PMM2基因突变所致先天性糖基化障碍二例临床特点及基因分析

Clinical and genetic analysis for two children with congenital disturbance of glycosylation with PMM2 gene mutations

目的探讨PMM2基因突变所致先天性糖基化障碍（PMM2-CDG）的临床及基因突变特点。方法以2012年在首都医科大学附属北京儿童医院神经内科临床诊断为PMM2．CDG的2例患儿为研究对象，分析其临床特征，采用PCR扩增双向测序法进行PMM2基因分析，再对发现的可能致病突变进行家系成员验证，并对基因结果进行分析。结果2例均为女婴，就诊年龄分别为1岁1个月和8个月，均以生后出现的发育迟缓、慢性腹泻合并代谢性酸中毒为主要特点，伴不同程度的血清转氨酶升高，抗凝血酶Ⅲ活性降低，体格检查均提示内斜视、乳头内陷、臀部上方皮下脂肪垫，头颅MRI示小脑萎缩。2例患儿均予作业治疗、物理治疗和语言治疗，随访至3岁余，语言运动发育均逐渐进步，但落后于同龄儿。2例均携带PMM2基因复合杂合突变，例l为外显子5的C．422G〉A（P．Argl41His），为已知热点致病突变；外显子8的c．669C〉A（P．Asp223Glu），为未报道新突变。例2为外屁子7的C．634A〉G（P．Met212Val）及外显子8的c．713G〉C（P．Arg238Pro），均为未报道新突变。结论PMM2-CDG是一种罕见的先天性代谢性疾病，主要表现为生长发育迟缓、血清转氨酶升高、抗凝血酶Ⅲ活性降低，查体可见乳头内陷、臀部上方皮下脂肪垫、内斜视，头颅MRI示小脑萎缩。对可疑病例及时进行PMM2基因检测可明确诊断。

Objective To analyze the clinical and PMM2 gene mutation features of congenital disturbance of glycosylation caused by PMM2 gene mutation （PMM2-CDG, previously known as CDG l a）. Method The clinical data of two Chinese patients who were clinically diagnosed as PMM2-CDG at neurology department of Beijing Children＇s Hospital in 2012 were retrospectively collected. The gene mutations were identified by Sanger sequencing. Result Both patients were female, aged 1 year and 1 month and 8 months respectively. The main clinical features of the two cases were developmental delay after birth, chronic diarrhea and metabolic acidosis, associated with elevated serum transaminases, and decreased antithrombin Ⅲ activity. Physical examination showed esotropia, inverted nipples, and abnormal subcutaneous fat pads. The cranial MRI showed cerebellar atrophy. Both cases were treated with occupational therapy, physical therapy and speech therapy. The development was gradually improved but also delayed as compared with normal peers during follow-up for more than 3 years. Genetic analysis showed that patient 1 was compound heterozygous for c. 422G 〉 A （ p. Argl41 His）, which was reported for known pathogenic mutation, and c. 669C 〉 A （p. Asp223Glu） , was a new mutation. The patient 2 showed compound heterozygous mutation for e. 634A 〉 G （ p. Met212Val ） and c. 713G 〉 C（ p. Arg238Pro）, which were both new mutations. Conclusion PMM2-CDG is a rare metabolic disease, and the diagnosis should be considered in a child with developmental delay, elevated serum transaminases, decreased antithrombin Ⅲ activity,inverted nipples,abnormal subcutaneous fat pads, esotropia,and cerebellar atrophy on MRI. It can be confirmed by PMM2 gene analysis.