儿童中央核肌病临床基因型分析及随访研究

Analysis of clinical phenotype and genotype of children with centronuclear myopathy and follow-up study

目的探讨儿童中央核肌病的临床表型、转归及基因型,以提高对该病的认识。方法回顾性分析2008年10月至2018年12月北京大学第一医院儿科经临床和病理检查确诊的中央核肌病9例患儿的临床、病理和基因检测资料,随访8个月~8.6年[(4.4±3.1)年]。结果1.临床表型:9例患儿中,男6例,女3例;起病年龄为出生1 d^10岁。8例以肢体无力或运动发育落后为主诉,1例因体检发现血清肌酸肌酶升高就诊。体格检查示患儿均存在骨骼肌无力,其中4例伴颜面肌受累。6例患儿接受随诊,其中4例运动功能无显著下降,2例改善;随诊患儿均无显著心脏受累;4例出现脊柱侧弯。5例接受肺功能检测,其中2例出现限制性通气障碍。2.基因型:接受检查的8例中4例诊断明确,其中2例DNM2基因新生变异c.1893+1G>A、c.1856C>T(已报道致病变异),1例RYR1基因复合杂合变异c.2044C>G和c.6823G>A,1例TTN基因复合杂合变异c.2106_2107insAAGCTGTA、c.107377+1G>A(已报道致病变异)。结论中央核肌病病程相对静止,易累及颜面肌,较少累及心肌。新发现中央核肌病相关基因变异位点4个。

Objective To investigate the phenotype,genotype and clinical course of centronuclear myopathy(CNM)in children.Methods Clinical data of patients with CNM in the Department of Pediatrics,Peking University First Hospital from October 2008 to December 2018 were collected.The clinical,pathological and genetic data of 9 children with CNM were retrospectively analyzed.The patients were followed up from 8 months to 8.6 years[(4.4±3.1)years].Results(1)Clinical phenotype:there were 6 males and 3 females with onset age ranging from 1 d to 10 years.Generalized muscle weakness or motor retardation was the main complaint in 8 cases,while elevated muscle enzymes presented in 1 case.Varying degrees of skeletal muscle weakness were noted on examination in all patients,with facial muscle involvement in 4 cases.Six patients were followed up.No deterioration in motor function was noted,while 2 patients had improvement.There was no significant cardiac involvement in all 6 patients.Scoliosis occurred in 4 patients.Restrictive ventilator disorder developed in 2 out of the 5 patients who underwent pulmonary function tests.(2)Genotype:8 out of 9 patients underwent gene test,confirmed gene diagnosis in 4 patients including:DNM2 gene(c.1856C>T,c.1893+1G>A was novel)de novo heterozygous mutation in 2 cases,RYR1 gene(c.2044C>G,c.6823G>A,both were novel)compound heterozygous mutation in 1 case,and TTN gene(c.107377+1G>A,c.2106_2107 insAAGCTGTA was novel)compound heterozygous mutation in 1 case.Conclusions The course of centronuclear myopathy is relatively static,with more frequent involvement of facial muscles than myocardium.This study enriched the gene mutation spectrum of centronuclear myopathy(4 novel mutations).