ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS: MIM 270550) is a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. This disorder, considered to be rare, was first described in the late seventies among French Canadians in the isolated Charlevoix-Saguenay region of Quebec. Nowadays, it is known that the disorder is not only limited to this region but occurs worldwide. Our objective was to identify cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) in Dutch patients with recessive early-onset cerebellar ataxia by sequencing the complete SACS gene. In a Dutch cohort of 43 index patients with ataxia onset before age 25, we identified 16 index patients (total 23 patients) with mutations in the SACS gene. Nine of them had homozygous mutations, and seven of them had compound heterozygous mutations. Retrospectively, the phenotype of patients carrying mutations was remarkably uniform: cerebellar ataxia with onset before age 13 years, lower limb spasticity and sensorimotor axonal neuropathy, and cerebellar (vermis) atrophy on magnetic resonance imaging, consistent with the core ARSACS phenotype previously described. The high rate of mutations (37%) identified in this cohort of Dutch patients suggests that ARSACS is substantially more frequent than previously estimated. We predict that the availability of SACS mutation analysis as well as an increasing awareness of the characteristic ARSACS phenotype will lead to the diagnosis of many additional patients, possibly even at a younger age.

Assessment of Whole-Brain White Matter by DTI in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

“…Supporting our nerve conduction studies and DTI findings, previous nerve conduction studies and sural nerve biopsy examinations also revealed demyelinating neuropathy with superimposed axonal involvement in patients with ARSACS. 11,[21][22][23] Severe CST involvement, as assessed by motor-evoked potential abnormalities, was attributed to the demyelination of the CST in an autopsy study. 24 Our current TBSS study, on the contrary, points out both axonal and myelin damage in the CST.…”

Teaching Video Neuro Images : Spastic ataxia syndrome

“…ARSACS is the second most common cause of autosomal recessive spastic ataxia syndrome (SACS mutations account for 37% of Friedreich-negative cases) 1 and should be considered in any population with suggestive MRI abnormalities. 2 …”

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects

“…More cases were then reported in Spain (Criscuolo et al, 2005), France (Anheim et al, 2008), Belgium (Ouyang et al, 2008), the Netherlands (Vermeer et al, 2008), Germany (Gerwig et al, 2010), Maritime Canada (Guernsey et al, 2010), and Morocco and eastern Europe (Baets et al, 2010). In eastern France, ARSACS was identified in two index patients among 102 autosomal recessive cerebellar ataxia (ARCA) ones (Anheim et al, 2008), meanwhile among 43 Dutch ARCA patients, 16 with mutations in the SACS gene were identified (Vermeer et al, 2008).…”

“…In eastern France, ARSACS was identified in two index patients among 102 autosomal recessive cerebellar ataxia (ARCA) ones (Anheim et al, 2008), meanwhile among 43 Dutch ARCA patients, 16 with mutations in the SACS gene were identified (Vermeer et al, 2008). In Japan, 17 Japanese ARSACS families have been discovered on SACS gene analysis so far (Ogawa et al, 2004;Hara et al, 2005;Shimazaki et al, 2005;Yamamoto et al, 2005;Ouyang et al, 2006;Yamamoto et al, 2006;Okawa et al, 2006;Hara et al, 2007;Takado et al, 2007;Shimazaki et al, 2007;Kamada et al, 2008;Tsugawa et al, 2009;Haga et al, 2011;Miyatake et al, 2011;Komure et al, 2006).…”

“…Since then, ARSACS has been reported worldwide, especially in the Mediterranean area (El Euch-Fayache et al, 2003;Criscuolo et al, 2004;Grieco et al, 2004;Richter et al, 2004) and Japan (Ogawa et al, 2004;Takiyama, 2006). More SACS gene mutations were also identified in other areas (Takiyama, 2007;Ouyang et al, 2008;Vermeer et al, 2008;Gerwig et al, 2010). Meanwhile, ARSACS in non-Quebec patients, especially in Japanese ones, showed marked clinical heterogeneity, i.e., there were patients without spasticity Hara et al, 2007;Shimazaki et al, 2007), without retinal hypermyelination , and with decreased mentality Yamamoto et al, 2005;Shimazaki et al, 2007;Hara et al, 2005).…”