Rodrigues L G, Ferraz M J, Rodrigues D, Pais-Vieira M, Lima D, Brady R O, Sousa M M, Sá-Miranda M C
Lysosome and Peroxisome Biology Unit, Instituto de Biologia Molecular e Celular, Porto, Portugal.
Neurobiol Dis. 2009 Jan;33(1):48-56. doi: 10.1016/j.nbd.2008.09.001. Epub 2008 Sep 23.
Fabry disease (OMIM 301500) is a rare X-linked recessive disorder caused by mutations in the alpha-galactosidase gene (GLA). Loss of alpha-galactosidase (alpha-Gal) activity leads to the abnormal accumulation of glycosphingolipids in lysosomes predominantly of vascular endothelial cells. Clinically the disorder presents with angiokeratomas, clouding of the cornea, and renal, cardiac, and cerebrovascular complications. In addition, there is an increased incidence of neuropathic pain in Fabry patients. In this study, we investigated the implications of loss of alpha-galactosidase A activity on sensorimotor function and peripheral nervous system. Similar to the described in Fabry disease patients, the sensorimotor assessment of Fabry mice revealed diminished locomotor activity and warm hypoalgesia as assessed in the hot-plate. Moreover Fabry mice displayed alterations both in balance and co-ordination. By histological analysis, the cyto-architecture of Fabry mice sciatic nerves showed an increase in mean cross-sectional area accompanied by a decrease in the density of non-myelinated fibers as well as a trend for a decreased number of small myelinated fibers, a well established feature of Fabry disease. A relative preservation of large myelinated fibers and nerve conduction velocity measurements was observed. Our findings demonstrate for the first time that Fabry knockout mice have Gb3 accumulation in the peripheral nervous system, alterations in sensorimotor function, hypoalgesia and no impairment of motor nerve conduction.
法布里病（OMIM 301500）是一种罕见的X连锁隐性疾病，由α-半乳糖苷酶基因（GLA）突变引起。α-半乳糖苷酶（α-Gal）活性丧失导致糖鞘脂在主要为血管内皮细胞的溶酶体中异常蓄积。临床上，该疾病表现为血管角质瘤、角膜混浊以及肾脏、心脏和脑血管并发症。此外，法布里病患者的神经性疼痛发病率增加。在本研究中，我们调查了α-半乳糖苷酶A活性丧失对感觉运动功能和周围神经系统的影响。与法布里病患者的描述相似，对法布里小鼠的感觉运动评估显示，如在热板试验中所评估的，运动活动减少和热感觉减退。此外，法布里小鼠在平衡和协调方面也表现出改变。通过组织学分析，法布里小鼠坐骨神经的细胞结构显示平均横截面积增加，同时无髓纤维密度降低，以及小的有髓纤维数量减少的趋势，这是法布里病的一个既定特征。观察到大型有髓纤维和神经传导速度测量相对保留。我们的研究结果首次证明，法布里基因敲除小鼠在外周神经系统中有Gb3蓄积，并存在感觉运动功能改变、感觉减退且运动神经传导未受损。
