晚期婴儿型神经元蜡样质脂褐素沉积病患者临床特点和基因改变

目的总结临床病理诊断为晚期婴儿型神经元蜡样质脂褐素沉积病(LINCL)患者的临床特点和基因改变。方法总结分析9例LINCL患者(其中3例为文献报道的患者)的临床特点,并对其中4例患者进行CLN2基因检测。结果癫痫是我国LINCL患者最主要的首发临床症状,其发作表现形式多样。CLN2基因检查结果显示,在两例患者分别发现位于第3内含子的IVS3-1G→A剪接突变和第6外显子的G217V杂合突变以及第13外显子的S538Y纯合突变,上述突变均为文献尚未报道过的新突变,在50名健康人中未发现这些基因突变。另两例患者CLN2基因检查正常。结论我国LINCL患者癫痫发作具有多种表现形式,肌阵挛癫痫不常见。我国CLN2基因的突变类型与其他国家或地区可能不同,也可能存在新的基因。     

晚期婴儿型神经元蜡样质脂褐质沉积病

目的报道１例晚期婴儿型神经元蜡样质脂褐质沉积病（ＬＮＣＬ）的临床和病理结果。方法对１例ＬＮＣＬ病人进行临床、影像学和病理观察。结果病人２岁开始出现行走不稳和智力发育倒退,此后出现癫痫发作和视力下降,在７岁４个月死亡。头颅ＭＲＩ检查发现显著脑萎缩。病理检查显示大脑和小脑皮层的神经元严重脱失,呈海绵样改变,丘脑和纹状体的神经元也受到较严重的累及,小脑分子层出现大量的巨大轴索,残存神经元内充满黄色自发荧光的颗粒沉积物,沉积物也出现在其他躯体细胞内。电镜下沉积物主要由曲线体构成。结论此例病人的临床和病理改变符合ＬＮＣＬ的诊断,但小脑分子层出现大量的巨大轴索不同于既往报道,此例是否为一个新的ＬＮＣＬ变异型有待进一步确定     

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。     

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。     

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 (theneuronalceroidlipofusci noses ,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。 182 6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/ 10 0 0 0。NCLs疾病至少包括 10种疾病亚型 (见表 1)。主要临床症状相似 ,包括快速的视力恶化 ,癫痫发作 ,进行性智力障碍 ,运动失调和行为变化〔2〕。主要病理…     

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。     

成人型与青少年型神经元蜡样质脂褐质沉积症

目的 :报道 2例神经元蜡样质脂褐质沉积症 (NCL)。方法 :临床和病理学观察。结果 :2例病人均有智能障碍 ,但ANCL同时伴有运动障碍 ,JNCL则伴有癫及性格改变。电镜下ANCL胶质细胞及神经元胞质内沉积物形式主要为脂褐素体 ,而JNCL主要为指纹体 ,同时有较多脂褐素体。结论 :根据起病年龄、临床表现及超微结构特点可分出本病的成年型和青少年型     

神经元蜡样质脂褐质沉积病伴癫痫持续状态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2～3min缓解。后每隔20d至1个月发作1次。持续数分钟至20min不等。     

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.     

The adult and a new late adult forms of neuronal ceroid lipofuscinosis

Summary Three cases of the late adult form of neuronal ceroid lipofuscinosis (NCL) are reported. Two of these are siblings with a late clinical onset at ages 26 and 44 years. The third case, sporadic, has the oldest reported age for the onset of NCL, at 63 years and may be regarded as the first example of the presenile form of NCL. The clinical, morphological, histochemical, ultrastructural and genetic features of these three cases are discussed. The literature of the clinicopathological NCL cases with an onset at age of 25 and older is reviewed. The clinical and morphological differences between the late adult form and the presenile form of NCL as well as the difficulties in making the diagnosis are discussed.Supported by NIH Grant NS23717     

Blood lymphocytes in neuronal ceroid lipofuscinosis

Ultrastructural examination of white blood cells of 8 patients with neuronal ceroid lipofuscinosis showed the characteristic cytosomes, i.e. curvilinear bodies, fingerprint profiles, osmiophilic bodies, as seen in nerve cells. The reliability of this simple technique in the diagnostic work-up of this progressive neurodegenerative disorder is emphasized.

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Sommario Vengono presentati i risultati dell'indagine ultrastrutturale dei linfociti circolanti in 8 pazienti affetti da Ceroido-Lipofuscinosi Neuronale. Nel citoplasma delle cellule ematiche sono stati osservati i medesimi citosomi (corpi curvilinei, processi ad impronte digitate, corpi osmiofili), che si riscontrano nei neuroni. Vengono sottolineati i vantaggi di questa semplice metodica nell'iter diagnostico di questa encefalopatia degenerativa a carattere progressivo.

