成年型神经元蜡样质脂褐质沉积症的临床和病理特征

目的 报道2例成年型神经元蜡样质脂褐质沉积症(ANCL)临床特点和病理改变。方法 综合分析临床资料和病理结果。结果 患者临床表现为智能障碍、肌阵挛、运动障碍、行为异常及锥体外系症状。电镜下可见神经元及胶质细胞胞浆内有大量脂褐素体沉积。结论 根据起病年龄、临床表现及超微结构特征可诊断为成年型神经元蜡样质脂褐质沉积症，脑活检电镜检查是确诊本病的可靠方法。     

青少年型神经元蜡样质脂褐素沉积病6例的临床特点和基因分析

目的报告6例经病理诊断为青少年型神经元蜡样质脂褐素沉积病(juvenlie neuronal ceroid lipofus-cinosis,JNCL)患者的临床特点以及部分患者的基因研究结果。方法总结分析6例JNCL患者的临床特点,并对其中3例患者进行CLN3基因检查。结果 6例患者,发病年龄为2~7岁,首发症状4例主要为癫痫,2例为视力下降。主要临床表现包括癫痫、视力下降、智能减退。基因检查3例患者均没有发现国外常见的CLN3基因的大片断缺失,在1例患者发现位于第一外显子的c3G→T杂合突变。结论国人JNCL具有自己的特点,在CLN3基因的突变类型方面和其他地区的病例可能不完全相同,也可能存在新的基因。     

一例晚期婴儿型神经元蜡样质脂褐素沉积病的临床、遗传和脑超微结构特点

目的 通过分析1例晚期婴儿型神经元蜡样质脂褐素沉积病(LINCL)病例.探讨LINCL的临床、遗传和病理特点. 方法 收集1例L1NCL患者的临床表现、家族史资料,并对其脑电图(EEG)、影像学和脑组织病理活检结果进行分析. 结果 EEG显示弥漫背景脑电慢化,间歇期阵发全面性棘慢波及尖慢波节律.头颅MRI检查发现患儿及其胞兄脑萎缩尤以小脑萎缩明显.脑组织活检光镜下见大脑皮层弥漫性损害,可见变性、萎缩和未成熟神经元.变性及萎缩的神经元内可见嗜银颗粒沉积,电镜下神经元胞浆中可见大量脂褐素样结构. 结论 此例患者的临床和病理改变符合LINCL的诊断,但其特殊的家族遗传史及病理特征提示其可能为新的LINCL变异型.     

慢性前脑缺血致血管性痴呆大鼠神经元超微结构的经时变化

目的 观察慢性前脑缺血致血管性痴呆大鼠额叶皮层、海马神经元不同时间点的超微结构改变.方法 采用双侧颈总动脉永久结扎方法(2VO)制备慢性前脑缺血动物模型,于术后不同时间点(1月、2月、3月、4月)电镜观察额叶皮层、海马区结构改变.结果 额叶皮层:1月时见额叶皮层大量脂褐素,2月有所下降,后与假手术对照组相仿,暗神经元则在2月时最多,后下降;海马区神经元胞质溶酶体逐渐增多,术后3月时暗神经元大量增多,并且出现大量脂褐素,术后4月神经元出现固缩.结论 电镜下脂褐素和暗神经元的改变提示慢性脑缺血初期脑损伤是可逆的,电镜下1个月或更早可能是可逆损伤的转折点.     

CLN5基因复合杂合突变致青少年型神经元腊样脂褐质沉积症的临床特征及基因分析

目的报道及分析CLN5基因复合杂合突变致青少年型神经元腊样脂褐质沉积症(JNCL)患者的临床特征和基因突变类型。方法观察分析1例JNCL病人的临床表现、影像学、脑电图改变,进行全外显子组基因测序,并对其家庭成员进行相关基因检测和临床检查。结果患者于6岁开始视力减退及智力倒退,9岁出现肌阵挛发作、行走不稳。头颅MRI显示小脑明显萎缩,大脑皮质和脑干轻度萎缩。视频脑电图显示弥漫性2.5~3.5 Hz慢活动及颞区尖波。全外显子测序发现患者CLN5等位基因上1个来源于父亲的错义突变:exon2 c.376TC,以及1个来源于母亲的无义突变:exon3 c.595 CT。患儿父亲及弟弟均有c.376 TC突变,两人体查均发现水平性及旋转性眼震,该位点突变目前尚未见报道。结论 CLN5基因c.376TC和c.595CT的复合杂合突变可以引起JNCL临床症状、影像学和脑电图改变。对于NCL可疑病例应该对患者及家族成员及早进行相关基因测序明确其基因型,并实施生育指导。     

