Leber氏病2家系报告

本文报告Ｌｅｂｅｒ氏病两家系。通过临床分析认为视乳头周围微血管病变和眼底荧光血管造影无着色是该病重要特征。但因伴或不伴有其它神经体征易与球后视神经炎或多发性硬化等相混淆，给临床诊断带来困难。遗传方式符合母系遗传。本病发病机理尚不完全清楚。目前认为是线粒体ＤＮＡ基因点突变引起。     

误诊为视神经脊髓炎的Leber遗传性视神经病1例

Leber遗传性视神经病(Leber hereditary optic neuroretinopathy,LHON)是一种线粒体遗传病,该病临床呈急性或亚急性起病,以单眼或双眼视力同时受损为首发症状,常合并中枢神经系统其他部分受累,因此,该病极易与视神经炎、视神经脊髓炎或多发性硬化相混淆。     

Leber遗传性视神经病的线粒体基因突变及临床特征

目的　了解Leber遗传性视神经病 (LHON)线粒体基因突变及其临床特征。方法　采用PCR法扩增96例视神经病变患者mtDNA中ND1、ND4、ND6上的 3个片段后 ,用 377测序仪对mtDNA上 11778、346 0、14 4 84位点进行序列分析确定有无碱基突变。结果　 96例患者中 4 0例 (41 7% )线粒体基因突变 ,其中男性 34例 (85 % ) ,女性 6例 (15 % ) ;34例 (85 % )为 11778位点突变 ,2例 (5 % ) 346 0位点突变 ,4例 (10 % ) 14 4 84位点突变 ;346 0及 14 4 84突变均为散发病例 ;有家族史者突变表达占 87 0 % (2 0 /2 3) ,无家族史者突变占 2 7 4 % (2 0 /73) ;头颅MR显示 11778突变者中 3例有脑白质区病灶 ,1例LHON合并垂体瘤 ;12例突变阳性者检查脑脊液 ,11例有炎性脱髓鞘改变。结论　LHON以 11778突变常见 ;起病及病程多样化、散发病例比例较高、眼底微血管病改变不易发现、脑脊液改变与炎性脱髓鞘雷同导致LHON在临床上易漏诊误诊 ,应尽早行突变检测明确诊断。     

线粒体DNA与某些神经肌肉疾病

发现某些神经肌肉疾病系线粒体DNA 突变所致,这是近几年神经病学和遗传病学的最新进展。它对一些具有遗传倾向的某些疾病的病因学研究带来了希望。作者就线粒体DNA 点突变、缺失及重复与某些神经肌肉疾病的关系,以及机制和前景作一综述。     

中国人Leber遗传性视神经病变(LHON)线粒体DNA3个原发致病基因突变遗传及临床特征

目的 对我国国人Leber遗传性视神经病变(LHON)线粒体DNA的3个原发致病基因突变遗传进行分析,并探讨其临床特征。方法 对100例LHON患者采用异源双链-单链构像多态性(HA-SSCP)、限制性片段长度多态性(RFLP)、突变特异性引物聚合酶链反应以及DNA测序的方法,对mtDNA11778、14484、3460位点的基因突变情况进行分析。并同时对所有发病患者的性别、年龄、视力等情况进行观察,对其临床特进行探讨。结果 经过检测,100例患者中,不同突变位点的LHON患者发病时的视力不同。发病年龄集中在10~20岁。结论 我国LHON以mtDNA11778位点突变为主,可作为国人常规筛选,属于母系遗传,对我国国人的视力造成严重威胁。     

中国人Leber遗传性视神经病变（LHON）线粒体DNA 3个原发致病基因突变遗传及临床特征

目的对我国国人Leber遗传性视神经病变（LHON）线粒体DNA的3个原发致病基因突变遗传进行分析,并探讨其临床特征。方法对100例LHON患者采用异源双链-单链构像多态性（HA-SSCP）、限制性片段长度多态性（RFLP）、突变特异性引物聚合酶链反应以及DNA测序的方法,对mtDNA11778、14484、3460位点的基因突变情况进行分析。并同时对所有发病患者的性别、年龄、视力等情况进行观察,对其临床特进行探讨。结果经过检测,100例患者中,不同突变位点的LHON患者发病时的视力不同。发病年龄集中在10～20岁。结论我国LHON以mtDNA11778位点突变为主,可作为国人常规筛选,属于母系遗传,对我国国人的视力造成严重威胁。     

线粒体DNA突变与线粒体脑肌病

本文简述了线粒体DNA的基本结构、功能及特性,并着重讨论线粒体DNA点突变与几种临床常见的线粒体疾病如Leber's病,MELAS,MERRF之间的联系及特异性线粒体DNA点突变的基因诊断意义。     

Leber遗传性视神经病的分子遗传学研究进展

Leber遗传性视神经病(LHON)是常见的线粒体遗传病之一。LHON的临床表型的多样性、外显率的不同与线粒体基因的不同突变位点、遗传异质性及haplogroup的多态性等因素有关。LHON的线粒体基因突变导致细胞内相关酶水平的变化,继而导致一些产物在细胞内聚集,诱发细胞凋亡,但是具体分子作用机制尚不完全清楚。本综述通过对近年来该病的分子遗传学研究方面的成果和进展作一阐述,为基因诊断,治疗,预后提供参考。     

