage,

and the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) (https://doi.org/10.1007/s12311-024-01697-8).¹⁹ The SPAXCOM was developed following similar principles, combining the most sensitive and representative items to better capture disease progression. The resulting scale (SPAXCOM) comprised three items from SARA (gait, sitting, and fast alternating hand movements), three items from SPRS (walking distance without pause, climbing stairs, and weakness of foot dorsiflexion), and one from FARS-ADL (personal hygiene). Three items of the seven directly assessed mobility (SPRS stairs, walking distance, SARA gait), one from SARA assessed the trunk control (SARA sitting), one from SPRS assessed lower limb weakness, one from SARA assessed kinetic function of the upper limb, and one from FARS-ADL evaluated personal hygiene activities. Interestingly, the latter has been shown to be gait- and stance-related.¹⁶ These items strongly correlated, as reflected by the good internal consistency and the fair unidimensional structure. Only the fast-alternating hand movement item from SARA did not strongly correlate with the others. The low correlation for this item might be explained by the fact that it assesses an effector domain (upper limb function) at least partly distinct from the other effector domains. As this item captures an important domain of patient daily living, and this item showed a strong sensitivity to change, it was retained in the final SPAXCOM. The two SPRS items that measure spasticity (items 7 and 8) were not included in the SPAXCOM. This is in line with a recent review that highlighted the difficulty of measuring spasticity with these two items.⁶

With only these seven items, the composite score showed a higher sensitivity to change than the widely used current reference scales for ataxia (SARA) and spasticity (SPRS). This is of importance as also the SARA score is partly influenced by non-ataxia features (eg, SARA item gait by gait spasticity), and the SPRS by non-spasticity features (eg, the SPRS gait items by gait ataxia), respectively. However, this unspecific influence by neurological system deficits for which the respective scale has not been primarily designed does not seem to help a lot with sensitivity to change in diseases with combined ataxia and spasticity.

Importantly, the SPAXCOM was as sensitive in participants with ARSACS as in those with SPG7. In contrast, SARA was more sensitive to change in participants with SPG7 than ARSACS. Interestingly, many items in the three scales had different sensitivity to change for the two genotypes. The SPAXCOM is composed of two items with similar effect sizes in both genotypes (SARA gait and sitting), two items with higher sensitivity in ARSACS than in SPG7 (SPRS walking distance, FARS-ADL personal hygiene), and three items more sensitive in SPG7 than in ARSACS (SARA alternating hand, SPRS stairs and weak foot). This contributes to the usefulness of SPAXCOM in
both diseases. FARS-ADL hygiene and walk were found to be the most sensitive to change among all the items of the FARS-ADL in patients with spinocerebellar ataxias.¹⁶ As for SARA items, gait was shown to be the most sensitive one.¹⁶,²⁰,²¹ According to studies in autosomal dominant²⁰,²¹ and autosomal recessive²² ataxias, gait and stance assessments are sensitive at the beginning of the disease, while sitting is impaired at later stages, and alternating hand movements show changes in the middle of the disease course. The SPAXCOM comprises items informing disease progression at different stages. Overall, the SPAXCOM showed a higher sensitivity in participants with a SARA score below 10 at baseline and those at intermediate disease stages than in those at advanced disease stages. This was also the case for SARA, but not for SPRS or FARS-ADL. This is consistent with recent work showing that in polyQ spinocerebellar ataxias, SARA was less sensitive to change for patients at an advanced disease stage compared with those at mild and intermediate stages.²⁰ Thus, the SPAXCOM could be a valuable scale in clinical trials targeting patients in the mild or intermediate stage of the disease, which is of greater interest for trials than the advanced stage, as neurodegeneration is less advanced and stabilization or even reversibility of the disease may be achievable.

To further demonstrate the validity of the composite scale, we showed the highest correlation with FARS disease stage and with disease duration. The relationship with disease duration of the SPRS was like those found with patients with hereditary spastic ataxias.¹⁴ For patients with Friedrich ataxia, the correlation between SARA and disease duration was like the one in our study.²³

To our knowledge, this study is the first that has evaluated the sensitivity to change of three reference scales in a large sample of ARSACS and SPG7 participants. The 2-year follow-up and the three assessment time points also constitute strengths to accurately estimate patients' progression and are seldom available for such rare diseases. Using anchor-based methods, we have shown that the SPAXCOM was responsive for patients with both genotypes. The effect sizes from the current study need to be confirmed with longer follow-up if used in longer clinical trials.

