尼曼匹克病C型的临床表现及基因突变特点分析

Clinical features and gene mutation analysis of patients with Niemann-Pick disease type C

目的分析尼曼匹克病c型（NPC）患者的临床表现和基因突变特点，观察疾病的治疗效果和预后。方法收集2013年7月至2017年2月在首都医科大学附属北京天坛医院就诊的10例NPC患者，对其临床表现、常规化验检查和基因突变特点进行分析，并随访其治疗效果和预后。结果10例NPC患者，男5例，女5例，就诊年龄42d～14岁；包括2例新生儿型、4例早期婴儿型、2例晚期婴儿型和2例青少年型。所有患者均有明显的脾大，5例伴有肝大。头部磁共振示8例脑萎缩、2例胼胝体变细及2例脑白质区异常信号。10例患者共检出18种NPCI基因突变，其中11种为已知突变，另7种为新突变，包括3种错义突变：c．3683T〉C（P．Met1128Thr）、c．1926G〉C（P．Met642Iie）和c．3006C〉G（P．Phe1002Leu）；2种无义突变：c．1142G〉A（p．Trp381Ter）和c．3229C〉T（p．Arg1077Ter）；1种微小缺失突变：c．1385-1386del；1种剪切位点突变：c．1757＋5G〉A。平均随访25（3-66）个月，丙咪嗪使5例患者的痴笑猝倒发作减轻，丙戊酸钠和卡马西平分别使2例和1例患者的癫痫发作程度减轻，随访结束时4例死亡，其余患者的病情均呈进行性加重。结论NPC1基因突变谱具有高度异质性，中国人NPC1基因的突变热点可能与欧州国家不同。NPC患者的神经系统表现与其发病年龄有关。丙咪嗪对控制痴笑猝倒发作有效，卡马西平或丙戊酸钠可能在病程早期对控制癫痫发作有效。

Objective To analyze the clinical manifestations, therapeutic efficacy, prognosis and characteristics of NPCl mutation in Chinese patients with Niemann-Pick disease type C （NPC）. Methods Ten unrelated Chinese NPC patients were diagnosed by NPCl mutation analysis from July 2013 to February 2017 in Beijing Tian Tan Hospital of Capital Medical University. Clinical data of 10 cases were analyzed retrospectively which included clinical manifestations, laboratory results and NPCl gene mutation features, and a series of follow-up were carried out about therapeutic efficacy and prognosis. Results Ten patients suffering from NPC included 5 males and 5 females, aged from 42 days to 14 years when they presented to Tian Tan Hospital. According to their age of neurological onset, 4 were in early infantile period, 2 in late infantile period, 2 in juvenile periods, and the other 2 cases in neonatal period. They all presented with splenomegaly, 5 of 10 accompanied with hepatomegaly. Two cases of neonatal subtype presented mainly with delayed neonatal cholestatic jaundice and hepatosplenomegaly, accompanied with decreased muscle tone and slight psychomotor retardation. The other 8 cases presented with severe neurological involvement, such as progressive encephalopathy, ataxia and language impairment, 4 with dystonia, 3 with decreased muscle tension, 5 with vertical supranuclear gaze palsy, 5 with gelastic cataplexy, and 4 with epilepsy. Eight of 9 cases presented with foam cells in their bone marrow. Head MRI showed diffuse cerebral atrophy in 8 cases, thin corpus callosum in 2 cases, and brain white matter abnormal signals in 2 cases. Among 10 cases, 18 different mutations of NPC1 allelic genes were identified including ll reported mutations, 3 novel missense mutations： c. 3683T 〉 C （p. Metl128Thr）,c. 1926G 〉 C （p. Met642Iie） and c. 3006C 〉 G （p. Phel002Leu）, 2 novel nonsense mutation： c. 1142G 〉 A （p. Trp381Ter ） and c. 3229C 〉 T （p. Arg1077Ter）, 1 novel minimal deletion mutation： e. 1385-1386del, and 1 novel intron mutation： e. 1757 ＋ 5G 〉 A. In 5 cases, the symptom of gelastic cataplexy was alleviated by imipramine, and the convulsion was relieved by valproate in 2 cases, by carbamazepine in 1 case at the beginning of seizure. During the 25 （3 - 66） months of follow-up, 4 cases died, the others＇ neurological symptoms were deteriorated progressively. Conclusions The NPCl gene mutation were high heterozygous in this group, and 7 novel mutations enriched the gene mutation spectrum of NPCl. The neurological manifestations were complicated in patients with NPC, and the symptomatology would be different according to their onset age of neurological symptoms. There might be effective symptomatic treatment for gelastic cataplexy by imipramine and for convulsion by valproate or carbamazepine.