晚发型糖原贮积病Ⅱ型1例患者的临床和病理及其家系GAA基因分析

Clinical and Pathological Characteristics and Genetic Analysis of A Patient with Late Onset Pompe Disease

目的研究1例晚发型糖原贮积病Ⅱ型(GSDⅡ)患者的临床、病理和遗传特征。方法回顾性分析1例晚发型GSDⅡ患者的临床资料和骨骼肌病理特征,同时取得患者和家属知情同意后对其家系进行遗传咨询,提取外周血白细胞基因组DNA,应用聚合酶链反应(PCR)扩增酸性-α-葡萄糖苷酶(GAA)的基因编码区,直接测序分析GAA基因突变情况。结果 1患者男性21岁,临床表现为呼吸肌、四肢近端肌无力。肌电图提示肌源性损害。三角肌病理和免疫组化染色提示肌源性损害,酸性磷酸酶染色(+)。血GAA活性明显低于正常,符合晚发型GSDⅡ诊断。2家系GAA基因分析提示,患者及其父亲和2位姑姑(父亲的妹妹)均携带一个未见报道的GAA基因新突变:位于第8号外显子的缺失突变(p.Met439del);患者及其母亲、外祖母均携带一个已报道的GAA基因16号外显子错义突变(p.Trp746Cys);该家系中发现一些非致病性杂合突变。结论在晚发型GSDⅡ家系中发现一个新的GAA基因第8号外显子缺失突变p.Met439del。先证者因存在双杂合突变导致GAA活性下降并出现晚发型GSDⅡ的临床和病理改变。

Aim To summarize the clinical, pathological and genetic characteristics of a pedigree with late onset Pompe disease （LOPD）. Methods Clinical and pathological data of the proband of LOPD were collected and GAA gene was analyzed using direct sequence of PCR-ampliifed genomic DNA. GAA gene analysis was performed in the pedigrees. Results The proband was a 21 year-old man presented with weakness in extremities and a sudden respiratory failure typeⅡ, along with severely decreased serum GAA enzyme activity, all of which were typical manifestations of LOPD. A new deletion mutation of p.Met439del in exon 8, which had not been reported elsewhere before was detected in one chromosome of the proband, his father and two aunts. The proband also had a known pathogenic missense mutation of p.Trp746Cys in the other chromosome. This missense mutation also existed in his mother and grandmother. Other known low pathogenic GAA gene mutations were found in the pedigree. Conclusion The compound heterozygosity with the deletion mutation of p.Met439del and known pathogenic missense mutation of p.Trp746Cys caused the clinical presentation of LOPD in the proband. A new deletion mutation of p.Met439del in exon 8 was postulated a pathogenic GAA gene mutation in LOPD.