婴儿型神经元蜡样质脂褐质沉积病：（附1例报告）

报告1例经脑活检、组化及电镜证实的婴儿型神经元蜡样质脂褐质沉积病。电镜检查见脑皮层神经细胞及胶质细胞胞浆内,除有大量脂褐质体沉积外,还发现有典型指纹体。首次提出指纹体也可存在于婴儿型的观点。     

颞叶内侧硬化的组织学分型及临床病理相关性

目的 探讨颞叶内侧硬化组织学特点和分型以及临床病理的相关性.方法 对51例颞叶内侧癫痫患者的手术切除标本,行神经元核抗原(NeuN)免疫组织化学染色后显微镜下计数海马4个亚区神经元数量,进行统计学分析(k-均值聚类分析).同时收集患者的临床资料,包括初次发作癫痫的年龄、有无突发脑损伤、潜伏期、癫痫病程、术后半年及1年癫痫疗效Engel评分,分析不同病理类型的临床特点.另选取8例无神经系统病变的尸检患者的海马标本作为对照组.结果 (1)海马神经元丢失表现为5种不同的组织学类型:1a型(21/51,41.18％):CA1区神经元重度丢失同时伴有CA3、CA4区神经元轻度丢失,CA2区神经元无明确丢失;1b型(18/51,35.29％):所有亚区神经元均严重丢失;2型(9/51,17.65％):仅有CAt区神经元重度丢失;3型(1/51,1.96％):仅CA4区神经元重度丢失;无海马硬化型(2/51,3.92％):与对照组相比海马各亚区神经元无明显丢失.(2)1型(1a、1b)海马硬化患者首次发作癫痫的年龄更小,潜伏期及病程更长,有突发脑损伤病史的比例更高,其中有热性惊厥病史的1 a型:10/19,1b型:7/16,2型:4/7,3型:0(x2=11.790,P =0.019).(3)海马硬化严重程度与手术预后呈正相关.结论 1型海马硬化为颞叶内侧硬化中最常见的类型,与早期突发脑损伤尤其是热性惊厥密切相关,术后癫痫的控制率高于其他三型.     

CLN6型神经元蜡样质脂褐素沉积病1例报告并文献复习

正神经元蜡样质脂褐素沉积病(neuronal ceroid lipofuscinoses,NCL)是一种儿童常见的进行性遗传性中枢神经系统变性病,以自发荧光物质聚集在神经元细胞和其它类型细胞内为特点~([1]),多呈常染色体隐性遗传(除CLN4型),临床特点为癫痫发作、智能减退、进行性运动功能下降、视力下降及早亡。目前认为NCL至少由10种基因发生突变引起~([2]),分别为CLN1(PPT1)、CLN2(PPT2)、CLN3、CLN4、CLN5、CLN6、     

神经元腊样质脂褐素沉积病的临床和影像学特点

目的探讨神经元腊样质脂褐素沉积病（NCL）的临床表现规律和影像学特点。方法回顾分析我院经病理检查确诊的11例NCL患者的临床和影像学资料，对比分析国内报道的15例同类型NCL的临床和影像学资料。结果26例患者中青少年型NCL12例，占46％，3～15岁发病，首发症状多为智力减退或癫痫发作。晚期婴儿型NCL8例，占31％，1～7岁发病，首发症状表现为癫痫发作。婴儿型NCL4例，占15％，出生后4～9个月发病，首发症状表现为智能和运动发育停滞。成年型NCL2例，占8％，26及32岁发病，以痴呆和精神异常为首发症状。磁共振成像（MRI）特点主要表现为弥漫性脑萎缩，部分患者伴随白质损害，婴儿型和晚期婴儿型NCL出现丘脑改变。结论NCL患者的发病类型以青少年型为主，不同类型的NCL临床症状及出现顺序各异，影像学改变类似，婴儿型及晚发婴儿型伴丘脑损害。     

神经元蜡样质脂褐素沉积病的遗传学和临床表现规律以及诊断策略

神经元蜡样质脂褐素沉积病(neuronal ceroid lipofuscinosis,NCL)为一组儿童最常见的遗传性进行性中枢神经系统变性疾病.目前已经发现10种不同的亚型[1],其基因突变导致细胞内可溶性或膜性蛋白质的结构和功能异常.     

