Lang-Orsini Melanie, Gonzalez-Perez Paloma
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
Front Neurol. 2022 Mar 8;13:846110. doi: 10.3389/fneur.2022.846110. eCollection 2022.
Mutations in nuclear-encoded genes that are involved in mitochondrial DNA replication and maintenance (e.g., ) have been associated with chronic progressive external ophthalmoplegia (CPEO) phenotype. These nuclear genome mutations may lead to multiple mitochondrial DNA deletions or mitochondrial DNA depletion. On the other hand, primary genetic defects of mitochondrial DNA (such as single large-scale deletion or point mutations) have also been associated with the CPEO phenotype. Chronic progressive external ophthalmoplegia (CPEO) may be a manifestation of specific syndromes that, when clinically recognized, prompt clinicians to investigate specific genetic defects. Thus, CPEO, as part of Kearns Sayre syndrome, suggests the presence of a large-scale deletion of mitochondrial DNA. However, in pure CPEO or CPEO plus phenotypes, it is more difficult to know whether causative genetic defects affect the nuclear or mitochondrial DNA. Here, we present a patient with a long-standing history of CPEO plus phenotype, in whom the sequencing of mitochondrial DNA from skeletal muscle was normal, and no other genetic defect was suspected at first. At the time of our evaluation, the presence of polyneuropathy and neuropathic pain prompted us to investigate nuclear genetic defects and, specifically, mutations in the gene. Thus, the sequencing of the gene revealed p.Thr251Ile and p.Pro587Leu mutations in one allele, and p.Ala467Thr mutation in another allele. Although one would expect that mutations in lead to multiple mitochondrial DNA deletions or depletion (loss of copies), the absence of mitochondrial DNA abnormalities in tissue may be explained by heteroplasmy, a lack or no significant involvement of biopsied tissue, or a sampling bias. So, the absence of secondary mitochondrial DNA alterations should not discourage clinicians from further investigating mutations in nuclear-encoded genes. Lastly, mitochondrial point mutations and single mitochondrial DNA deletions very rarely cause CPEO associated with polyneuropathy and neuropathic pain, and POLG-related disease should be considered in this scenario, instead.
参与线粒体DNA复制和维持的核编码基因（如 ）中的突变已与慢性进行性外眼肌麻痹（CPEO）表型相关。这些核基因组突变可能导致多个线粒体DNA缺失或线粒体DNA耗竭。另一方面，线粒体DNA的原发性遗传缺陷（如单个大规模缺失或点突变）也与CPEO表型相关。慢性进行性外眼肌麻痹（CPEO）可能是特定综合征的一种表现，当临床识别时，会促使临床医生研究特定的遗传缺陷。因此，作为卡恩斯·塞尔综合征一部分的CPEO提示存在线粒体DNA的大规模缺失。然而，在单纯CPEO或CPEO加其他表型中，很难知道致病的遗传缺陷是影响核DNA还是线粒体DNA。在此，我们报告一名有长期CPEO加其他表型病史的患者，其骨骼肌线粒体DNA测序正常，最初未怀疑有其他遗传缺陷。在我们评估时，多神经病和神经性疼痛的存在促使我们研究核遗传缺陷，特别是 基因中的突变。因此， 基因测序显示一个等位基因中有p.Thr251Ile和p.Pro587Leu突变，另一个等位基因中有p.Ala467Thr突变。尽管人们预期 基因中的突变会导致多个线粒体DNA缺失或耗竭（拷贝数丢失），但组织中线粒体DNA异常的缺失可能由异质性、活检组织缺乏或无显著受累或抽样偏差来解释。因此，继发性线粒体DNA改变的缺失不应阻碍临床医生进一步研究核编码基因中的突变。最后，线粒体点突变和单个线粒体DNA缺失极少导致与多神经病和神经性疼痛相关的CPEO，在这种情况下应考虑与POLG相关的疾病。
