Chambers James K, Thongtharb Atigan, Shiga Takanori, Azakami Daigo, Saito Miyoko, Sato Masumi, Morozumi Motoji, Nakayama Hiroyuki, Uchida Kazuyuki
1 Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyō, Tokyo, Japan.
2 Laboratory of Veterinary Nursing, Nippon Veterinary and Life Science University, Musashino, Tokyo, Japan.
Vet Pathol. 2018 Jul;55(4):543-551. doi: 10.1177/0300985818758471. Epub 2018 Feb 14.
Canine Lafora disease (LD) is an autosomal recessive genetic disorder causing nonfatal structural epilepsy, mainly affecting miniature wirehaired dachshunds. Repeat expansion in the EPM2B gene causes a functional impairment of the ubiquitin ligase malin which regulates glycogen metabolism. Abnormally structured glycogen accumulates and develop polyglucosan bodies predominantly in the central nervous system. The authors performed a comprehensive clinical, genetic, and pathological study of 4 LD cases affecting miniature wirehaired dachshund dogs with EPM2B repeat expansions, with systemic distribution of polyglucosan bodies and accumulation of laforin and other functionally associated proteins in the polyglucosan bodies. Myoclonic seizures first appeared at 7-9 years of age, and the dogs died at 14-16 years of age. Immunohistochemistry for calbindin revealed that the polyglucosan bodies were located in the cell bodies and dendritic processes of Purkinje cells. Polyglucosan bodies were also positive for laforin, hsp70, α/β-synuclein, ubiquitin, LC3, and p62. Laforin-positive polyglucosan bodies were located in neurofilament-positive neurons but not in GFAP-positive astrocytes. In nonneural tissues, periodic acid-Schiff (PAS)-positive polyglucosan bodies were observed in the heart, skeletal muscle, liver, apocrine sweat gland, and smooth muscle layer of the urinary bladder. In the skeletal muscle, polyglucosan bodies were observed only in type 1 fibers and not in type 2 fibers. The results indicate that although the repeat expansion of the EPM2B gene is specific to dogs, the immunohistochemical properties of polyglucosan body in canine LD are comparable to human LD. However, important phenotypic variations exist between the 2 species including the affected skeletal muscle fiber type.
犬类拉福拉病（LD）是一种常染色体隐性遗传疾病，会引发非致命性结构性癫痫，主要影响小型刚毛腊肠犬。EPM2B基因中的重复序列扩增会导致泛素连接酶malin功能受损，而该酶负责调节糖原代谢。结构异常的糖原会积累，并主要在中枢神经系统中形成多聚葡萄糖体。作者对4例患有EPM2B重复序列扩增的小型刚毛腊肠犬进行了全面的临床、基因和病理研究，这些犬的多聚葡萄糖体呈全身分布，且多聚葡萄糖体中存在拉福林和其他功能相关蛋白的积累。肌阵挛性癫痫首次发作于7至9岁，这些犬在14至16岁时死亡。钙结合蛋白免疫组织化学显示，多聚葡萄糖体位于浦肯野细胞的细胞体和树突状突起中。多聚葡萄糖体对拉福林、热休克蛋白70、α/β-突触核蛋白、泛素、微管相关蛋白轻链3和p62也呈阳性。拉福林阳性的多聚葡萄糖体位于神经丝阳性神经元中，而不在胶质纤维酸性蛋白阳性的星形胶质细胞中。在非神经组织中，在心脏、骨骼肌、肝脏、顶泌汗腺和膀胱平滑肌层中观察到过碘酸希夫（PAS）阳性的多聚葡萄糖体。在骨骼肌中，仅在1型纤维中观察到多聚葡萄糖体，而在2型纤维中未观察到。结果表明，虽然EPM2B基因的重复序列扩增是犬类特有的，但犬类LD中多聚葡萄糖体的免疫组织化学特性与人类LD相当。然而，这两个物种之间存在重要的表型差异，包括受影响的骨骼肌纤维类型。
