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Synofzik, Matthis; Soehn, Anne S.; Gburek-Augustat, Janina; Schicks, Julia; Karle, Kathrin N.; Schuele, Rebecca; Haack, Tobias B.; Schoening, Martin; Biskup, Saskia; Rudnik-Schoeneborn, Sabine; Senderek, Jan; Hoffmann, Karl-Titus; MacLeod, Patrick; Schwarz, Johannes; Bender, Benjamin; Krueger, Stefan; Kreuz, Friedmar; Bauer, Peter; Schoels, Ludger: Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum. In: Orphanet Journal of Rare Diseases 2013, 8:41




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{''