Takaichi Yuta, Chambers James K, Shiroma-Kohyama Moeko, Haritani Makoto, Une Yumi, Yamato Osamu, Nakayama Hiroyuki, Uchida Kazuyuki
The University of Tokyo, Tokyo, Japan.
Kagoshima University, Kagoshima, Japan.
Vet Pathol. 2021 Jul;58(4):705-712. doi: 10.1177/03009858211002176. Epub 2021 Mar 29.
Canavan disease is an autosomal recessive leukodystrophy caused by mutations in the gene encoding aspartoacylase (ASPA), which hydrolyses N-acetylaspartate (NAA) to acetate and aspartate. A similar feline neurodegenerative disease associated with a mutation in the gene is reported herein. Comprehensive clinical, genetic, and pathological analyses were performed on 4 affected cats. Gait disturbance and head tremors initially appeared at 1 to 19 months of age. These cats eventually exhibited dysstasia and seizures and died at 7 to 53 months of age. Magnetic resonance imaging of the brain revealed diffuse symmetrical intensity change of the cerebral cortex, brainstem, and cerebellum. Gas chromatography-mass spectrometry analysis of urine showed significant excretion of NAA. Genetic analysis of the 4 affected cats identified a missense mutation (c.859G>C) in exon 6 of the gene, which was not detected in 4 neurologically intact cats examined as controls. Postmortem analysis revealed vacuolar changes predominantly distributed in the gray matter of the cerebrum and brain stem as well as in the cerebellar Purkinje cell layer. Immunohistochemically, these vacuoles were surrounded by neurofilaments and sometimes contained MBP- and Olig2-positive cells. Ultrastructurally, a large number of intracytoplasmic vacuoles containing mitochondria and electron-dense granules were detected in the cerebral cortex. All 4 cats were diagnosed as spongy encephalopathy with a mutation in the gene, a syndrome analogous to human Canavan disease. The histopathological findings suggest that feline ASPA deficiency induces intracytoplasmic edema in neurons and oligodendrocytes, resulting in spongy degeneration of the central nervous system.
卡纳万病是一种常染色体隐性白质营养不良症，由编码天冬氨酸酰基转移酶（ASPA）的基因突变引起，该酶可将N-乙酰天门冬氨酸（NAA）水解为乙酸盐和天门冬氨酸。本文报道了一种与该基因突变相关的类似猫神经退行性疾病。对4只患病猫进行了全面的临床、基因和病理分析。步态障碍和头部震颤最初出现在1至19月龄。这些猫最终出现共济失调和癫痫发作，并在7至53月龄死亡。脑部磁共振成像显示大脑皮层、脑干和小脑出现弥漫性对称强度变化。尿液的气相色谱-质谱分析显示NAA大量排泄。对4只患病猫的基因分析确定了该基因第6外显子中的一个错义突变（c.859G>C），在作为对照检查的4只神经功能正常的猫中未检测到。尸检分析显示空泡变化主要分布在大脑和脑干的灰质以及小脑浦肯野细胞层。免疫组织化学分析显示，这些空泡被神经丝包围，有时含有髓鞘碱性蛋白（MBP）和少突胶质细胞转录因子2（Olig2）阳性细胞。超微结构分析显示，在大脑皮层中检测到大量含有线粒体和电子致密颗粒的胞浆内空泡。所有4只猫均被诊断为患有该基因突变的海绵状脑病，这是一种与人类卡纳万病类似的综合征。组织病理学结果表明，猫ASPA缺乏会导致神经元和少突胶质细胞内的胞浆水肿，从而导致中枢神经系统的海绵状变性。