     

A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinoses (NCL) are lysosomal storage disorders and constitute the most common group of progressive neurodegenerative diseases in childhood. Most NCLs are inherited in a recessive manner and are clinically characterised by a variable age at onset, epileptic seizures, psychomotor decline, visual impairment and premature death. To date, eight causative genes have been identified to underlie various clinical forms of NCL. We performed a genome-wide linkage analysis followed by sequencing the recently described NCL gene MFSD8 in three affected and three unaffected members of a consanguineous Egyptian family with an autosomal recessively inherited progressive neurodegenerative disorder. The clinical picture of the patients was compatible with a late infantile NCL (LINCL); however, impairment of the visual system was not a cardinal symptom in the respective family. By linkage analysis, we identified two putative loci on chromosome 1p36.11-p35.1 and 4q28.1-q28.2. The latter locus (4q28.1-q28.2) contained the MFSD8 gene, comprising a novel homozygous missense mutation in exon 5 (c.362a>g /p.Tyr121Cys), which segregated with the disease in the three affected sibs. We describe a novel mutation in the previously identified MFSD8 gene in a family with a common phenotype of LINCL, but no clinical report of vision loss. Our results enlarge the mutational and perhaps the nosological spectrum of one of the recently identified subtypes of NCL, called CLN7. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Structural basis of neuronal ceroid lipofuscinosis 1

To elucidate the basis of neuronal ceroid lipofuscinosis 1 (CLN1) from the viewpoint of enzyme structure, we constructed structural models of mutant palmitoyl protein thioesterase 1 (PPT1) proteins using molecular modeling software, jackal and TINKER. We classified the amino acid substitutions responsible for CLN1 and divided them into two groups, groups 1 and 2, based on the biochemical phenotype. Then, we examined the structural changes in the PPT1 protein for each group by calculating the solvent-accessible surface area (ASA) and the number of atoms affected. Our results revealed that the structural changes in group 1, which exhibits a complete deficiency of PPT1 activity, were generally large and located in the core region of the enzyme molecule. In group 2 exhibiting residual PPT1 activity, the structural changes in PPT1 were smaller and localized near the surface of the enzyme molecule. Coloring of affected atoms based on the distances between those in the wild type and mutants revealed the characteristic structural changes in the PPT1 protein geographically and semi-quantitatively. Structural investigation provides us with a deeper insight into the basis of CLN1.     

Juvenile-onset neuronal ceroid lipofuscinosis with infantile CLN1 mutation and palmitoyl-protein thioesterase deficiency

Accurate diagnosis, especially in progressive hereditary diseases, is essential for the treatment and genetic counseling of the patient and the family. Neuronal ceroid lipofuscinoses (NCL) are amongst the most common groups of neurodegenerative diseases. Infantile, juvenile, and adult-onset types with multiple genotype–phenotype associations have been described. A fluorimetric enzyme assay for palmitoyl protein thioesterase (PPT) from leukocytes and fibroblasts has been previously developed to confirm the diagnosis of infantile NCL. We describe a patient with juvenile-onset NCL phenotype with a new CLN1 mutation and deficient PPT activity.
Over 40 different mutations have been found in patients with PPT deficiency, indicating that screening for known mutations is not an efficient way to diagnose this disorder. Therefore, PPT enzyme analysis should precede mutation analysis in suspected PPT deficiency, particularly in patients with granular osmiophilic deposits (GROD) or in patients who have negative ultrastructural data. The use of enzyme assay led to the diagnosis of this patient with juvenile-onset Finnish variant NCL with PPT deficiency, and we expect that greater awareness of the utility of the enzymatic assay may lead to identification of other similar cases awaiting a definitive diagnosis.     

Accumulation of mitochondrial ATP synthase subunit c in muscle in a patient with neuronal ceroid lipofuscinosis (late infantile form)

We report a case of late infantile neuronal ceroid lipofuscinosis (NCL). Abnormal granules were found in the skeletal muscle fibers, Schwann cells, perineurial cells, endothelial cells, fibroblasts, and perivascular smooth muscle cells in the sural nerve. Electron microscopy revealed that these granules showed fingerprint profiles, curvilinear profiles or membrane-bound membranous structures. Acid phosphatase reaction was increased in these cells. Immunohistochemical studies for mitochondrial ATP synthase subunit c showed a strong reaction in these cells, suggesting abnormal accumulation of subunit c. Immunohistochemistry for subunit c in muscle may be useful in the diagnosis of late infantile NCL. Received: 8 July 1996 / Revised: 24 October 1996 / Accepted: 18 November 1996     

Angulate lysosomes in skin biopsies of patients with degenerative neurological disorders: high frequency in neuronal ceroid lipofuscinosis

Angulate lysosomes with intralysosomal trilamellar structures were first described in patients with metabolic peroxisomal disorders. In this ultrastructural study of skin biopsies of 139 patients with degenerative neurological disorders and 45 patients with static encephalopathies, we observed angulate lysosomes with similar ultrastructure exclusively in degenerative neurological disorders. They were found in only a few cases (8%), but especially in patients with degenerative metabolic disorders (72%). Because they were never observed in patients with static encephalopathies, angulate lysosomes in the skin would seem to be a sign of progressive encephalopathy. The great majority (75%) of angulate lysosomes were associated with neuronal ceroid-lipofuscinosis (NCL). Their presence in skin biopsy could suggest the diagnosis of NCL and eliminate a peroxisomal disorder. In the latter pathology, angulate lysosomes, numerous in the liver and in the brain, were never observed in the skin. As described in pigmentary retinopathy, a conspicuous feature of NCL, we suggest that in this lysosomal storage disorder, the angulate lysosomes in skin biopsies could result from the phagocytosis of melanin. Received: 21 July 1998 / Revised: 7 October 1998, 15 December 1998 / Accepted: 17 December 1998