Pediatric ataxic gait and posture- assessment provides an important instrument to identify children and young adults with indisputable EOA (Brandsma et al., 2016a; Lawerman et al., 2016). The availability of validated gait and posture- biomarkers in children is also important for the entry of high quality data in international EOA databases (Durr, 2015; Brandsma et al., 2016a; Lawerman et al., 2016) and also for the evaluation of treatment (Romano et al., 2015), especially when the training of core-muscles is involved (such as by exergame-training) (van Diest et al., 2016; Schatton et al., 2017). In young, often disabled, EOA patients with limited concentration and physical endurance, optimally applicable gait and posture biomarkers are characterized as: non-invasive, quick and easy, compatible with adult parameters, reliable and also associated with a good construct validity (Schmidt and Embretson, 2003; Saute et al., 2012). Until now, insight in the validity of clinically available gait and posture- biomarkers is incomplete. The SARA is described as a reliable, quickly assessable, and non-invasive rating scale for patients with ataxia (Schmitz-Hubsch et al., 2006). SARA scores consist of summed: gait and posture- (SARA_GAIT/POSTURE measuring gait, stance, sitting performances), kinetics (SARA_KINETIC) and speech (SARA_SPEECH) sub-scores (Schmitz-Hubsch et al., 2006). In EOA, we aimed to investigate the construct validity of the pediatric SARA_GAIT/POSTURE sub-scale scores.

For the investigation of the EOA SARA_GAIT/POSTURE construct validity, it is important to realize two points. First, it is important to realize that the SARA was originally designed and validated as a complete, total score in the domains of gait/posture, kinetics, and speech (Schmitz-Hubsch et al., 2006). However, under the assumption that the SARA sub-scale scores SARA_GAIT/POSTURE and SARA_KINETIC measure cerebellar functioning in different domains (i.e., vermis and anterior lobe and cerebellar hemispheres, respectively), we hypothesized that the SARA_GAIT/POSTURE sub-scale could be separately validated. Second, it is important to realize that the SARA was originally designed and validated in adult patients with AOA (Schmitz-Hubsch et al., 2006). However, due to the short clinical assessment time and good score reproducibility, the scale was soon applied in children too (Brandsma et al., 2014a, 2016b; Hartley et al., 2015; Reetz et al., 2015). Before SARA scores can be analogously interpreted in AOA and EOA patients, it is thus important to take the effect of potential group differences into account. In comparison with the AOA patient group, EOA patients may reveal a large variety of disorders, with a heterogeneous phenotypic presentation and co-morbidity (such as myopathy and/or myoclonus). This explains why SARA score characteristics can differ between AOA and EOA patient groups (Sival and Brunt, 2009; Sival et al., 2011; Brandsma et al., 2014a, 2016b). For instance, in AOA patients, total SARA scores relate with ataxia as one single factor [i.e., ‘ataxia’ (Schmitz-Hubsch et al., 2006)]. This is contrasted by total SARA scores in EOA patients, which are also attributed to: (1) pediatric age (i.e., cerebellar maturation; Largo et al., 2003; Sival and Brunt, 2009; Brandsma et al., 2014a), (2) comorbid muscle weakness [in FA (Sival et al., 2011)], and (3) comorbid movement disorders (Brandsma et al., 2016b).

In children and young adults with EOA, we thus aimed to investigate the construct validity of the SARA_GAIT/POSTURE sub-scale. Under the premise that parameters for SARA_GAIT/POSTURE would depend on the integrated cerebellar processing of visual, vestibular, and sensory signals of the limbs and trunk (Sival, 2012; Delabasita et al., 2016; Takakusaki, 2017), SARA_GAIT/POSTURE sub-scales would be expected to correlate with biomarkers for dynamic and passive balance, such as: the scale for ASMK [dynamic balance (Klockgether et al., 1998)] and the PBS (static balance; Franjoine et al., 2010). Additionally, we reasoned that clinically meaningful and effective SARA_GAIT/POSTURE sub-scores would relate with a validated, age-related classification system for functional motility in children, such as the GMFCS (Palisano et al., 1997) – the extended and revised version (E&R; Palisano et al., 2008), which is originally designed for children with cerebral palsy. Furthermore, accurate kinematics for SARA_GAITPOSTURE performances would also correlate with biomarkers for kinetic-limb function, such as: SARA_KINETIC (upper and lower limbs) and AS [upper limb kinetic scores (Trouillas et al., 1997)]. Finally, effective EOA SARA_GAIT/POSTURE scores would be expected to correlate with SARA_TOTAL. Strong and significant correlations would underpin a good convergent validity of SARA_GAIT/POSTURE sub-scale scores. Absent influence by EOA co-morbidity factors (such as muscle weakness and/or myoclonus) on the scores would underpin sufficient discriminant validity of the SARA_GAIT/POSTURE sub-scale.

In the present study, we thus aimed to elucidate the construct validity and reliability of EOA SARA_GAIT/POSTURE sub-scale scores in children and young adults.

