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神经元蜡样脂褐质沉积病芬兰变异型二家系的临床特点及遗传学研究
目的 总结神经元蜡样脂褐质沉积病芬兰变异型患儿的临床特点及基因检测结果.方法 回顾性分析归纳2014年10月至2016年12月广州妇女儿童医疗中心遗传与内分泌科收治的基因诊断明确的2个家系3例临床表现为神经退行性病变患儿的临床及辅助检查特点,并采用全外显子组测序、Sanger测序对患儿及其父母进行分子遗传学分析.结果 患儿分别为11岁3月龄男性、9岁1月龄女性和10岁1月龄男性,均出生时正常,5～6岁开始出现认知和运动能力倒退,伴视力下降.初次诊治时体检:神志清,但不会认人,不能言语,不能理解指令,不能站立,不能直立身体独坐,全身僵硬;头颅磁共振成像提示:全脑萎缩,脑白质损害;血生化、乳酸、酸碱平衡无异常.外周血淋巴细胞电镜检查:细胞核肿胀,自噬现象,细胞内见团块状沉积物并有异常空泡.CLN5基因检查发现2例同胞兄妹为c.334C＞T(p.Arg112Cys)与c.595C＞T(p.Arg199Ter)复合杂合变异,另1例为c.335G＞A(p.Arg112His)纯合变异,分别遗传自患儿父母.结论 神经元蜡样脂褐质沉积病芬兰变异型表现为出生时正常,学龄前期认知、运动功能倒退,头颅磁共振成像表现为全脑萎缩、脑白质病变,血生化和淋巴细胞病理检查无特异性改变,致病基因为CLN5基因,多呈常染色体隐性遗传.
关键词： 神经元蜡样质脂褐质沉积病 突变 高通量核苷酸测序 -
神经元蜡样质脂褐质沉积病的神经干细胞移植治疗(附3例报道)
目的 研究应用神经干细胞移植治疗神经元蜡样质脂褐质沉积病的效果.方法 2005年6月～2006年12月我们对3例神经元蜡样质脂褐质沉积病患者采用立体定向技术,选取基底节区作为靶点进行神经干细胞移植术.结果 全部接受神经干细胞移植的神经元蜡样质脂褐质沉积病患者均取得一定疗效,无手术并发症.3例患者神经功能均获得一定的提高,其中1例1年后正电子发射体层摄影术结果显示大脑皮质代谢明显提高.结论 神经干细胞移植可作为神经元蜡样质脂褐质沉积病的一种有效治疗方法,但其长期疗效仍需进一步观察.
关键词： 神经元蜡样质脂褐质沉积病 神经干细胞 干细胞移植 -
CLN3编码蛋白Battenin的N-端是与蛋白结合的功能域
Objective: Batten disease (BD), the juvenile form of neuronal ceroid lipofuscinosis (NCLs), is pathological characterized by finding lysosomal storage of autofluorescent lipofuscins with unique ultrastructural profiles. The gene underlying BD is designated CLN3 and encodes a protein, Battenin, of unknown function that localizes in lysosomes and/or mitochondria. Previously, we hypothesized that Battenin associates with other membrane protein(s) to form a membrane complex. Dysfunction of this complex could result in the pathological changes of BD, and possibly in other NCLs. Two such membranous proteins, the slow and fast Battenin-interactive proteins (BIPs and BIPf) of unknown functions, have been identified. In this study, we have characterized the functional domains of Battenin that interact with both BIP proteins. Methods: Protein-protein interactions with a yeast two-hybrid system were employed. A "deletion assay" was employed to localize the interactive segment(s). Different lengths of cDNA sequences lacking exon 1-5 were used to express CLN3-encoded proteins lacking N-terminal segments in the yeast two-hybrid system. N-terminal exons of CLN3 were deleted with PCR-cloning strategies.Results: We eliminated the possibility of interacting domains from the exon 7-encoded region because both Battenin and mBattenin interact with the BIP proteins. We have shown that peptide sequences encoded by exons 2 and 4 of CLN3 gene include the functional domains by which Battenin interacts with the BIP proteins. Conclusion: Our studies provide evidence that the N-terminus of Battenin is the functional domain for these protein interactions.
关键词： 神经元蜡样质脂褐质沉积病 基因 CLN3 蛋白质相互作用 -
神经元蜡样质脂褐质沉积病(NCL)的基因型与表型相关性研究
Objective:Genotype-phenotype associations were studied in 517 subjects clinically affected by classical neuronal ceroid lipofuscinosis (NCL). Methods:Genetic loci CLN1-3 were analyzed in regard to age of onset, initial neurological symptoms, and electron microscope (EM) profiles. Results: The most common initial symptom leading to a clinical evaluation was developmental delay (30%) in NCL1, seizures (42.4%) in NCL2, and vision problems (53.5%) in NCL3. Eighty-two percent of NCL1 cases had granular osmiophilic deposits (GRODs) or mixed-GROD-containing EM profiles; 94% of NCL2 cases had curvilinear (CV) or mixed-CV-containing profiles; and 91% of NCL3 had fingerprint (FP) or mixed-FP-containing profiles. The mixed-type EM profile was found in approximately one-third of the NCL cases. DNA mutations within a specific CLN gene were further correlated with NCL phenotypes. Seizures were noticed to associate with common mutations 523G>A and 636C>T of CLN2 in NCL2 but not with common mutations 223G>A and 451C>T of CLN1 in NCL1. Vision loss was the initial symptom in all types of mutations in NCL3. Surprisingly, our data showed that the age of onset was atypical in 51.3% of NCL1 (infantile form) cases, 19.7% of NCL2 (late-infantile form) cases, and 42.8% of NCL3 (juvenile form) cases.Conclusion:Our data provide an overall picture regarding the clinical recognition of classical childhood NCLs. This may assist in the prediction and genetic identification of NCL1-3 via their characteristic clinical features.
