尼曼匹克病C型18例血7-酮胆固醇水平、临床表现及基因突变分析

Blood 7-ketocholesterol level, clinical features and gene mutation analysis of 18 children with Niemann-Pick disease type C

目的 分析尼曼匹克病C型（NPC）血7-酮胆固醇水平、临床表现以及基因突变谱,探讨NPC患儿血7-酮胆固醇水平与临床表型的相关性及中国人NPC1突变谱特点.方法 2013年2月至2014年10月在新华医院儿科就诊的18例NPC患儿,男13例,女5例,就诊年龄5月龄至21岁,对患儿血中7-酮胆固醇水平、临床表现及基因型进行回顾性分析.结果 18例患儿中14例有神经系统症状,出现时间1 ～16岁,其中早期婴儿型7例,晚期婴儿型1例,青少年型5例,成人型1例.血中7-酮胆固醇浓度：早期婴儿型（348.5±168.7） μg/L,晚期婴儿型150.6μg/L,青少年型（145.0±46.3）μg/L,成人型32.0μg/L,均高于正常参考值;另有4例就诊时无明显神经系统损伤的患儿,7-酮胆固醇浓度（345.6±134.2） μg/L.18例中有16例脾肿大或肝脾肿大.18例共检出34种NPC1基因突变,包括27种已知突变,1个新发现的微小缺失/插入3609_3610delAC;5个新发现外显子点突变：c.3683T＞C（p.M1228T）、c.3679A＞T（p.R1227W）、c.1070C＞T（p.S357L）、c.1456A＞C（p.N486H）和c.1142G＞A（p.W381X）;1个新发现内含子突变：c.881 ＋3A＞G.结论 NPC患儿血中7-酮胆固醇水平升高,与神经系统症状出现时间呈负相关趋势,多伴有脾肿大或肝脾肿大,18例检出34种NPC1基因突变,其中7种新突变,丰富了NPC1基因突变谱.

Objecti3ve To investigate 7-ketocholesterol （7-KC） level in the blood,clinical features and gene mutation of Niemann-Pick disease type C （NPC）.Method Eighteen patients diagnosed as NPC in Shanghai Xinhua Hospital seen from February 2013 to October 2014 were enrolled in this study.They included 13 males and 5 females and aged from 5 months to 21 years.The plasma 7-KC concentrations,clinical features and gene mutations of NPC patients were reviewed retrospectively.Result Fourteen NPC patients had neurological symptoms with the age of neurological onset from 1 year to 16 years.In seven cases the disease was early-infantile subtype,in 1 late-infantile subtype,in five juvenile subtype and in one adult subtype.The 7-KC value in the plasma of NPC patients was higher than the normal range,（348.5±168.7）μg/L in the early-infantile subtype,150.6 μg/L in the late-infantile subtype,（145.0 ±46.3） μg/L in the juvenile subtype,and 32.0 μg/L in the adult subtype,respectively,additionally,four NPC patients had no observable neuropsychiatric disability when confirmed to be NPC by genetic testing,with the plasma 7-KC value （345.6± 134.2） μg/L;16 of 18 patients had splenomegaly or hepatosplenomegaly.Among 18 patients,34 different mutations in the NPC1 gene were identified including 27 reported mutations,1 novel small deletion 3609_3610delAC,five novel exonic point mutations,c.3683T 〉 C（M1228T）,c.3679A 〉 T （R1227W）,c.1070C〉T（S357L）,c.1456A〉C（N486H） and c.1142G〉A（W381X） and 1 novel intronic mutation c.881 ＋ 3A 〉 G.Conclusion The 7-KC levels in the blood of patient was remarkably increased,and there was a tendency that 7-KC levels inversely correlated with the age of neurological onset.Most NPC patient had splenomegaly or hepatosplenomegaly.Among 18 patients,34 different mutations in the NPC1 gene were identified including seven novel mutations,which enriched the gene mutation spectrum.