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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 To analyze the clinical phenotypes and genetic characteristics of 26 infants with infant neuromuscular blockade (INAD) in China and lay the foundation for the molecular diagnosis and genetic counseling. Methods The clinical features of INAD children were analyzed. Clinical follow-up was performed 10 months to 8 years after the first visit to understand the progress of motor cognitive function. Motor function assessment using cerebral palsy (cerebral palsy) coarse motor function classification system (GMFCS) Chinese version. Detection of PLA2G6 gene mutation and copy number anomalies were performed by direct sequencing and high-density oligo comparison genomic hybridization chip technique (aCGH) respectively. Results From September 2003 to August 2011, a total of 26 cases of INAD were collected. 1. Phenotypic characteristics: Pre-onset mental motor development more than normal, the average age of onset of 1 year and 3 months, are manifested as rapid intellectual movement backwards. The average duration of first visit was 1.41 years. Most of the patients had severe motor dysfunction, of which 11 were GMFCS grade V, 12 were grade IV, 1 was grade III and 2 were grade II. Most children with positive pathology. Electromyography suggests neurogenic damage, and cranial MRI shows cerebellar atrophy. The clinical follow-up of 23 children was followed up. The average duration of follow-up was 3.88 years. Two patients died and the rest 21 patients had severe reversal of motor function. Among them, 18 patients had GMFCS grade V. Genotype characteristics: 23 cases detected by sequencing PLA2G6 gene mutations, of which only 7 found in 1 allele mutation. A total of 24 mutations were found, of which 12 were new mutations. For patients with only one allele mutation and one mutation negative, no abnormalities in copy number were found by aCGH assay. Conclusions This study summarizes the largest number of INAD cases in our country. Twelve non-reported new mutations were found in this study, which amplified the mutation spectrum of PLA2G6 gene and laid the foundation for further understanding of the disease and genetic counseling for prenatal diagnosis in domestic pediatricians.