中国婴儿神经轴索营养不良患儿临床随访及分子遗传学研究

Follow-Up Study and Genetic Analysis of Chinese Patients with Infantile Neuroaxonal Dystrophy

目的通过分析26例中国婴儿神经轴索营养不良(INAD)患儿的临床表型及遗传学特点,为开展该病的分子诊断及遗传咨询打下基础。方法对临床诊断的INAD患儿进行临床特点分析,并于首次就诊后10个月～8 a进行临床随访,以了解其运动认知功能进展。运动功能评估采用脑性瘫痪(脑瘫)粗大运动功能分级系统(GMFCS)中文版。PLA2G6基因突变及拷贝数异常的检测分别通过直接测序和高密度寡核苷酸比较基因组杂交芯片技术(aCGH)进行。结果 2003年9月-2011年8月共收集INAD 26例。1.表型特点:起病前智力运动发育多正常,起病年龄平均1岁3个月,均表现为快速智力运动倒退。首次就诊时平均病程1.41 a,多数已存在严重运动功能障碍,其中GMFCSⅤ级11例,Ⅳ级12例,Ⅲ级1例,Ⅱ级2例。多数患儿病理征阳性。肌电图提示神经源性损害,头颅MRI显示小脑萎缩。对23例患儿进行临床随访,随访时平均病程3.88 a,2例死亡,其余21例运动功能严重倒退,其中18例GMFCSⅤ级。2.基因型特点:23例通过测序检测到PLA2G6基因突变,其中7例仅发现1个等位基因的突变。共发现突变24种,其中12种为新突变。对于仅检测到1个等位基因突变及突变阴性的患者,通过aCGH检测未发现存在该基因拷贝数异常。结论该研究为国内最大数量的INAD病例总结,发现了12种未报道的新突变,扩大了PLA2G6基因的突变谱,为提高国内儿科医师对该病的认识及遗传咨询产前诊断奠定基础。

Objective Phenotype and genotype of 26 Chinese patients were analyzed in this study, which is helpful for the molecular diagnosis and genetic counseling in China. Methods Clinical diagnosis of infantile neuroaxonal dystrophy （INAD） was based on the criteria proposed. Patients were followed up from lO months to 8 years since their first visit to evaluate the progression of motor and cognitive func- tions. Motor function was classified on Chinese version of Gross Motor Function Classification System （GMFCS）. Mutations and copy number variations in PLA2G6 were detected by DNA sequencing and high - density oligonucleotide - microarray - based comparative genomic Hybridization（ aCGH）, respectively. Results Twenty - six patients were clinically diagnosed from Sep. 2003 to Aug. 2011.1. Clinical fea- tures were that almost all individuals were free of symptoms at birth and achieved normal developmental milestones before disease onset. The average age at onset was I year and 3 months. All patients presented with rapid motor and cognitive regression. Severe motor function impair- ments were shown in most patients at their first visit, with the average disease course 1.41 years. GMFCS V was found in 11 cases, GMFCS Ⅳ in 12 cases,GMFCS Ⅲ in 1 case,and GMFCS Ⅱ in 2 cases. Babinski signs in physical examination, cerebellar atrophy shown in brain MRI and denervation in the electromyography were found in most of the patients. Twenty - three patients were followed up, with the average disease course 3.88 years,2 boys died from infection. The remaining 21 patients suffered from severe motor impairments, with GMFCS V in 18 cases. 2. Genotype： PLA2G6 mutations were detected in 23 individuals by DNA sequencing,24 mutations were identified, with 12 novel muta- tions. In 7 patients, mutation was found only in 1 allele. Copy number variation of PLA2G6 was not detected in any patients either with muta- tion in only 1 allele or without mutations. Conclusions This is an important largest report on INAD in China. The 12 novel mutations expan- ded the PIA2G6 mutation spectrum. The research will enhance understanding of pediatrician to this rare disease and be helpful for the genetic counseling and prenatal diagnosis in China.