Leber氏病2家系报告(附文献复习)

本文报告Leber氏病两家系。通过临床分析认为视乳头周围微血管病变和眼底荧光血管造影无着色是该病重要特征。但因伴或不伴有其它神经体征易与球后视神经炎或多发性硬化（MS）等相混淆，给临床诊断带来困难。遗传方式符合母系遗传，本病发病机理尚不完全清楚．目前认为是线粒体（mt）DNA基因点突变引起。核基因对发病可能有一定影响。     

Alzheimer病线粒体DNA突变分子生物学研究进展

脑能量代谢降低为AD发病的危险因素之一 ,而线粒体是细胞能量储存和供给的重要场所。近年研究认为 ,线粒体DNA突变与AD的发病有关 ,本文就线粒体DNA突变在AD发病中的致病作用予以综述     

Leber's hereditary optic neuropathy mutations in ethambutol-induced optic neuropathy

Primary mitochondrial DNA (mtDNA) mutation at the nt 11778 site in Leber's hereditary optic neuropathy (LHON) has been reported to be present in patients with ethambutol-induced optic neuropathy. To study further this association between LHON and ethambutol-induced optic neuropathy, we tested ethambutol-induced optic neuropathy patients for the presence of the mtDNA mutations at nucleotides (nt)–11778, nt–14484, nt–3460, nt–15257, nt–9438, nt–9804, nt–13730, and nt–14459 in 24, 15, 8, 6, 5, 5, 5, and 5 patients respectively. However, none of the ethambutol-induced optic neuropathy patients was found to exhibit any pathogenic LHON mtDNA mutation. In conclusion, we found no evidence of any association between ethambutol-induced optic neuropathy and the LHON mutations. Received: 21 January 2002, Received in revised form: 26 August 2002, Accepted: 30 August 2002 Correspondence to Jeong-Min Hwang, M. D.     

Leber hereditary optic neuropathy: clinical and molecular genetic findings

Leber hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by acute or subacute painless central visual loss usually in young adults, predominantly in males. Except for optic atrophy, LHON patients are usually otherwise healthy. Occasionally, LHON is associated with neurological, cardiac, and skeletal changes. The clinical course of LHON has several stages. Peripapillary microangiopathy is present from the beginning. Microangiopathy disappears as the disease progresses towards the end stages. Simultaneously, the retinal nerve fiber layer fades from view, first papillomacular nerve fiber bundles, and months later, the whole nerve fiber layer becomes atrophic. At the end stage the centrocecal scotoma is large and absolute. Loss of vision is usually permanent, but spontaneous recovery can occur. Despite a few attempts, no effective treatment to prevent or halt LHON has been found. Several mitochondrial DNA (mtDNA) mutations are associated with LHON, but the pathogenic processes leading to optic nerve atrophy are largely unknown. About 15% of the families are heteroplasmic, i.e., both mutant and wild type mtDNA coexist within an individual. The level of heteroplasmy between different tissues can vary markedly. mtDNA mutations are not sufficient to cause visual loss in LHON, since not all individuals harboring a pathogenic LHON mutation express the disease. There are additional genetic and/or environmental precipitating factors, but thus far they are unknown. Electronic Publication     

Leber's hereditary optic neuropathy associated with a disorder indistinguishable from multiple sclerosis in a male harbouring the mitochondrial DNA 11778 mutation

This report describes a multiple sclerosis (MS)-like disorder in a male patient with Leber's hereditary optic neuropathy (LHON) harbouring the mitochondrial DNA 11778 base pair mutation. Given the population frequencies of MS and LHON, coincidental occurrence is unlikely. Hypothetically the mitochondrial mutation underlying LHON may contribute to presumably immunologically mediated involvement of other myelinated axons in the central nervous system in susceptible individuals, producing a disorder indistinguishable from MS. We recommend that investigation for oligoclonal bands in CSF, evoked potentials and MR brain scan in these patients be supplemented with mitochondrial DNA analysis.     

Spectrum of the mitochondrial DNA mutations of Leber's hereditary optic neuropathy in Koreans

We investigated 14 primary mitochondrial DNA (mtDNA) mutations at nucleotide positions (nps) 3460A, 4160C, 5244A, 9101C, 9804A, 10663C, 11778A, 13730A, 14459A, 14482G, 14484C, 14495G, 14498T, and 14568T, and one common secondary mutation at np 15257A, in 82 Korean patients with suspected Leber's hereditary optic neuropathy (LHON). Only three kinds of LHON mutations were identified in 60 (73 %) of the 82 probands, these being the 11778A, 14484C, and 3460A mutations with 46 (56 %), 13 (16 %), and 1 (1 %) cases, respectively. None of the other mtDNA mutations was detected. Of the 60 probands with LHON positive mutations, 19 (32 %) had relevant family histories. Heteroplasmy was determined in 2 (4 %) of the 46 probands with the 11778A mutation and 1 (8 %) of the 13 probands with the 14484C mutation. In conclusion, the 11778A mutation was the most common cause (56 %), with a high prevalence of the 14484C and a lower prevalence of the 3460A mutations being characteristic of Korean patients with LHON. The 3460A mutation especially showed a remarkable racial difference from that in Caucasians. With the exceptions of the 3460A, 11778A, and 14484C, the mutations screened may not be involved in the pathogenesis of LHON in Koreans and may not have a synergistic effect on its clinical expression. Received: 20 June 2002, Received in revised form: 25 September 2002, Accepted: 9 October 2002 Correspondence to Sung Sup Park     

