病理表现为炎症性肌病的LMNA相关先天性肌营养不良4例的表型／基因型研究

Phenotype/genotype analysis of 4 cases of LMNA related congenital muscular dystrophy with inflammatory changes

目的分析与确立4例肌活检病理表现为炎症性肌病的LMNA相关先天性肌营养不良（L—CMD）患儿的临床、肌活检组织病理特征，并行致病基因突变研究。方法收集先证者临床资料，对先证者进行腓肠肌活检；提取外周血基因组DNA与RNA，采用PCR、反转录（RT）．PCR与DNA直接测序方法进行mfM基因突变检测，确定基因突变的类型。结果4例患儿于胎儿期或出生后数月发病，主要表现为运动发育落后，上肢近端、下肢远端及颈伸肌肌无力，肌张力减低，关节畸形，肌酸激酶轻中度升高，腓肠肌活检病理学检查提示肌营养不良样改变，伴大量炎性细胞浸润，电镜下肌细胞核形态异常。LMNA基因突变分析发现4例患儿均为显性新生突变，其中3例为未报道的致病突变。4例患儿的父母删AH基因相应突变位点均为野生型。结论通过分子遗传学分析，确诊分别由LMNA的新生突变导致的4例L—CMD，为这些家庭的遗传咨询提供了可能。对出生时或出生后数月出现双上肢近端、双下肢远端、颈伸肌肌无力明显，肌张力低，关节畸形，肌活检提示肌营养不良改变，但伴大量炎性细胞浸润的患者，应分析LMNA基因。基因分析是确诊L—CMD最可靠的方法．．

Objective To analyze the-clinical characteristics, muscle pathological features and pathogenic gene mutation in 4 cases with LMNA-related congenital muscular dystrophy （L-CMD）. Methods Clinical data of the probands and the parents were collected. Skeletal muscle specimens were biopsied from the probands for pathological a- nalysis. Genomic DNA and RNA were extracted from peripheral blood leukocytes, and PCR, reverse transcription （RT）- PCR and DNA direct sequencing were employed to analyze the LMNA gene to determine the gene mutation and confirm the pathogenicity. Results Four patients had symptoms from fetal period to several months after birth. They presented with motor retardation, muscle weakness with prominent the proximal upper limbs, distal lower limbs and neck extensor, hypotonia, contraetures, with mild to moderate elevation of CK level. The muscle biopsies showed muscular dystrophic and with inflammatory changes, and the abnolznal nuclear morphology was observed with transmission electron microsco- py. Genetic analysis of them detected 4 dominant de novo mutations. Three of them had unreported pathogenic muta- tions. The same sites of the LMNA gene were wild type in their parents. Conclusions Four cases of L-CMD are geneti- cally identified. Genetic counseling of the family can be possible. The patients should be considered LMNA gene muta- tion of they present themselves with muscle weakness with the proximal upper limbs, distal lower limbs and neck exten- sor,hypotonia, contractures, mild to moderate elevation of CK level,and if the biopsies show muscular dystrophic chan- ges but also with inflammatory changes should be considered LMNA gene mutation. Genetic analysis is the most reliable method for diagnosing L-CMD.