From motor performance to participation: a quantitative descriptive study in adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an autosomal recessive disorder more prevalent in the French-Canadian population [1] but with cohorts reported worldwide [2, 3]. International prevalence of ARSACS is not well known, but the carrier rate was estimated at 1/22 inhabitants in the Saguenay-Lac-St-Jean region (Quebec, Canada), and the incidence at birth at 1/1932 liveborn infants [4]. ARSACS is caused by mutations in the SACS gene [5] which is located on chromosome 13q12 [6]. Most of the French-Canadian cases (92.6%) are homozygous for the c.8844delT mutation and do not produce any sacsin protein [7]. Over 150 other mutations have been identified internationally [7]. These mutations lead to different level of sacsin protein expression, that may contribute to the differences observed in phenotypes [8].

Based on clinical observations and review of medical records, ARSACS clinical phenotype of French Canadian cases has been previously described. It consists of an early childhood onset of the disease with youngsters generally showing unsteadiness at gait initiation [6, 9]. Walking is delayed in most cases to around 18 months of age and walking difficulties is often the symptom leading to the first consultation [10]. The disease progression becomes most obvious in the late teens or early twenties [9]. Individuals will lose walking around their forties [9] but may experience severe walking limitations as soon as their early adulthood. Mean age of becoming constant wheelchair user is 41 years with a large range of 17 to 58 years [9], illustrating the great variability in the clinical spectrum even among a genetically homogeneous cohort. However, the documentation of the clinical portrait of ARSACS using quantified testing is scarce, and only one study has documented the impact of ARSACS on functional autonomy and participation [11]. So it is highly complex for clinicians to give prognostic in regard to disease severity and functional impacts, or anticipate the future steps and interventions needed for their patients since data do not exist in the literature. In addition, the increasing knowledge of ARSACS’ pathophysiology and the availability of a good mice transgenic model [12] increase the likelihood that clinical trials will be launched in a foreseeable future. But natural history studies using quantified measures are essential in order to design robust clinical trial protocols. As stated by the U.S. Food and Drug Administration, natural history studies are essential to provide the scientific foundation to build drug development programs, which require a deep understanding of the disease. The more these data are available early, the more it is informative to design efficacy trials [13].

This cross-sectional study aimed to: 1) Document motor performance in a genetically homogeneous cohort of adults with ARSACS in terms of dexterity, coordination, strength, mobility, and balance and overall disease severity; 2) Explore other systems involvement; 3) Document participation and health-related quality of life; and 4) Compare patients’ performances between different disease stages, age groups and with reference values.

This is the first study to document motor performance as well as overall disease severity using quantitative assessment among a cohort of ARSACS patients homozygous for the c.8844delT mutation. This is the first step in the documentation of the natural history of the disease, which is an essential step in drug development programs and their eventually trial for efficacy [13]. These results may also serve as comparative data for clinicians to anticipate disease progression of their patients.

This study illustrates the high level of variability within disease stage in regard to clinical presentation and disease severity. ARSACS is a progressive disease where overall severity increase with age, but results show important differences in performance level between individuals within a disease stage or age group. Despite its genetic homogeneity, a great variability in ataxia and spasticity severity as measured respectively by SARA and SPRS was observed across age groups. However, since participants’ number in each age group is small (5 to 10 participants/group) the extent of disease severity variability still needs to be further studied with larger cohorts. The age to become constant wheelchair user also illustrates the large clinical variability (mean 38.9; SD ±7.7), though close to the previously reported 41 years-old [9], with a wide range from 30 to 49 years, with even some not yet wheelchair-bound by age 50.

When comparing our results with those obtained in other ARSACS populations, disease severity as assessed by the SARA is similar to the results obtained by Vermeer et al. in 2008 in a cohort of 16 cases within the same age range (SARA mean score = 22.2; ranging from 14 to 28) [36]. However, disease severity of our cohort is slightly higher than ARSACS cases (n = 8) assessed by Synofzik et al. (mean age = 35.4 ± 6.6, SARA mean score = 16.1 ± 7.0) [37].

