Gray-Edwards Heather L, Brunson Brandon L, Holland Merrilee, Hespel Adrien-Maxence, Bradbury Allison M, McCurdy Victoria J, Beadlescomb Patricia M, Randle Ashley N, Salibi Nouha, Denney Thomas S, Beyers Ronald J, Johnson Aime K, Voyles Meredith L, Montgomery Ronald D, Wilson Diane U, Hudson Judith A, Cox Nancy R, Baker Henry J, Sena-Esteves Miguel, Martin Douglas R
Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
Mol Genet Metab. 2015 Sep-Oct;116(1-2):80-7. doi: 10.1016/j.ymgme.2015.05.003. Epub 2015 May 8.
Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme β-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and swallowing problems, eventually reaching a vegetative state with death typically by 4years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeletal changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5±0.5months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease.
桑德霍夫病（SD）是一种由β-N-乙酰己糖胺酶突变引起的致命性神经退行性疾病。婴儿期发病的SD患儿会出现癫痫发作、肌张力丧失和吞咽问题，最终进入植物人状态，通常在4岁时死亡。其他症状包括脊柱后凸和心脏异常，与黏多糖贮积症极为相似。来自SD患者的分离成纤维细胞对糖胺聚糖（GAGs）的分解代谢受损。为了评估猫SD模型的黏多糖贮积症样特征，我们利用了X线摄影、磁共振成像、超声心动图、组织病理学以及对中枢神经系统和外周组织/液体进行GAG定量分析。猫SD模型表现出心脏瓣膜和结构异常、骨骼变化以及脊髓受压，这些与GAGs的蓄积一致，但远不如定义人道终点（4.5±0.5个月）的严重神经疾病那么突出。颅内腺相关病毒基因治疗16周后，SD猫的大脑皮质和肝脏中的GAG贮积被清除，但心脏、肺、骨骼肌、肾脏、脾脏、胰腺、小肠、皮肤或尿液中的GAG贮积未被清除。GAG贮积会随着时间恶化，因此对于那些因基因治疗或针对原发性神经疾病的其他新疗法而大幅延长寿命的人类来说，GAG贮积可能会成为一个重要的病理来源。