This study nonetheless has limitations. To build the composite score, a compromise had to be made between structure (ie, how items correlate together) and sensitivity to change. As sensitivity to change is typically the limiting factor of outcome measures for slowly progressive diseases, we prioritized it over structure. With only seven items, the SPAXCOM is a new tool to monitor disease progression in individuals with spastic ataxia with a higher sensitivity to change than the current reference scales, allowing a reduction of the required sample size in future clinical trials. It shows

homogeneous properties across genotypes. SPAXCOM is also highly correlated with disease stage and disease duration. A replication cohort is needed to validate this scale and allow its use as an endpoint in progression studies and treatment trials. The SPAXCOM scale may also be a promising outcome measure for other spastic ataxias, such as spinocerebellar ataxia. ■

**Author Roles:** (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
C.D.F.: 2B, 3A.
C.D.-F.: 2B, 3B.
A.T.: 1C, 3B.
C.K.: 1C, 3B.
S.R.: 2B, 3B.
C.G.: 1C, 3B.
I.L.: 1C, 3B.
X.R.: 1C, 3B.
S.C.: 1C, 3B.
S.S.: 1C, 3B.
F.M.S.: 1C, 3B.
A.D.: 1C, 3B.
A.H.: 1C, 3B.
B.P.v.d.W.: 1C, 3B.
I.H.J.W.: 1C, 3B.
A.N.B.: 1C, 3B.
A.V.: 1C, 3B.
B.B.: 1C, 3B.
S.K.: 1C, 3B.
R.H.: 1C, 3B.
R.S.: 1A, 2A, 2C, 3B.
M.S.: 1A, 2A, 2C, 3B.
S.T.d.M.: 1A, 2A, 2C, 3A.

**Acknowledgments:** We are grateful to Katrin Dillmann-Jehn and Doreen Müller for their excellent assistance in conducting the PROSPAX Natural History Study.

**Financial Disclosures of All Authors (for the Previous 12 Months):** C.D.F., C.D.-F., A.T., C.K., S.R., I.L., X.R., S.S., F.M.S., A.H., I.H.J.W., A.N.B., A.V., B.B., S.K., R.H., and R.S. declare no financial disclosure. C.G. has received funding from the Fondation de l'Ataxie de Charlevoix-Saguenay, Canadian Institutes of Health Research and Muscular Dystrophy Canada for projects related to the present work. C.G. has served on advisory boards and received consultancy fees from Dyne Therapeutics unrelated to the present work; and received research grants from Canadian Institutes of Health Research, European Joint Program on Rare Diseases, Muscular Dystrophy Canada, Association Française Contre les Myopathies, and Vertex Pharmaceuticals. S.C. consulted for TTLC SRL, has served on the scientific advisory board of Amicus Therapeutics, and has received research grants from FISM and Telethon. A.D. declares that her institution (Paris Brain Institute) receives consulting fees on her behalf from Huntix, UCB, Biogen, and PTC Therapeutics as well as research grants from the National Institutes of Health (NIH), Agency for Research (ANR), National Hospital Clinical Research Program (PHRC), and Foundation of Recherche Médicale (FRM), and partly holds a Patent B 06291873.5 on "Anaplerotic therapy of Huntington's disease and other polyglutamine diseases". B.P.v.d.W. has served on advisory boards and/or received consultancy fees from Biogen, Biohaven Pharmaceuticals, Servier, and Vico Therapeutics, all unrelated to the present work. M.S. has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Servier, Reata, GenOrph, AviadoBio, Biohaven, Solaxa, Biogen, Zevra, and Lilly, all unrelated to the present work. S.T.d.M. has received consultancy honoraria from Vico Therapeutics unrelated to the present work.

## Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
References

1. Synofzik M, Schüle R. Overcoming the divide between ataxias and spastic paraplegias: shared phenotypes, genes, and pathways. Mov Disord 2017;32(3):332–345.

2. Pedroso JL, Vale TC, França Junior MC, Kauffman MA, Teive H, Barsottini OGP, Munhoz RP. A diagnostic approach to spastic ataxia syndromes. Cerebellum 2022;21(6):1073–1084.

3. Traschütz A, Adarmes-Gomez AD, Anheim M, et al. Autosomal recessive cerebellar ataxias in Europe: frequency, onset, and severity in 677 patients. Mov Disord 2023;38(6):1109–1112.

4. Lallemant-Dudek P, Darios F, Durr A. Recent advances in understanding hereditary spastic paraplegias and emerging therapies. Fac Rev 2021;10:27.

5. Perez-Lloret S, Warrenburg B, Rossi M, et al. Assessment of ataxia rating scales and cerebellar functional tests: critique and recommendations. Mov Disord 2021;36(2):283–297.

6. Gal O, Baude M, Deltombe T, et al. Clinical outcome assessments for spasticity: review, critique, and recommendations. Mov Disord 2025;40(1):22–43.

