Syndromic parkinsonism and dementia associated with OPA1 missense mutations.
Syndromic parkinsonism and dementia associated with OPA1 missense mutations.
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DOI：
10.1002/ana.24410
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发表时间：
2015-07
影响因子：
11.2
通讯作者：
Zeviani, Massimo
中科院分区：
文献类型：
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作者：
Carelli, Valerio;Musumeci, Olimpia;Caporali, Leonardo;Zanna, Claudia;La Morgia, Chiara;Del Dotto, Valentina;Porcelli, Anna Maria;Rugolo, Michela;Valentino, Maria Lucia;Iommarini, Luisa;Maresca, Alessandra;Barboni, Piero;Carbonelli, Michele;Trombetta, Costantino;Valente, Enza Maria;Patergnani, Simone;Giorgi, Carlotta;Pinton, Paolo;Rizzo, Giovanni;Tonon, Caterina;Lodi, Raffaele;Avoni, Patrizia;Liguori, Rocco;Baruzzi, Agostino;Toscano, Antonio;Zeviani, Massimo
越来越多的证据将神经退行性疾病如帕金森病和阿尔茨海默病与线粒体功能障碍联系起来，最近的重点集中在线粒体动力学和质量控制上。线粒体动力学和mtDNA维持是最近出现的另一个联系，涉及线粒体融合基因OPA 1和MFN 2的突变在多系统综合征的发病机制，其特征是神经变性和有丝分裂后组织中mtDNA多重缺失的积累。在这里，我们报告了2个意大利家庭的影响占主导地位的慢性进行性眼外肌麻痹（CPEO）并发帕金森综合征和痴呆症。通过光学相干断层扫描（OCT）对患者进行了广泛研究，以评估视网膜神经纤维，并进行了肌肉和大脑磁共振波谱（MRS），并对肌肉活检和成纤维细胞进行了分析。对候选基因进行测序，并分析mtDNA重排。受影响的个体表现出以CPEO、线粒体肌病、感音神经性耳聋、周围神经病、帕金森综合征和/或认知障碍为特征的缓慢进行性综合征，在大多数情况下没有视觉主诉，但在OCT时伴有视网膜神经纤维的亚临床缺失。肌肉活检显示细胞色素c氧化酶阴性纤维和mtDNA多重缺失，MRS显示肌肉和大脑中的氧化代谢缺陷。我们发现了2个杂合OPA 1错义突变，影响鸟苷三磷酸酶结构域中高度保守的氨基酸位置（p.G488R，p.A495V），每个与受影响的个体分离。成纤维细胞的研究表明，减少量的OPA 1蛋白与正常的mRNA表达，破碎的线粒体，受损的生物能，增加自噬和线粒体自噬。CPEO和帕金森症/痴呆与亚临床视神经病变的关联拓宽了OPA 1突变的表型谱，突出了线粒体动力学缺陷、mtDNA多重缺失和线粒体自噬改变与帕金森症的关联。《神经病学年鉴》2015;78：21-38
Mounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia. Patients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements. Affected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy. The association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38
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DOI：
10.1007/8904_2013_239
发表时间：
2014-01-01
期刊：
JIMD REPORTS, VOL 12
影响因子：
--
作者：
Hannah-Shmouni, Fady;Sirrs, Sandra;Mattman, Andre
通讯作者：
Mattman, Andre
影响因子：
6.6
作者：
Mancuso, Michelangelo;Ricci, Giulia;Siciliano, Gabriele
通讯作者：
Siciliano, Gabriele
影响因子：
56.9
作者：
Kaukonen, J;Juselius, JK;Suomalainen, A
通讯作者：
Suomalainen, A
影响因子：
14.5
作者：
Hudson, Gavin;Amati-Bonneau, Patrizia;Taylor, Robert W.
通讯作者：
Taylor, Robert W.
影响因子：
3.9
作者：
Marongiu, Roberta;Ferraris, Alessandro;Valente, Enza Maria
通讯作者：
Valente, Enza Maria