The Medical Ethical Committee of the University Medical Center Groningen (UMCG), Netherlands, approved the study (METc 2011/165). According to the Dutch medical ethical law, both parents and children older than 12 years of age provided written informed consent. Children younger than 12 years of age provided assent. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the ‘The Medical Ethical Committee of the University Medical Center Groningen (UMCG), Netherlands’. In the absence of preceding pediatric data for a power calculation, we performed a prospective, explorative study.

In children and young adults with EOA, we aimed to investigate the construct validity of SARA_GAIT/POSTURE sub-scores. SARA_GAIT/POSTURE sub-scores revealed a high inter-observer agreement (ICC) and were strongly associated with other quantitative scales for coordinative motor function, such as: active and static balance (ASMK, PBS), kinetic limb performances (SARA_KINETIC, AS) and total ataxia scores (SARA_TOTAL). Furthermore, we also observed a strong correlation between SARA_GAIT/POSTURE sub-scores and the classification levels of the GMFCS (E&R), which is originally designed for the assessment of functional motility in children with cerebral palsy (Palisano et al., 1997, 2008). The discriminant validity of the SARA_GAIT/POSTURE subscale between the measurement of ataxia and co-morbidity factors (muscle weakness and myoclonus) was incomplete. In children and young adults with EOA, we conclude that SARA_GAIT/POSTURE scores are reliable. However, SARA_GAIT/POSTURE parameters discriminate insufficiently between the influence by ataxia and muscle weakness. This implicates that gait and posture scores should be interpreted in homogeneous EOA subgroups that take comorbid muscle weakness into account.

In previous EOA studies, we have shown that tools for the assessment of ataxic gait may contribute to the early recognition of indisputable EOA in young patients (Lawerman et al., 2016). Furthermore, well-validated clinical biomarkers for EOA gait and posture assessment are useful for the evaluation of pediatric treatment strategies, targeting at the training of core-muscle function (van Diest et al., 2016; Schatton et al., 2017). In the present study, we observed an excellent inter-observer agreement (ICC) on SARA_GAIT/POSTURE sub-scores, which was in the same range as SARA_TOTAL and SARA_KINETIC sub-scores. These SARA_TOTAL outcomes are in agreement with previously published ICC data in adult patients with predominantly AOA phenotypes (Schmitz-Hubsch et al., 2006).

We determined convergent validity of SARA_GAIT/POSTURE sub-scores under the premise that all ataxic gait parameters for walking, standing, and balancing would depend on the same integrated cerebellar processing of sensory, visual, and vestibular signals (Takakusaki, 2017) with upper- and lower- limb and trunk motor performances (Sival, 2012; Delabasita et al., 2016). We thus hypothesized that the construct validity of SARA_GAIT/POSTURE could be reflected by the association with other coordinative motor function tests requiring cerebellar integration of multimodal signals. Accordingly, we observed that SARA_GAIT/POSTURE sub-scores were strongly associated with the tested parameters for coordinated motor function. The SARA_GAIT/POSTURE items for active and passive balance were strongly related with ASMK and PBS scores and also with GFMCS classifications, implicating that the closely associated test objectives have a functional significance. Furthermore, SARA_GAIT/POSTURE scores were also correlated with kinetic functions of the upper and lower extremities, which can be understood by the fact that gait kinetics (including arm swing, turning, balance and tandem -stance and -gait performances) also require accurate limb kinetics. Finally, SARA_GAIT/POSTURE scores appeared strongly associated with SARA_TOTAL scores. Although correlated, SARA_GAIT/POSTURE and AS scores revealed the lowest correlation. In perspective of the differences in tested cerebellar domains (vermis versus hemispheres) and the differences regarding motor function tasks (gross versus fine motor function tasks), the lower correlation is in accordance with our expectations. As focal cerebellar damage was excluded from the present study group inclusion, one could attribute the above mentioned correlations between different cerebellar domains and/or motor function tasks to global functional pathology of the cerebellum. In young, ataxic EOA patients without focal cerebellar lesions, these results may thus implicate that SARA_GAIT/POSTURE scores can provide a global impression of the total ataxia-severity. When ambulant EOA children without focal lesions are too young (<4 years of age) or lack the motivation and/or concentration to complete all SARA motor task performances, SARA_GAIT/POSTURE parameters could theoretically provide a fast and easy biomarker to estimate ataxia-progression. Altogether, in children and young adults with distinct EOA features, SARA_GAIT/POSTURE can reliably measure ‘ataxic’ gait severity and may also provide a global impression of the total ataxia severity.