7. Schüle R, Holland-Letz T, Klimpe S, et al. The spastic paraplegia rating scale (SPRS): a reliable and valid measure of disease severity. Neurology 2006;67(3):430–434.

8. Schmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 2006;66(11):1717–1720.

9. Traschütz A, Adarmes-Gómez AD, Anheim M, et al. Responsiveness of the scale for the assessment and rating of ataxia and natural history in 884 recessive and early onset ataxia patients. Ann Neurol 2023;94(3):470–485.

10. Coarelli G, Schule R, van de, van de Warrenburg B, et al. Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7. Neurology 2019;92:e2679–e2690.

11. Amprosi M, Indelicato E, Eigentler A, Fritz J, Nachbauer W, Boesch S. Toward the definition of patient-reported outcome measurements in hereditary spastic paraplegia. Neurol Genet 2023;9(1):e200052.

12. Bourcier D, Bélanger M, Côté I, et al. Documenting the psychometric properties of the scale for the assessment and rating of ataxia to advance trial readiness of autosomal recessive spastic ataxia of Charlevoix-Saguenay. J Neurol Sci 2020;417:117050.

13. Hendrickx N, Mentré F, Traschütz A, et al. Prediction of individual disease progression including parameter uncertainty in rare neurodegenerative diseases: the example of autosomal-recessive spastic ataxia Charlevoix Saguenay (ARSACS). AAPS J 2024;26(3):e57.

14. Giordani GM, Diniz F, Fussiger H, et al. Clinical and molecular characterization of a large cohort of childhood onset hereditary spastic paraplegias. Sci Rep 2021;11:22248.

15. Schöls L, Rattay TW, Martus P, et al. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain 2017;140(12):3112–3127.

16. Cubillos Arcila DM, Dariva Machado G, Martins VF, et al. Long-term progression of clinician-reported and gait performance outcomes in hereditary spastic paraplegias. Front Neurosci 2023;17:1226479. https://doi.org/10.3389/fnins.2023.1226479

17. Subramony SH, May W, Lynch D, et al. Measuring Friedreich ataxia: interrater reliability of a neurologic rating scale. Neurology 2005;64:1261–1262.

18. Traschütz A, Fleszar Z, Hengel H, et al. FARS-ADL across ataxias: construct validity, sensitivity to change, and minimal important change. Mov Disord 2024;39(6):965–974.

19. L'Italien G, Popoff E, Rogula B, et al. Development and validation of SCACOMS, a composite scale for assessing disease progression and treatment effects in spinocerebellar ataxia. Cerebellum 2024;23(5):2028–2041.

20. Petit E, Schmitz-Hübsch T, Coarelli G, et al. SARA captures dispersion progression and responsiveness in spinocerebellar ataxias. J Neurol 2024;271(7):3743–3753. https://doi.org/10.1007/s00415-024-12475-1

21. Moulaire P, Poulet PE, Petit E, Klockgether T, Durr A, Ashisawa T, Tezenas du Montcel S. Temporal dynamics of the scale for the assessment and rating of ataxia in spinocerebellar ataxias. Mov Disord 2022;38(1):35–44. Portico. https://doi.org/10.1002/mds.29255

22. Hamdan A, Hooker AC, Chen X, Traschütz A, Schüle R, Synofzik M, Karlsson MO. Item performance of the scale for the assessment and rating of ataxia in rare and ultra-rare genetic ataxias. CPT Pharmacometrics Syst Pharmacol 2024;13(8):1327–1340. Portico. https://doi.org/10.1002/psp4.13162

23. Marelli C, Figoni J, Charles P, et al. Annual change in Friedreich's ataxia evaluated by the scale for the assessment and rating of ataxia (SARA) is independent of disease severity. Mov Disord 2011;27(1):135–139. Portico. https://doi.org/10.1002/mds.23879

Appendix

May Yung Tiet¹, Heather Biggs¹, Emma Harrison¹, Dagmar Timmann², Nicole Jeschonneck², Paulina Cunha³, Hortense Hurmic³, Lucie Pierron³, Giulia Coarelli³, Claire Ewenczyk³, Ivana Ricca⁴, Melissa Barghigiani⁴, Nazan Akkaya⁵, Özgür Öztop Çakmak⁶.

¹Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

²Department of Neurology, University Hospital Essen, Essen, Germany.

³Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, CNRS, Inria, Inserm, AP-HP, Groupe Hospitalier Sorbonne Université, Paris, France.

⁴IRCCS Fondazione Stella Maris, Pisa, Italy.

⁵ Koç University Translational Medicine Research Center (KUTTAM), Koc University, Istanbul, Turkey.

⁶Department of Neurology, Koç University, Istanbul, Turkey.

Supporting Data

Additional Supporting Information may be found in the online version of this article at the publisher's web-site.