Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia
Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia
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DOI：
10.1136/jmedgenet-2019-106649
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发表时间：
2020-09-01
影响因子：
4
通讯作者：
Dominguez-Gonzalez, Cristina
中科院分区：
文献类型：
--
作者：
Rodriguez-Lopez, Claudia;Garcia-Cardaba, Luis M.;Dominguez-Gonzalez, Cristina
背景线粒体进行性眼外肌麻痹（PEO）包括广泛的临床和遗传性疾病。我们描述了PEO的表型亚型及其与分子缺陷的相关性，并提出了诊断算法。方法回顾性分析89例乳腺癌的临床、病理及遗传学特点。结果发现三种主要表型：“单纯性PEO”（42%），包括孤立性上睑下垂伴眼麻痹; Kearns-Sayre综合征（10%）;“PEO+”，与眼外症状相关，可区分以下亚型：肌病型（33%）、球型（12%）和其他型（3%）。肌肉活检是最准确的测试，显示95%的线粒体变化。96%的患者获得了基因诊断。单个大规模线粒体DNA（mtDNA）缺失是最常见的发现（63%），其次是多个mtDNA缺失（26%），原因是TWNK（n=8），POLG（n=7），TK 2（n=6）或RRM 2B（n=2）基因突变，以及mtDNA点突变（7%）。在TWNK和MT-TN基因中发现了三个新的可能致病的突变。结论线粒体PEO不存在表型-基因型相关性。当怀疑线粒体病因时，肌肉活检应该是PEO诊断流程的第一步，因为它也可以研究线粒体DNA重排。如果未发现mtDNA缺失，则应进行全mtDNA测序。
Background Mitochondrial progressive external ophthalmoplegia (PEO) encompasses a broad spectrum of clinical and genetic disorders. We describe the phenotypic subtypes of PEO and its correlation with molecular defects and propose a diagnostic algorithm. Methods Retrospective analysis of the clinical, pathological and genetic features of 89 cases. Results Three main phenotypes were found: 'pure PEO' (42%), consisting of isolated palpebral ptosis with ophthalmoparesis; Kearns-Sayre syndrome (10%); and 'PEO plus', which associates extraocular symptoms, distinguishing the following subtypes: : myopathic (33%), bulbar (12%) and others (3%). Muscle biopsy was the most accurate test, showing mitochondrial changes in 95%. Genetic diagnosis was achieved in 96% of the patients. Single large-scale mitochondrial DNA (mtDNA) deletion was the most frequent finding (63%), followed by multiple mtDNA deletions (26%) due to mutations inTWNK(n=8),POLG(n=7),TK2(n=6) orRRM2B(n=2) genes, and point mtDNA mutations (7%). Three new likely pathogenic mutations were identified in theTWNKandMT-TNgenes. Conclusions Phenotype-genotype correlations cannot be brought in mitochondrial PEO. Muscle biopsy should be the first step in the diagnostic flow of PEO when mitochondrial aetiology is suspected since it also enables the study of mtDNA rearrangements. If no mtDNA deletions are identified, whole mtDNA sequencing should be performed.