伴脑血管病的晚发型Pompe病一家系临床、病理和分子遗传学特点

Clinical, pathological and molecular genetic studies on a pedigree with late-onset Pompe＇ s disease complicated with cerebral vascular diseases

目的报道1个以脑血管病为主要临床表现的晚发型Pompe病家系，总结其临床、病理和分子遗传学特点。方法对1个伴脑血管病的兄妹共患病晚发型Pompe病家系进行家系调查和临床、病理资料收集；5名家系成员均行酸性α-糖苷酶（GAA）基因目的片段PCR扩增与测序。结果患病者为兄妹2人，均有自青少年期出现的进行性肢带肌无力，近来出现眩晕、共济失调等症状方就诊，颅脑CT和MRI示梗死、出血和脑白质多发缺血变性灶，其中哥哥颅脑CT血管成像（CTA）示脑动脉多处狭窄与后循环系统多发动脉瘤，妹妹颅脑CTA仅显示有多处动脉串珠样狭窄。前者肌肉活体组织检查病理表现为典型的空泡样变性和肌纤维内糖原的沉积。2例患者GAA酶活性均明显低于正常。对该家系5位家族成员（包括2例患者）的GAA基因分析发现2例患者及其母亲存在第9号外显子自1388位点起19个碱基的杂合缺失突变。结论以后循环受累为主的脑血管病是Pompe病少见的特殊表型。GAA基因c．1388 del 19为新发突变，与临床表型的关系尚不能确定。

Objective To report a pedigree with late-onset Pompe＇ s disease complicated with cerebral vascular diseases as to summarize their clinical, pathological and molecular genetic characteristics. Methods We investigated the clinical and pathological data of the two affected siblings with late-onset Pompe＇ s disease complicated with cerebral vascular diseases. All the 5 members of this pedigree accepted the GAA gene analysis. Results Both affected siblings had progressive pelvic girdle muscle weakness from young adult age, and recently developed vertigo and ataxia. Brain imaging of them revealed multiple cerebral hemorrhage, infarction and diffuse ischemic white matter lesions. The brother had multiple aaeurysms and stenoses of cerebral arteries revealed by brain CTA. However, his sister was only found to have multi-beaded stenoses of cerebral arteries. The muscle pathology of the brother showed typical vacuolar degeneration and glycogen storage in muscle fibers. The GAA enzyme activity of 2 siblings were dramatically lower than normal. A beterozygous 19 bp-deletion （c. 1388-c. 1406, exon 9） were found in GAA gene in the 2 siblings and their healthy mother. Conclusions Cerebrovascular involvement should be a special phenotype of Pompe＇ s disease. A novel heterozygous mutation c. 1388de119 in GAA gene was found in this pedigree, but the relationship between the mutation and the rare clinical phenotype needs further study.