Antibodies to human optic nerve in Leber's hereditary optic neuropathy

Mutations of mitochondrial DNA have now been identified in the majority of patients with Leber's hereditary optic neuropathy (LHON). However, these mutations do not explain all the clinical features of LHON, and other pathogenetic factors are likely to be operating. We have analysed serum from 69 LHON patients and their relatives, 58 controls and 14 patients with ischemic or compressive optic neuropathy. A significant proportion of LHON patients had circulating antibodies to tubulin protein. This finding supports the theory that autoimmunity may play some role in the pathogenesis of LHON.     

Cerebellar ataxia in patients with Leber's hereditary optic neuropathy

We report the cases of a mother and son with Leber's hereditary optic neuropathy (LHON), where a point mutation of mitochondria DNA from guanine to adenine on nucleotide position 11778 was verified. Both also had cerebellar ataxia and dysarthria and in both cases cerebellar atrophies were detected by computed tomography or magnetic resonance imaging. It was not possible to elucidate the relationship between LHON and the cerebellar atrophy, but it should be kept in mind that various neurological complications may occur in LHON.     

Mitochondrial mutations of Leber's hereditary optic neuropathy: a risk factor for multiple sclerosis

Multiple sclerosis (MS) and Leber's hereditary optic neuropathy (LHON) have been found to occur in combination. Based on an extensive literature search and on a clinical analysis of 55 LHON pedigrees (103 patients) and 40 patients with definite MS, this study concludes that the association of LHON and MS is more than a coincidence, and that carrying a primary LHON mutation is a risk factor for developing MS. All three primary LHON mutations occurring in the European and North American populations have been found to be associated with an MS-like syndrome. The neurological characteristics of MS associated with LHON are indistinguishable from those of MS in general, but the severe and bilateral visual symptoms and signs justify considering these patients as a clinical subgroup of MS and screening them for LHON mutations. However, screening LHON patients for MS appears to be more rewarding. Received: 21 July 1999, Received in revised form: 10 January 2000, Accepted: 8 March 2000     

遗传性视神经萎缩伴肌张力障碍一个家系报告

目的报道一个五代母系遗传的未知神经变性疾病家系。方法家系调查、临床资料收集、线粒体DNA分子遗传学检测。结果本家系5代,共43人,17人患病,男性9人,女性8人,发病年龄5～40岁,呈母系遗传。所有患者均有视神经萎缩,部分患者伴严重肌张力障碍和双侧基底节异常MR信号。分子遗传学检测未发现与Leber遗传性视神经病(LHON)有关的已知突变,亦未发现与神经性肌无力-共济失调-色素性视网膜炎(NARP)有关的8893位点突变。结论本家系临床表现独特,且未见与此表型类似的已知线粒体疾病突变位点存在,可能是一种与已知突变不同的LHON或新型线粒体疾病。     

Evidence for retrochiasmatic tissue loss in Leber's hereditary optic neuropathy

Patients with Leber's hereditary optic neuropathy (LHON) have loss of central vision with severe damage of small‐caliber fibers of the papillomacular bundle and optic nerve atrophy. The aim of this study was to define the presence and topographical distribution of brain grey matter (GM) and white matter (WM) injury in LHON patients using voxel‐based morphometry (VBM). The correlation of such changes with neuro‐ophthalmologic findings and measurements of peripapillary retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) was also assessed. Dual‐echo and fast‐field echo scans were acquired from 12 LHON patients and 12 matched controls. VBM analysis was performed using SPM5 and an ANCOVA model. A complete neuro‐ophthalmologic examination, including standardized automated Humphrey perimetry as well as average and temporal peripapillary RNFL thickness measurements were obtained in all the patients. Compared with controls, average peripapillary RNFL thickness was significantly decreased in LHON patients. LHON patients also had significant reduced GM volume in the bilateral primary visual cortex, and reduced WM volume in the optic chiasm, optic tract, and several areas located in the optic radiations (OR), bilaterally. Visual cortex and OR atrophy were significantly correlated with average and temporal peripapillary RNFL thickness (P < 0.001; r values ranging from 0.76 to 0.89). Brain damage in patients with LHON is not limited to the anterior visual pathways, but extends posteriorly to the OR and the primary visual cortex. Such a damage to the posterior parts of the visual pathways may be due either to trans‐synaptic degeneration secondary to neuroaxonal damage in the retina and optic nerve or to local mitochondrial dysfunction. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.