Retinal pathology and function in a Cln3 knockout mouse model of juvenile Neuronal Ceroid Lipofuscinosis (batten disease)

Batten disease or JNCL, is the juvenile form of Neuronal Ceroid Lipofuscinosis (NCL) an autosomal recessive neurodegenerative disorder. Since retinal degeneration is an early consequence of Batten disease, we examined the eyes of Cln3 knockout mice (1-20 months of age), along with heterozygotes and appropriate controls, to determine whether or not the Cln3 defect would lead to characteristic retinal degeneration and visual loss. Accumulation of autofluorescent material and intracellular inclusions were markedly increased in Cln3 knockout retinal ganglion cells, as well as most other nuclear layers. Nerve fiber density was also significantly decreased in Cln3 knockout retinae. Apoptosis was observed in the photoreceptor layer of Cln3 knockout. However, the degree of retinal degeneration up to age 20 months was not extensive. Fundus examinations of Cln3 knockout mice showed no significant abnormalities, while electroretinograms remained robust through 11 months of age. In summary, it appears that accumulation of autofluorescent material, carbohydrate storage material, as well as apoptotic cell death are retinal manifestations of the Cln3 defect that do not appear to extinguish retinal function in this mouse model of Batten disease.     

Lamotrigine Therapy in Juvenile Neuronal Ceroid Lipofuscinosis

PURPOSE: To evaluate the effects of lamotrigine (LTG) therapy on epileptic seizures and general well-being in patients with juvenile neuronal ceroid lipofuscinosis (JNCL). METHODS: LTG was initiated in 28 patients with JNCL. The mean age of the patients at the initiation of LTG was 13.7 years (range, 6.7-28.2 years). LTG was started at a dosage of 0.1-0.5 mg/kg/day and increased every 2 weeks until a maintenance dose of 1.25-15 mg/kg/day was reached. On the basis of the indication for LTG therapy, the patients could be divided into four groups. In the first group, LTG was initiated on an add-on basis; in the second group, LTG was started as the first antiepileptic drug (AED) because of seizures, and in the third group, despite no preceding seizures, because of epileptiform activity in the whole-night polysomnography; in the fourth group, LTG replaced valproate (VPA), which was discontinued because of adverse side effects. The efficacy was assessed after 1 year on LTG. The mean follow-up time was 2.8 years (range, 1.3-5.8). RESULTS: LTG had a favorable effect in 23 of 28 patients. A decrease in frequency of seizures of > or =50% was observed in 10 and a decrease in severity of seizures in nine of the 22 patients who had preceding seizures. Increases in well-being were found in 18 of 28. During the follow-up, LTG was continued as monotherapy in 13 of 19 patients. CONCLUSIONS: In light of our experiences, LTG seems to be a valuable drug in JNCL.     

An Autopsy Case of Adult Neuronal Ceroid Lipofuscinosis

Abstract: This is a report of an autopsy case (45-year-old woman) of adult neuronal ceroid lipofuscinosis with a long-lasting course of 25 years. In the course of her illness, gait disturbance, bulbar palsy and dementia were observed.
Pathologically severe neuronal loss and hemosiderin-like granules were found in the cortex, basal nuclei, thalamus and others. The residual cells of these tissues were swollen with lipofuscin-like pigments. The extremely swollen nerve cells were found in the anterior horn of the spinal cord.
Electron microscopically, numerous curvilinear bodies, myelin figures and fingerprint profiles were seen in those cytoplasms.
Ceroid and lipofuscin were proven by a histochemical examination.     

Immunosuppression alters disease severity in juvenile Batten disease mice

Autoantibodies to brain proteins are present in Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease) patients and in the Cln3-/- mouse model of this disease, suggesting an autoimmune component to pathogenesis. Using genetic or pharmaceutical approaches to attenuate this immune response in Cln3-/- mice, we demonstrate decreased neuroinflammation, decreased deposition of immunoglobulin G in the brain and protection of vulnerable neuron populations. Moreover, immune suppression results in a significant improvement in motor performance providing for the first plausible therapeutic approach for juvenile Batten disease.     

Neuronal Ceroid Lipofuscinosis and Associated Sleep Abnormalities

PurposeThe aims of this study were to evaluate sleep difficulties in children with neuronal ceroid lipofuscinosis and to determine the association between the sleep difficulties and the onset of seizures and loss of vision.MethodWe recruited individuals with a confirmed diagnosis of neuronal ceroid lipofuscinosis. We obtained information from the caregiver using the validated Children's Sleep Habits Questionnaire which is a sleep instrument for both behaviorally and medically based problems. Additional information was collected including onset of symptoms, treatment trials, and screen for restless leg syndrome symptoms.ResultsIn our cohort of 54 individuals, 96.3% had sleep scores consistent with a sleep disturbance. Sleep subscale analysis provided additional insight into the characteristics of the sleep disturbance. Fifty two of the 54 patients had at least one abnormal sleep subscale. The onset of sleep disturbance was associated with the onset of both seizures (ρ = 0.5834, P < 0.0001) and loss of vision (ρ = 0.3840, P = 0.0084). Restless leg syndrome symptoms were reported in 35.2%.ConclusionChildren with neuronal ceroid lipofuscinosis have a high burden of sleep disturbances. Using the results of a sleep disturbance screening tool can help to identify the most disturbing symptoms. Targeted treatment of sleep disturbance may improve the quality of life for the patient and family.     

