ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is a human neurological disorder characterized by progressive cerebellar ataxia and peripheral neuropathy. A recently recognized disorder in Great Pyrenees dogs is similarly characterized by widespread central nervous system degeneration leading to progressive cerebellar ataxia and spasticity, combined with peripheral neuropathy. Onset of clinical signs occurred in puppies as young as 4 months of age, with slow progression over several years. A multi-generation pedigree suggested an autosomal recessive mode of inheritance. Histopathology revealed consistent cerebellar Purkinje cell degeneration, neuronal degeneration in brainstem nuclei, widespread spinal cord white matter degeneration, ganglion cell degeneration, inappropriately thin myelin sheaths or fully demyelinated peripheral nerve fibers, and normal or only mild patterns of denervation atrophy in skeletal muscles. Genome-wide single nucleotide polymorphism (SNP) genotype data was collected from 6 cases and 26 controls, where homozygosity mapping identified a 3.3 Mb region on CFA25 in which all cases were homozygous and all controls were either heterozygous or homozygous for alternate haplotypes. This region tagged the SACS gene where variants are known to cause ARSACS. Sanger sequencing of SACS in affected dogs identified a 4 bp deletion that causes a frame shift and truncates 343 amino acids from the C terminus of the encoded sacsin protein (p.Val4244AlafsTer32). Our clinical and histopathological descriptions of this canine disorder contribute to the description of human ARSACS and represents the first naturally occurring large animal model of this disorder.

ARSACS（常染色体隐性遗传性夏勒瓦-萨格奈痉挛性共济失调）是一种以进行性小脑性共济失调和周围神经病变为特征的人类神经系统疾病。最近在大比利牛斯犬中发现的一种疾病具有类似的特征，即广泛的中枢神经系统变性，导致进行性小脑共济失调和痉挛，并伴有周围神经病变。临床症状发生在 4 个月大的幼犬身上，并在几年内缓慢进展。多代谱系表明常染色体隐性遗传模式。组织病理学显示一致的小脑浦肯野细胞变性、脑干核神经元变性、广泛的脊髓白质变性、神经节细胞变性、髓鞘不适当薄或完全脱髓鞘的周围神经纤维，以及骨骼肌中正常或仅轻度的去神经萎缩模式。从 6 个病例和 26 个对照中收集了全基因组单核苷酸多态性 (SNP) 基因型数据，其中纯合性作图鉴定了 CFA25 上的 3.3 Mb 区域，其中所有病例都是纯合的，所有对照都是杂合的或替代单倍型的纯合。该区域标记了SACS基因，其中已知变异会导致 ARSACS。对受影响狗的SACS进行 Sanger 测序，发现 4 bp 缺失会导致移码，并从编码的 sacsin 蛋白 (p.Val4244AlafsTer32) 的 C 末端截断 343 个氨基酸。我们对这种犬类疾病的临床和组织病理学描述有助于对人类 ARSACS 的描述，并代表了这种疾病的第一个自然发生的大型动物模型。