In this study we identified 9 novel index patients with two pathogenic or likely pathogenic SACS variants. These patients were part of a consecutive series of n=172 patients with early-onset ataxia. Thus, ARSACS accounts for at least 5% (9/172) of early-onset ataxias - which makes it the second most common ataxia after Friedreich’s ataxia (29%; 50/172) in our series. SACS mutations were responsible for at least 11% (9/83) of patients with unexplained ataxia. This finding is comparable to recent studies observing relative frequencies of 12% (in 232 cerebellar ataxia patients ) and 13% (in 85 patients with at least 2 of the 3 cardinal features of ARSACS ).
The majority of our ARSACS patients (78%) presented with the classical early-onset triad of cerebellar ataxia, lower limb pyramidal tract signs and axonal-demyelinating sensorimotor peripheral neuropathy, thus corroborating other recent ARSACS case series [5, 6, 16]. However, one index patient and his likewise affected brother did not show cerebellar ataxia or clinical pyramidal tract signs (no spasticity, no extensor plantar response), and were thus initially presumed to suffer from Charcot-Marie-Tooth (CMT) Disease. This finding corroborates a recent finding of two ARSACS siblings presenting with a CMT-like picture . Importantly, however, in contrast to these previously reported siblings, our index patient and his brother did not even show mild spasticity or cerebellar ataxia. This suggests that SACS should be considered in both complicated and uncomplicated CMT.
On the other side of the phenotypic spectrum – and in sharp contrast to these CMT-like subjects – neuropathy might also be absent in ARSACS as indicated by patient #8 who did not show clinical or electrophysiological evidence of peripheral neuropathy. So far, only one ARSACS individual has been reported without clinical and electrophysiologic signs of peripheral neuropathy, suffering from a very late onset phenotype (ataxia starting at age 40 years) . Our finding demonstrates that even in early-onset cases, neuropathy is not an obligate feature of ARSACS. It might, however, develop at later stages of the disease.
Interestingly, patient #8 did also show neither spasticity nor extensor plantar response. So far, only two ARSACS individuals without lower-limb spasticity were described , but both displayed bilateral extensor plantar response, thus suggesting that pyramidal involvement might have been likely masked by the severe neuropathy in these two individuals . Since neuropathy was absent in our index patient, the lack of spasticity cannot simply be explained by a masking neuropathy. Thus, taken together, in contrast to the name of this “spastic ataxia of Charlevoix-Saguenay”, neither spasticity (absent in 2/9=22%) nor extensor plantar response (absent in 3/9=33%) nor cerebellar ataxia (absent in 1/9=11%) are obligate features of this disease. Although pyramidal tract involvement is common in ARSACS patients, as illustrated by the fact that all of our patients had abnormal MEPs, it might be only subclinical in some of them.
Increased demarcation of retinal nerve fibres is also not an obligatory feature of ARSACS. It was exhibited only by 1 (17%) of our patients. This finding is line with other recent studies that observed this feature only 1 out of 8  or in none out of 12 ARSACS patients , respectively. Taken together, these findings illustrate that increased demarcation of retinal nerve fibres might be a specific, but not obligatory finding in ARSACS , especially in non-Quebec ARSACS individuals . While the high frequency of urge incontinence (77%) might be due to either autonomic dysfunction or pyramidal damage  (or a combination of both), erectile dysfunction observed in one out of three male patients aged ≥16 years (33%) is clearly an indicator of autonomic dysfunction. So far, erectile dysfunction has only been reported in one ARSACS patient , but might be underdiagnosed. Thus, patients with ARSACS should be actively investigated for autonomic disturbances.
Our imaging findings extend the range of diagnostic features that help to diagnose ARSACS in patients with unexplained ataxia, spasticity or CMT. All patients with two pathogenic SACS variants showed not only the well-established linear pontine T2-hypointensities [2, 3], but also bilateral FLAIR-T2-hyperintensities of the lateral pons as well as a thickening of the MCP. The structural correlate of this finding, which corroborates and extends recent findings from other groups [3, 16, 20], are probably abnormally large transverse pontocerebellar fibres . The frequent finding of an arachnoidal cyst in the posterior fossa (75%) and of developmental cerebellar hemispheric atrophy in one patient underlines the hypothesis that disease processes in ARSACS are not only of neurodegenerative, but also of neurodevelopmental origin [16, 18]. These findings might help to differentiate ARSACS from many other recessive neuropathic ataxias, since they are not found e.g. in Friedreich’s ataxia or POLG-associated ataxia .
It was recently suggested that structural brain damage in ARSACS is not limited to infratentorial regions . Here we extend this notion, demonstrating for the first time that it also involves the cerebral cortex: 63% of our patients showed bilateral parietal cerebral atrophy. 63% of our patients also showed a short-stretched thinning of the posterior mid-body of the corpus callosum. Although this frequency is lower than in a previous study reporting a thin corpus callosum (TCC) in all patients , this finding substantiates the notion that disease processes in ARSACS also frequently involve key associative fibre bundles . Thus, ARSACS should be part of the differential diagnosis in spastic ataxias with TCC, like e.g. SPG11, SPG15  or GBA2.
We identified 17 novel SACS variants. Two of them – p.Thr458Ile and p.Val995Phe - were also observed in controls with a frequency of 0.4% or 0.3%, respectively. This indicates that they will likely be identified by many labs in the future, thus warranting a timely discussion whether they should be reported as pathogenic or not. The finding of a recessive mutation in a heterozygous state in controls does not per se refute a possible pathogenic role, in particular if the variant is common (as e.g. demonstrated by the expanded allele of FXN [Friedreich’s ataxia gene], which is observed with a heterozygous carrier rate of 1/60 to 1/90 in controls , or by the two frequent, clearly pathogenic c.1399 G>A [p.Ala467Thr] and c.2243 G>C [p.Trp748Ser] POLG mutations, which are observed with a heterozygous carrier rate of up to 1% in several European populations ). In particular, the p.Thr458Ile SACS variant might be pathogenic, given the in silico predictions, the high conservation index, and the MRI findings of a TCC as well as of a neurodevelopmental posterior fossa disorder consisting of an arachnoid cyst and herniation of tonsils in the homozygous carrier. Yet, for the time being, we here prefer not to claim any pathogenic significance, in particular given the large phenotypic differences compared to the other subjects with pathogenic SACS mutations. These findings illustrate a problem that is likely to occur frequently in the future: findings of variants with unknown significance may be frequent in SACS sequencing, given the fact that is has now entered clinical routine in many ataxia clinics. Thus, seemingly “atypical ARSACS phenotypes” should be scrutinized with particular caution and underlying SACS variants should ideally be analyzed functionally, e.g. with their impact on mitochondrial fission dynamics .