Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B) is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase activity, leading to increased levels of nondegraded heparan sulfate (HS). A mouse model has been useful to evaluate novel treatments for MPS IIIB, but has limitations. In this study, we evaluated the naturally occurring canine model of MPS IIIB for the onset and progression of biochemical and neuropathological changes during the preclinical stages (onset approximately 24–30 months of age) of canine MPS IIIB disease. Even by 1 month of age, MPS IIIB dogs had elevated HS levels in brain and cerebrospinal fluid. Analysis of histopathology of several disease-relevant regions of the forebrain demonstrated progressive lysosomal storage and microglial activation despite a lack of cerebrocortical atrophy in the oldest animals studied. More pronounced histopathology changes were detected in the cerebellum, where progressive lysosomal storage, astrocytosis and microglial activation were observed. Microglial activation was particularly prominent in cerebellar white matter and within the deep cerebellar nuclei, where neuron loss also occurred. The findings in this study will form the basis of future assessments of therapeutic efficacy in this large animal disease model.

IIIB型粘多糖贮积病（MPS IIIB； Sanfilippo综合征B）是由α- N缺乏引起的常染色体隐性溶酶体贮积病-乙酰氨基葡萄糖苷酶活性，导致未降解硫酸乙酰肝素（HS）含量增加。小鼠模型可用于评估MPS IIIB的新型治疗方法，但有局限性。在这项研究中，我们评估了MPS IIIB疾病的临床前阶段（大约24至30个月大的发作）期间生化和神经病理学变化的发作和发展过程，对MPS IIIB的天然犬模型进行了评估。甚至在1个月大时，MPS IIIB狗的脑和脑脊液中的HS含量也升高。尽管研究的最老的动物缺乏脑皮质萎缩，但前脑几个疾病相关区域的组织病理学分析显示溶酶体贮藏和小胶质细胞活化逐渐进行。在小脑中发现了更明显的组织病理学变化，观察到进行性溶酶体储存，星形胶质细胞增多和小胶质细胞活化。小脑胶质细胞的激活在小脑白质和小脑深核中尤为突出，那里也发生了神经元丢失。这项研究中的发现将构成对该大型动物疾病模型未来疗效评估的基础。