LOS ANGELES – Having just a small amount of heteroplasmy –– multiple mitochondrial genotype variants coexisting in the same cell –– may result in electron transport chain (ETC) abnormalities that contribute to mitochondrial dysfunction in people with single large-scale mitochondrial DNA deletion syndromes (SLSMDSs)..

洛杉矶——拥有少量异质性——即多个线粒体基因型变异共存于同一个细胞中——可能导致电子传递链（ETC）异常，从而引发单一大片段线粒体DNA缺失综合征（SLSMDS）患者的线粒体功能障碍。

This finding, from a study conducted by Baylor Genetics researchers and

这项发现来自贝勒遗传学研究人员进行的一项研究，

presented at

发布于

the annual meeting of the American College of Medical Genetics, shows that low heteroplasmy plays a bigger role in SLSMDSs than previously thought and suggests that a combination of genetic and functional tests are needed to effectively diagnose these disorders.

美国医学遗传学学院年会上发表的研究表明，低水平异质性在SLSMDSs中的作用比以前认为的更大，并建议需要结合遗传和功能测试来有效诊断这些疾病。

'It was always thought that these patients had a relatively high degree of heteroplasmy for these mitochondrial deletions in order to have a phenotype,' Christine Eng, chief medical officer of Baylor Genetics and a coauthor on the study, told GenomeWeb.

“一直以来，人们认为这些患者必须具有相对较高程度的异质性线粒体缺失才会表现出某种表型，”贝勒遗传学首席医学官、该研究的共同作者克里斯汀·恩格对《基因组网络》表示。

However, by correlating data between mitochondrial genome sequencing and functional ETC studies, the Baylor team found that patients with mitochondrial deletions involving even small levels of heteroplasmy and certain ETC deficiencies still resulted in the types of mitochondrial dysfunction characteristic of SLSMDSs..

然而，通过将线粒体基因组测序数据与功能性ETC研究相关联，贝勒团队发现，即使是异质性水平较低的线粒体缺失以及某些ETC缺陷的患者，仍然会导致SLSMDS特征性的线粒体功能障碍。

The major disorders associated with SLSMDSs are chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome, and Pearson syndrome, each of which presents differently. CPEO is a late-onset disease characterized by opthalmoplegia (paralysis or weakness of the eye muscles), ptosis (a drooping of the eyelid that covers all or part of the pupil), and varying degrees of skeletal muscle weakness.

与SLSMDS相关的主要疾病包括慢性进行性外眼肌麻痹（CPEO）、Kearns-Sayre综合征和Pearson综合征，每种疾病的表征各不相同。CPEO是一种迟发性疾病，特征为眼肌麻痹（眼部肌肉瘫痪或无力）、上睑下垂（眼睑下垂，覆盖部分或全部瞳孔）以及不同程度的骨骼肌无力。

Kearns-Sayre syndrome is a more severe manifestation of CPEO, often manifesting before the age of 20. Kearns-Sayre can present all the symptoms observed in CPEO, but typically with more pronounced muscle involvement. .

Kearns-Sayre综合征是CPEO的一种更严重的表型，通常在20岁之前显现。Kearns-Sayre可以呈现CPEO中观察到的所有症状，但通常肌肉受累更为明显。

Differing from the others, Pearson syndrome is an early-onset disease that typically manifests at infancy and initially presents with anemia and pancreatic insufficiency instead of muscle involvement. In many cases Pearson syndrome can spontaneously resolve after the first few years, and many surviving patients go on to be affected by later-stage Kearns-Sayre syndrome, suggesting that the two diseases share the same mechanism..

与其他疾病不同，皮尔逊综合征是一种早发性疾病，通常在婴儿期发病，最初表现为贫血和胰腺功能不全，而非肌肉受累。在许多情况下，皮尔逊综合征可能在头几年后自发缓解，而许多幸存患者随后会发展为晚期的Kearns-Sayre综合征，这表明这两种疾病具有相同的机制。

Xueyang Pan, a clinical biochemical genetics

潘雪阳，临床生化遗传学

fellow at Baylor Genetics who led the study, explained that SLSMDS patients often show varying degrees of heteroplasmy, giving rise to the hypothesis that higher mutation loads may correlate with the severity of cellular dysfunction.

