Germain Dominique P
Unité de Génétique Clinique, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015 Paris.
J Soc Biol. 2002;196(2):183-90.
Fabry disease (FD, OMIM 301500) is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the accumulation of neutral glycosphingolipids throughout the body, particularly within endothelial cells. Resulting narrowing and tortuosity of small blood vessels with endothelial dysfunction lead to tissue ischaemia and infarction. Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity and mortality from early onset strokes, cardiomyopathy and renal failure in adulthood. Medical management is symptomatic and consists of partial pain relief with analgesic drugs (gabapentin, carbamazepine), antihypertensive drugs, whereas renal transplantation or dialysis is available for patients experiencing end-stage renal failure. However, the ability to produce high doses of alpha-galactosidase A in vitro has opened the way to preclinical studies in the mouse model, and to the development of the first clinical trials in patients with Fabry disease. Enzyme replacement therapy has recently been validated as a therapeutic agent for Fabry disease patients. Long term safety and efficacy of replacement therapy are currently being investigated. Substrate deprivation and gene therapy may also prove future alternative therapeutic options.
法布里病（FD，OMIM 301500）是一种X连锁遗传性代谢紊乱疾病，由编码α-半乳糖苷酶A（一种溶酶体酶）的基因突变引起。酶缺陷导致全身中性糖鞘脂蓄积，尤其是在内皮细胞内。由此导致的小血管狭窄和迂曲以及内皮功能障碍会引起组织缺血和梗死。无法阻止糖鞘脂沉积的进展会导致成年期早发性中风、心肌病和肾衰竭，从而造成显著的发病率和死亡率。药物治疗主要是对症治疗，包括使用镇痛药（加巴喷丁、卡马西平）缓解部分疼痛、使用抗高血压药物，而终末期肾衰竭患者可进行肾移植或透析。然而，在体外生产高剂量α-半乳糖苷酶A的能力为在小鼠模型中开展临床前研究以及为法布里病患者开展首批临床试验开辟了道路。酶替代疗法最近已被确认为法布里病患者的一种治疗药物。目前正在研究替代疗法的长期安全性和疗效。底物剥夺和基因疗法也可能成为未来的替代治疗选择。
