16例经典型Fabry病患者的临床表现和基因突变分析

目的 了解中国人经典型Fabry病患者的临床特征,并进行致病基因突变分析以提高国内对Fabry病的诊断水平.方法 对16例无血缘关系、经外周血白细胞α-半乳糖苷酶A活性检测确诊的Fabry病男性患者的临床表现进行总结分析;提取患者外周血DNA,对α-乳糖苷酶A基因(GLA基因)的每个外显子及旁侧内含子序列进行PCR产物直接测序;对所发现的新突变进行保守性分析及群体筛查以确定其致病性.结果 16例患者年龄为11-40岁,均具有Fabry病的典型特征,从发病到确诊拖延4～30年.在16例先证者中检测到14个突变,其中错义突变11个、无义突变1个、单碱基缺失1个、剪接位点突变1个,其中8个为新突变(c.119 C>A、c.275 A>T、c.520T>C、c.547G>C、c.647A>G、c.929T>G、c.1045T>A、IVS1-1G>A).群体酶切筛查均未发现有与患者相同的突变.新的错义突变在不同物种GLA基因中均具高度保守性.结论 Fabry病在国内的误诊率高;中国人GLA基因突变无突变热点;基因突变检测是诊断Fabry病的可靠方法.

Clinical manifestations and mutation study in 16 Chinese patients with Fabry disease

Objective To investigate the clinical manifestations and to characterize mutations of the GLA gene in Chinese patients with Fabry disease so to enhance the diagnosis of Fabry disease. Methods Sixteen Chinese affected males (from 16 unrelated families) with the classic phenotype of Fabry disease were investigated. The patients were diagnosed by a deficiency of α-galactesidase A(α-Gal A) activity. All seven exons and the neighboring intronic sequences of GLA gene were analyzed by PCR amplification and automated sequencing. ResultsA total of 14 mutations were identified including 12 single-base substitutions( 11 missense and 1 nonsense mutations) ,1 small deletion and 1 splicing mutation. Eight novel mutations( c. 119 C>A, c. 275 A>T, c. 520T>C, c. 547G>C, c. 647A>G, c. 929T>G, c. 1045T>A,IVS1-1G>A)were identified. The novel mutations were not tested by RFLP on 100 GLA alleles in Chinese population, and were highly conservative in mammalian species. ConclusionFabry disease is often misdiagnosed in China. There is no hot spot for mutations in Chinese patients. GLA gene mutation analysis is a reliable method to diagnosis for Fabry disease.