We obtained the above mentioned results under the premise that SARA and other coordination scales measure the same objective. However, as already stated for the AS, this is not necessarily correct, as the other biomarkers (such as for active and passive balance, and kinetic function) may measure more than the objective ‘ataxia,’ alone. This implicates that other factors than ataxia could theoretically influence SARA_GAIT/POSTURE scores. For instance, in previous studies, we have shown that the age of the child (i.e., cerebellar maturation) has an influence on SARA scores (Sival and Brunt, 2009; Brandsma et al., 2014a). Although mean age-related effects are comparatively small in relation to pathologic SARA scores in ataxic patients, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society has recently shown that children younger than 8 years of life can also reveal considerable variation in SARA_TOTAL scores, which may affect the interpretation of the longitudinal scores (Lawerman et al., 2017). However, as the variation of SARA_GAIT/POSTURE sub-scores in young children appeared much smaller (Lawerman et al., 2017), one could use the SARA_GAIT/POSTURE sub-scale as an internal control to discriminate between physiological age-related and ataxia effects on the SARA_TOTAL scores. To elucidate the SARA_GAIT/POSTURE test construct, we also investigated the potential effects of co-morbidity factors on the SARA_GAIT/POSTURE sub-scores. SARA_GAIT/POSTURE and SARA_TOTAL scores revealed an incomplete discriminant validity between ataxia and comorbid ‘muscle weakness.’ Although this does not automatically implicate a causal relationship, absence of a relationship between muscle weakness and SARA_GAIT/POSTURE and SARA_TOTAL scores cannot be assumed, either. For instance, when the child has difficulties to raise an arm against gravity, or when the child has just sufficient MF to walk with support, muscle weakness is likely to affect the scores. Furthermore, in case of limiting muscle weakness to execute the SARA rating scale task, maximal scores should be given. In the latter case, ataxia itself has not determined the score, but limiting muscle weakness instead. This implicates that the discriminant validity of SARA _GAIT/POSTURE sub-scores between muscle weakness and ataxia is incomplete.

Analyzing the patient inclusion of the myopathic EOA cohort, revealed a majority of patients with FA. This underpins our previously reported study data on the association between muscle weakness and ataxia scores in FA children (Sival et al., 2011). Interestingly, in another FA cohort, this association between SARA scores and muscle weakness was not reported (Bürk et al., 2009). However, in the latter study, MF Z-scores were not available, implicating that exact correlations cannot be made. Furthermore, one should be aware that correlations between muscle weakness and SARA scores would require patient sub-groups with sufficient variety in MF. For example, in homogeneous EOA groups with normal physiological muscle strength, the influence by muscle weakness on SARA scores would not be addressed. Similarly, in homogeneous EOA groups with severely progressed muscle weakness (represented by non-ambulant patients), plateauing SARA scores would also obscure an association with muscle weakness. These results implicate that it is advisable to obtain SARA_GAIT/POSTURE scores in homogeneous EOA subgroups and to stratify outcomes for substantial variations in muscle weakness. Finally, we investigated the EOA influence of comorbid myoclonus on SARA_GAIT/POSTURE sub-scores. In the comorbid myoclonus subgroup, the percentage (%) contribution of SARA_GAIT/POSTURE to SARA_TOTAL scores was low compared to non-myoclonus subgroup, reflecting a negative effect. Interestingly, the percentage (%) contribution of SARA_KINETIC to SARA_TOTAL scores was high in the comorbid myoclonus subgroup, compared to non-myoclonus subgroup, implicating a predominant effect of comorbid myoclonus on SARA_KINETIC, instead of SARA_GAIT/POSTURE scores. As myoclonic jerks in GOSR2 patients may start at the upper extremities and increase during intended kinetic limb movements, these findings are understandable.

We are aware that this study has several limitations. First, the EOA patients fulfilling the requirements for patient inclusion are rare, implicating that the number of patients was limited. However, as the present data are obtained in a specialized movement disorder center over a study period of 5 years (with an inclusion rate of 100%), investigation of a larger patient cohort will not easily be accomplished. Second, we realize that statistically significant correlations do not necessarily implicate causality (Field, 2009). But, as significant correlations between SARA_GAIT/POSTURE sub-scores and MF were consistently absent in patients without MF loss, our findings do not reject causality, either. Third, to avoid an unacceptable test burden and exhaustion for the patients, we planned different tests during successive medical visits to our outpatient clinic (see Supplementary Table I). However, as latent time intervals between tests would only exert a negative influence on the correlations, the positive inter-correlations between SARA_GAIT/POSTURE and other ataxia biomarkers cannot be attributed to it. Fourth, we cannot exclude that other, yet unexplored confounders may also exist (such as neuropathy, concentration, behavior, and tiredness). Altogether, in the perspective of the presented findings, we conclude that SARA_GAIT/POSTURE scores are associated with MF loss. In EOA patients with comorbid myopathy, it appears prudent to interpret SARA_GAIT/POSTURE scores for the severity of muscle weakness.

The inter-observer agreement and convergent validity of SARA_GAIT/POSTURE scores in EOA patients are high, implicating the reliability of the scores. Regarding the incomplete discriminant validity of the scores, it is advisable to interpret SARA_GAIT/POSTURE scores for comorbid muscle weakness.

TL: draft of the manuscript, data acquisition, data analysis, interpretation of data. RB: data acquisition, revising the manuscript for important intellectual content. RV: data acquisition, interpretation of data, revising the manuscript for important intellectual content. JvdH: data acquisition, interpretation of data, revising the manuscript for important intellectual content. RL: data acquisition, revising the manuscript for important intellectual content. HK: data interpretation, drafting, and revising the manuscript for important intellectual content. DS: concept and design of the manuscript, data acquisition, interpretation of data, drafting, revising, and final version of the manuscript. All authors approved the final version and agreed to be accountable for all aspects of the work.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.