Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum

Background: Mutations in SACS, leading to autosomal-recessive
spastic ataxia of Charlevoix-Saguenay (ARSACS), have been
identified as a frequent cause of recessive early-onset ataxia
around the world. Here we aimed to enlarge the spectrum of SACS
mutations outside Quebec, to establish the pathogenicity of novel
variants, and to expand the clinical and imaging phenotype.
Methods: Sequencing of SACS in 22 patients with unexplained
early-onset ataxia, assessment of novel SACS variants in 3.500
European control chromosomes and extensive phenotypic
investigations of all SACS carriers. Results: We identified 11
index patients harbouring 17 novel SACS variants. 9/11 patients
harboured two variants of at least probable pathogenicity which
were not observed in controls and, in case of missense mutations,
were located in highly conserved domains. These 9 patients
accounted for at least 11\% (9/83) in our series of unexplained
early onset ataxia subjects. While most patients (7/9) showed the
classical ARSACS triad, the presenting phenotype reached from pure
neuropathy (leading to the initial diagnosis of Charcot-Marie-Tooth
disease) in one subject to the absence of any signs of neuropathy
in another. In contrast to its name ``spastic ataxia{''