Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.
Cerebellum. 2007;6(4):353-9. doi: 10.1080/14734220701230466. Epub 2007 Feb 28.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) was originally found among inhabitants of the Charlevoix-Saguenay region of northeastern Quebec in Canada. This disease is a neurodegenerative disorder characterized by early-onset spastic ataxia, dysarthria, nystagmus, distal muscle wasting, finger and foot deformities, and retinal hypermyelination. The principal neuropathology comprises atrophy of the upper vermis and the loss of Purkinje cells in the cerebellum. The SACS gene was originally reported to consist of a single gigantic exon spanning 12.8 kb with an 11.5-kb open reading frame (ORF), and to encode the protein sacsin. Recently, eight exons upstream from the original gigantic one, however, have been found, and the new ORF has elongated to 13.7 kb. To date, at least 28 mutations have been found in Quebec and non-Quebec patients including ones in Italy, Japan, Spain, Tunisia, and Turkey, and ARSACS thus shows a worldwide occurrence. Although most of the mutations reported have been in the gigantic exon, the genotype is now expanding upstream from this gigantic exon. Therefore, the new exons upstream of the gigantic one should be analyzed when a case is clinically compatible with ARSACS, even without any mutation in the gigantic exon. Although Quebec patients show a homogeneous phenotype, non-Quebec patients exhibit some atypical clinical features, as follows: slightly later onset than that in Quebec patients, absence of retinal hypermyelination, intellectual impairment, and lack of spasticity. Thus, since ARSACS shows the clinical diversity, the SACS gene should be analyzed not only in typical cases as Quebec patients but also in atypical cases as non-Quebec patients. As more SACS mutations are identified worldwide, the clinical spectrum of 'sacsinopathies' will expand, and a finer genotype-phenotype correlation study will become possible and shed light on the molecular mechanism underlying ARSACS.
常染色体隐性痉挛性共济失调型小脑性共济失调（ARCSACS）最初发现于加拿大魁北克省东北部的沙格奈-圣劳伦斯地区的居民中。这种疾病是一种神经退行性疾病，其特征是早发性痉挛性共济失调、构音障碍、眼球震颤、远端肌肉萎缩、手指和足畸形以及视网膜髓鞘过度形成。主要的神经病理学包括上蚓部萎缩和小脑浦肯野细胞丢失。最初报道的 SACS 基因由一个横跨 12.8kb 的巨大外显子组成，其开放阅读框（ORF）为 11.5kb，并编码 sacsin 蛋白。然而，最近在原始巨大外显子的上游发现了另外 8 个外显子，新的 ORF 已经延长到 13.7kb。迄今为止，在魁北克和非魁北克患者中已经发现了至少 28 种突变，包括意大利、日本、西班牙、突尼斯和土耳其的患者，因此 ARSACS 具有全球发生。虽然报告的大多数突变都在外显子中，但现在基因型正在从这个巨大的外显子上游扩展。因此，即使在巨大外显子中没有任何突变，当病例与 ARSACS 临床相符时，也应该分析巨大外显子上游的新外显子。尽管魁北克患者表现出同质表型，但非魁北克患者表现出一些非典型的临床特征，如下：发病比魁北克患者稍晚，无视网膜髓鞘过度形成、智力障碍和无痉挛。因此，由于 ARSACS 表现出临床多样性，不仅应该在典型病例（如魁北克患者）中分析 SACS 基因，也应该在非典型病例（如非魁北克患者）中分析 SACS 基因。随着全世界发现更多的 SACS 突变，“sacsinopathies”的临床谱将会扩大，更精细的基因型-表型相关性研究将成为可能，并揭示 ARSACS 的分子机制。