贝勒遗传学研究所的研究员解释说，SLSMDS 患者通常表现出不同程度的异质性，这引发了较高突变负荷可能与细胞功能障碍严重程度相关的假设。

'However,' he said, 'we don't observe such a correlation, and so far, [we] don't have a clear idea about the threshold above which the mitochondrial deletion could cause a phenotype.'

“但是，”他说，“我们没有观察到这样的相关性，到目前为止，[我们]对线粒体缺失可能引起表型的阈值还没有一个清晰的认识。”

This led Yang and his colleagues to wonder whether low-level heteroplasmy might cause functional mitochondrial deficiencies. To investigate this, they conducted a retrospective study of all SLSMDS cases in Baylor Genetics' database where ETC functional testing and mitochondrial DNA (mtDNA) genome sequencing were performed on muscle samples.

这使得杨和他的同事们怀疑低水平的异质性是否可能导致功能性线粒体缺陷。为了研究这个问题，他们对贝勒遗传学数据库中所有进行了ETC功能测试和线粒体DNA（mtDNA）基因组测序的SLSMDS病例进行了一项回顾性研究。

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From 1,118 cases, the team identified seven instances of CPEO and Kearns-Sayre syndrome that matched their criteria.

从1118个病例中，研究团队找出了七个符合他们标准的CPEO和Kearns-Sayre综合征实例。

'Surprisingly, in all these cases we found a low heteroplasmy level with mitochondrial DNA deletions,' Yang said. Additionally, clinical notes for these cases included cytochrome C oxidase (COX) deficiencies in muscle pathology biopsies. COX defects can lead to numerous dysfunctions, including loss of mental function, movement problems, hypertrophic cardiomyopathy, and eating difficulties..

“令人惊讶的是，在所有这些病例中，我们发现线粒体DNA缺失的异质性水平较低，”杨说。此外，这些病例的临床记录中还包括肌肉病理活检中的细胞色素C氧化酶（COX）缺陷。COX缺陷可能导致多种功能障碍，包括智力功能丧失、运动问题、肥厚型心肌病和进食困难。

The investigators amplified mtDNA samples with long-range PCR and sequenced them via next-generation sequencing, which revealed that all seven samples showed mtDNA deletions.

研究人员使用长片段PCR扩增了mtDNA样本，并通过下一代测序技术对它们进行了测序，结果显示所有七个样本均出现mtDNA缺失。

'All these deletions disrupt protein-coding genes involved in mitochondrial ETC functions,' Yang said.

“所有这些缺失都会破坏与线粒体ETC功能相关的蛋白质编码基因，”杨说。

ETC deficiencies were then confirmed in functional studies that showed impaired activity of several ETC enzymes. Although most observed ETC abormalities correlated with the deleted genes, some did not, which Yang said will be the topic of future work.

随后的功能研究证实了ETC的缺陷，这些研究显示了多个ETC酶的活性受损。尽管大多数观察到的ETC异常与被删除的基因相关，但也有部分并不相关，杨表示这将是未来研究的主题。

These findings, Yang said, underscore the clinical significance of low-level mitochondria deletions, and highlight the value of integrating molecular and functional assessments for the accurate diagnosis of SLSMDSs

杨表示，这些发现强调了低水平线粒体缺失的临床意义，并突显了整合分子和功能评估对于准确诊断SLSMDS的价值。

'Low levels of heteroplasmy have led physicians to think [that] this was relatively not significant for their phenotype,' said Eng. 'Putting that together with functional data, however, brought more insight into the fact that low heteroplasmy can actually lead to clinical symptomatology.'

“低水平的异质性曾让医生们认为这对他们的表型影响相对不显著，”Eng说道。“然而，将这一点与功能数据结合起来，却让人们更深入地认识到，低水平的异质性实际上可能导致临床症状。”

As a result, the Baylor team suggests that physicians perform functional assessments on muscle samples to better verify the pathogenicity of mtDNA deletions in this set of syndromes.

因此，贝勒团队建议医生对肌肉样本进行功能评估，以更好地验证这套综合征中mtDNA缺失的致病性。

'We learn a lot from the genome,' Eng said, 'but we think that there are ways of improving our understanding of the genome by adding additional functional studies.'

“我们从基因组中学到了很多，”Eng说，“但我们认为，通过增加额外的功能研究，可以提高我们对基因组的理解。”