Neuronal Ceroid Lipofuscinosis: Impact of Recent Genetic Advances and Expansion of the Clinicopathologic Spectrum

Neuronal ceroid lipofuscinosis (NCL), first clinically described in 1826 and pathologically defined in the 1960s, refers to a group of disorders mostly diagnosed in the childhood years that involve the accumulation of lysosomal storage material with characteristic ultrastructure and prominent neurodegenerative features including vision loss, seizures, motor and cognitive function deterioration, and often times, psychiatric disturbances. All NCL disorders evidence early morbidity and treatment options are limited to symptomatic and palliative care. While distinct genetic forms of NCL have long been recognized, recent genetic advances are considerably widening the NCL genotypic and phenotypic spectrum, highlighting significant overlap with other neurodegenerative diseases. This review will discuss these recent advances and the expanded potential for increased awareness and new research that will ultimately lead to effective treatments for NCL and related disorders.     

Effects of AETT-Induced Neuronal Ceroid Lipofuscinosis on Learning Ability in Rats

Abstract: The behavioral effects of ceroid-lipofuscin accumulation, induced by intraperitoneal administration of acetyl-ethyl-tetramethyl-tetralin (AETT) in Wistar rats for 3 months, were examined in the present studies. A significant increase in neuronal ceroid-lipofuscin was demonstrated neuropathologically as well as morphometrically. Although the AETT-intoxicated rats showed neither alteration of locomotor activity nor shock sensitivity, a significant impairment of learning ability, especially an acquisition trial in passive avoidance tests, was observed. Results of the present studies indicate the possibility that a diffuse lipofuscin accumulation causes a learning impairment in rats. The results also imply the possibility of a significant role of age-related lipofuscin accumulation in the dementing processes of human especially in the elderly.     

Chorea in Late-Infantile Neuronal Ceroid Lipofuscinosis: An Atypical Presentation

PurposeClassic late-infantile neuronal ceroid lipofuscinosis is characterized by progressive intellectual and motor deterioration, seizures, vision loss, and early death. Prominent chorea is an atypical feature and is rarely described in children.MethodsA four-year-old girl with seizures followed by a year-long progressive cognitive decline and a three month history of intermittent chorea leading to rapid motor deterioration. The onset of illness was marked by seizures occurring as generalized tonic–clonic seizures and myoclonic jerks. There was gradual regression of cognitive milestones with increasing forgetfulness and impaired quality and content of speech. Nine months later, she developed chorea. These movements were associated with clumsiness, incoordination, and progressive loss of motor milestones. She was unable to perform manual tasks or maintain antigravity posture resulting in unsteadiness and frequent falls. The movements were aggravated by action or excitement and were absent in sleep.ResultsMagnetic resonance imaging depicted diffuse cerebral and cerebellar atrophy. Sequencing analysis of TPP1 gene showed a novel, homozygous, splice site mutation c.89+1G>A which resulted in nil enzyme activity and a severe phenotype with onset of disease symptoms at an early age of three years.ConclusionsThe presence of chorea in late-infantile neuronal ceroid lipofuscinoses is atypical but does not exclude the diagnosis of late-infantile neuronal ceroid lipofuscinoses, especially in children with psychomotor regression, seizures and diffuse brain atrophy.     

Neuronal ceroid lipofuscinoses: pathological features of bioptic specimens from 28 patients

Clinical findings and pathological features of 28 patients affected with neuronal ceroid lipofuscinoses (NCL) are reviewed. The patient group included 15 children affected with the late-infantile form of NCL (LINCL), 10 patients affected with the juvenile form (JNCL), and 3 adult cases. Ultrastructural examinations of 50 biopsies from 6 tissues were consistent with clinical features in all LINCL and JNCL cases but one. The importance of electron microscopic (EM) examination of blood lymphocytes in these forms is outlined, particularly when combined with molecular analysis of the CLN2 or CLN3 genes, respectively. This approach leads to a definite diagnosis of LINCL and JNCL is a relatively short time. In adult NCL, diagnosis still relies on pathological grounds, and difficulties in interpreting the osmiophilic storage bodies in different tissues are outlined. EM investigation of blood lymphocytes was not helpful in any case of adult NCL. Results of one stereotactic brain biopsy are also reported.