PDF(Pubmed)
Abstract：
A 23-month-old neutered male dog of unknown ancestry presented with a history of progressive neurological signs that included anxiety, cognitive impairment, tremors, seizure activity, ataxia, and pronounced visual impairment. The clinical signs were accompanied by global brain atrophy. Due to progression in the severity of disease signs, the dog was euthanized at 26 months of age. An examination of the tissues collected at necropsy revealed dramatic intracellular accumulations of autofluorescent inclusions in the brain, retina, and cardiac muscle. The inclusions were immunopositive for subunit c of mitochondrial ATP synthase, and their ultrastructural appearances were similar to those of lysosomal storage bodies that accumulate in some neuronal ceroid lipofuscinosis (NCL) diseases. The dog also exhibited widespread neuroinflammation. Based on these findings, the dog was deemed likely to have suffered from a form of NCL. A whole genome sequence analysis of the proband\'s DNA revealed a homozygous C to T substitution that altered the intron 3-exon 4 splice site of CLN6. Other mutations in CLN6 cause NCL diseases in humans and animals, including dogs. The CLN6 protein was undetectable with immunolabeling in the tissues of the proband. Based on the clinical history, fluorescence and electron-microscopy, immunohistochemistry, and molecular genetic findings, the disorder in this dog was classified as an NCL resulting from the absence of the CLN6 protein. Screening the dog\'s genome for a panel of breed-specific polymorphisms indicated that its ancestry included numerous breeds, with no single breed predominating. This suggests that the CLN6 disease variant is likely to be present in other mixed-breed dogs and at least some ancestral breeds, although it is likely to be rare since other cases have not been reported to date.
摘要：
一只23个月大的雄性狗，血统不明，有包括焦虑在内的进行性神经系统症状，认知障碍，震颤,癫痫发作活动,共济失调,和明显的视力障碍。临床症状伴有整体脑萎缩。由于疾病体征严重程度的进展，这只狗在26个月大时被安乐死。尸检时收集的组织检查显示，大脑中强烈的细胞内自发荧光内含物积累，视网膜,和心肌。包涵体对线粒体ATP合酶c亚基免疫阳性，它们的超微结构表现类似于在某些神经元类脂褐变（NCL）疾病中积累的溶酶体贮积体。狗还表现出广泛的神经炎症。基于这些发现,这只狗被认为可能患有某种形式的NCL。先证者DNA的全基因组序列分析显示纯合的C到T取代改变了CLN6的内含子3-外显子4剪接位点。CLN6中的其他突变会导致人类和动物的NCL疾病，包括狗。在先证者的组织中免疫标记无法检测到CLN6蛋白。根据病史,荧光和电子显微镜，免疫组织化学，和分子遗传学发现，由于缺乏CLN6蛋白，该犬的疾病被分类为NCL。对狗的基因组进行一组特定品种的多态性筛选表明，它的祖先包括许多品种，没有单一品种占主导地位。这表明CLN6疾病变异可能存在于其他混种犬和至少一些祖先品种中，尽管这种情况可能很少见，因为迄今为止尚未报告其他病例。
