Ellinwood N M, Wang P, Skeen T, Sharp N J H, Cesta M, Decker S, Edwards N J, Bublot I, Thompson J N, Bush W, Hardam E, Haskins M E, Giger U
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6010, USA.
J Inherit Metab Dis. 2003;26(5):489-504. doi: 10.1023/a:1025177411938.
Mucopolysaccharidosis III (MPS III) is characterized by lysosomal accumulation of the glycosaminoglycan (GAG) heparan sulphate (HS). In humans, the disease manifests in early childhood, and is characterized by a progressive central neuropathy leading to death in the second decade. This disease has also been described in mice (MPS IIIA and IIIB), dogs (MPS IIIA), emus (MPS IIIB) and goats (MPS IIID). We now report on dogs with naturally occurring MPS IIIB, detailing the clinical signs, diagnosis, histopathology, tissue enzymology and substrate levels. Two 3-year-old Schipperke dogs were evaluated for tremors and episodes of stumbling. Examination of the animals found signs consistent with cerebellar disease including dysmetria, hind limb ataxia and a wide-based stance with truncal swaying. There were mildly dystrophic corneas and small peripheral foci of retinal degeneration. Magnetic resonance imaging of the brain and skeletal radiographs were normal. Intracytoplasmic granules were found in the white cells of peripheral blood and cerebral spinal fluid, and in myeloid lineages in bone marrow. Electrophoresis of urinary GAGs indicated the presence of HS, while assays of cultured fibroblasts found N-acetyl-alpha-D-glucosaminidase (Naglu) activity of between 4.3% and 9.2% of normal. Owing to neurological deterioration, both dogs were euthanized, and post-mortem examinations were performed. Biochemical studies of liver and kidney from both animals demonstrated profound deficiency of Naglu activity and abnormally high GAG levels. Pathology of the brain included severe cerebellar atrophy, Purkinje cell loss, and cytoplasmic vacuolation in neurons and perithelial cells throughout the central nervous system. Pedigree analyses and Naglu levels of family members supported an autosomal recessive mode of inheritance. Using an obligate heterozygote, a breeding colony has been established to aid in understanding the pathogenesis of MPS IIIB and testing of potential therapies.
黏多糖贮积症III型（MPS III）的特征是溶酶体中糖胺聚糖（GAG）硫酸乙酰肝素（HS）的蓄积。在人类中，该疾病在幼儿期表现出来，其特征是进行性中枢神经病变，导致患者在第二个十年死亡。这种疾病也在小鼠（MPS IIIA和IIIB）、狗（MPS IIIA）、鸸鹋（MPS IIIB）和山羊（MPS IIID）中被描述过。我们现在报告患有自然发生的MPS IIIB的犬只，详细介绍其临床症状、诊断、组织病理学、组织酶学和底物水平。对两只3岁的舒柏奇犬进行了震颤和绊倒发作的评估。对这些动物的检查发现了与小脑疾病一致的体征，包括辨距不良、后肢共济失调以及伴有躯干摇摆的宽基步态。角膜有轻度营养不良，视网膜有小的周边变性灶。脑部磁共振成像和骨骼X光片均正常。在外周血和脑脊液的白细胞以及骨髓的髓系细胞中发现了胞质颗粒。尿GAG的电泳表明存在HS，而对培养的成纤维细胞的检测发现N-乙酰-α-D-氨基葡萄糖苷酶（Naglu）活性为正常水平的4.3%至9.2%。由于神经功能恶化，两只犬只均被安乐死，并进行了尸检。对两只动物的肝脏和肾脏进行的生化研究表明，Naglu活性严重缺乏，GAG水平异常高。脑部病理学表现包括严重的小脑萎缩、浦肯野细胞丢失以及整个中枢神经系统神经元和血管周细胞的胞质空泡化。家系分析和家庭成员的Naglu水平支持常染色体隐性遗传模式。利用一个必然的杂合子，已经建立了一个繁殖群体，以帮助了解MPS IIIB的发病机制并测试潜在的治疗方法。