There is yet no longitudinal study in ARSACS but our study, to some extent, captures some aspects of progression by correlating the performance with participants’ age. Gagnon et al. [11] have previously observed this progression over time in upper limb tasks. However, the performance of the younger group is already below reference values for most upper limb tasks underlining early impairment onset. For grip and pinch strength, no significant correlations were seen with age, a result similar to Gagnon et al. [11]. However, since the progressive intrinsic hand muscles weakness is usually observed in the clinic at an early stage, it is possible that the relatively small sample size may have lead to a type II error, meaning that the existing difference was not detected.

The poor performance of the younger group as compared to reference value also supports lower limbs functions, balance and mobility early impairment in ARSACS. As indicated by the BBS score, 75% of younger and 100% of older participants are at high risk of falling (BBS score < 45) while walking, transferring or simply standing up without support. A recent study in Friedreich ataxia has shown a mean BBS score of 48 ± 1.3 for a group of seven participants aged from 21 to 43 years [38], well illustrating the high level of balance impairment of our participants, where the younger participants obtained a mean score of 34.6.

In regard to other symptoms less frequently associated with ARSACS in the literature, three symptoms have been pointed out. Dysphagia, which has been previously reported in 30% [36] and 35.7% [1] of patients with ARSACS, was reported in 21 participants (75%) in this study. Vesical problems were also previously reported in ARSACS [1, 36], with an incidence of about 50% of cases presenting with urine urgency and incontinence, compared to 75% in our cohort. This problem seemed to be more prevalent among older participants. Spasms are associated with presence of spasticity and upper motoneurons lesions but this symptom has never been reported in previous study. These results highlight the importance to systematically ask about dysphagia, vesical problems and spasms using standardized assessments in the follow-up because of the possible impact on quality of life and the availability of treatment.

If we look at the participation level of this ARSACS cohort, participants in the Wheelchair and Walking aid disease stages reported a lower level of participation as measured by the LIFE-H, with a mean score of 6.9 and 7.7 respectively, compared to a LIFE-H score of 9 which mean an absence of participation restriction [39]. The lower performance of participants on most upper and lower functions, mobility, and balance outcome measures may explain the lower level of social participation in these two more severe disease stages. However, decrease of physical performance does not influence Health-related quality of life. Results seem to be comparable with those of 7069 US healthy people (mean age: 50.7 years), who obtained a mean of 50 ± 10 for both SF-12 PCS and MCS composite scores [40]. However, cautions are needed in regard to these results as although often consider a gold standard, the use of SF-12v2 in a slowly progressive disease is questionable in regards to the short time lapse reference of 4 weeks used throughout the questionnaire where the condition is most likely to have been stable.

Some limitations of this study can be highlighted. Among these, we can note the overall small number of participants in the study, and particularly the small number of older participants who were able to perform the walking tests (6MWT and 10mWT). This clearly limits the power of the statistical analyses to detect a difference, although most of the comparisons were statistically significant. The other limitation is the homogeneity of our sample, which may limit to some extent the generalizability of the study in other ARSACS populations where the specific mutation causes only partial protein production in opposition to complete absence of protein production in our population [7]. Finally, some additional steps need to be accomplished to have a global portrait of the ARSACS population: 1) muscle strength impairment is not well documented, but a protocol must be first developed since presence of lower limbs co-contractions prevent valid assessment of muscle strength, and 2) the disease presentation in the paediatric population should be documented in regard to prognosis, care recommendations and trial readiness.

Altogether, results showed overall impaired motor performances, but this study is the first to clearly demonstrate the high level of clinical variability in ARSACS patients homozygous for the same mutation at different ages. Despite the early mild impairments, the underperformance of the younger participants compared to the reference values underline the insidious onset of this disease that is increasingly being diagnosed by next generation sequencing worldwide. This study represents a unique source of quantified data about ARSACS adult population for clinicians and lays the foundation for future clinical trials.