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等位基因特异性引物延伸法在婴儿型和幼儿型神经元蜡样质脂褐质沉积病产前诊断中的应用
SUMMARY Infantile (INCL, NCL1) and late-infantile (LINCL, NCL2) neuronal ceroid lipofuscinoses have been found to result from genetic deficiency of genes CLN1 and CLN2, respectively. The application of molecular analyses can facilitate prenatal diagnosis for families affected by NCL1 or NCL2, in which the familial mutation(s) have been identified. Molecular testing with allele-specific primer extension and DNA sequencing was performed in nine pregnancies, four from two NCL1 families and five from five NCL2 families. Lysosomal enzyme activity assays were carried out as well.Four fetuses from three pregnancies in NCL1 families were found to be carriers for a mutation 451C-T in the CLN1 gene and one was normal. Prenatal testing of three NCL2 families who carried mutation R208X in the CLN2 gene showed that all fetuses were carriers. In NCL2 families who carried either mutation IVS5-1C or/and IVS5-1A two normal pregnancies were detected. Our studies indicate that DNA testing, which may provide definitive prenatal diagnosis for NCL, may be used in combination with lysosomal enzyme activity analyses.
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以癫(癎)发作为首发症状的晚期婴儿型神经元蜡样质脂褐质沉积病一例
患儿 女性,5岁3个月,因间断性无热抽搐发作2年,肢体抖动、行走不稳1.50年,于2016年4月24日入院.患儿2年前玩耍时左侧额部轻微碰撞墙角后哭闹,继而出现双眼左侧斜视、呼之不应、四肢发软、口唇发绀,2～3 min后出现恶心、干呕,持续约10 min后自行缓解,缓解后哭闹入睡,急诊至当地医院,头部CT未见明显异常,未予特殊处理.
关键词： 癫(癎) 神经元蜡样质脂褐质沉积病 儿童 病例报告 -
神经元蜡样质脂褐质沉积病研究进展
神经元蜡样质脂褐质沉积病(neuronal ceroidlipofuscinosis,NCL)是一组进行性加重的神经系统变性病,多呈常染色体隐性遗传.儿童期发病多见,少数成年人发病.特征性病理改变:神经细胞和(或)皮肤上皮细胞、肌细胞、淋巴细胞内脂褐索沉积.细胞内脂褐素沉积导致靶器官--大脑皮层、视网膜神经细胞变性,出现典型临床症状:进行性加重的智力、运动功能障碍,肌阵挛癫痫和视力减退.
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神经元蜡样质脂褐质沉积病
1 概述及分类神经元蜡样质脂褐质沉积病(the neuronal ceroid lipofuscinoses,NCLs)是一组儿童常见的进行性神经系统变性疾病,多为常染色体隐性遗传.1826年Stengel对此病进行了描述,并提出了蜡样脂褐质沉积病的概念.1963年Zeman等在家族性黑蒙性痴呆病人中首次发现脑内沉积物具有自体免疫荧光,6年后把此病命名为神经元蜡样质脂褐质沉积病[1].全球发病率约为1～8/10000.
关键词： 神经元蜡样质脂褐质沉积病 发病机制 临床特征 -
Kufs病(附两例报告并文献复习)
[目的]探讨Kufs病的临床表现及病理特点.[方法]对两例患者进行脑组织活检,并结合临床及病理资料加以分析.[结果]两例临床表现为痴呆、癫痫、共济失调或行为改变,均无视力受累;超微结构改变有神经元变性及神经细胞内脂褐素体沉积.[结论]根据起病年龄、临床表现及脑活检电镜检查结果分析是确诊Kufs病的可靠办法.
关键词： 神经元蜡样质脂褐质沉积病 -
神经元蜡样质脂褐质沉积病伴癫(癎)持续状态1例报告
1 病例报告患儿女性,7岁,因“发作性抽搐伴智力、语言、运动及发育迟缓4年,持续性抽搐5h”于2013年12月5日入院.患儿4岁前智力、语言、运动及视力发育均正常.3年前无明显诱因突然出现全身性抽搐伴意识丧失,持续2～3 min缓解.后每隔20 d至1个月发作1次,持续数分钟至20 min不等.2年前出现肌阵挛发作,以后两种发作形式交替出现,频繁时1d发作10余次,少时1周出现1次.
关键词： 神经元蜡样质脂褐质沉积病 癫(癎)持续状态
