Department of Neurology, Peking University First Hospital, Beijing, China.
Department of Geriatrics, Peking University First Hospital, Beijing, China.
Mol Genet Genomic Med. 2022 May;10(5):e1921. doi: 10.1002/mgg3.1921. Epub 2022 Mar 15.
This study aimed to investigate the clinical and genetic spectrum in Chinese patients with multiple mtDNA deletions presenting with autosomal-inherited mitochondrial progressive external ophthalmoplegia (PEO).
Long-range polymerase chain reaction and massively parallel sequencing of the mitochondrial genome were performed to detect deletions in muscle mtDNA of 274 unrelated families. Then, targeted next generation sequencing was used to detect nuclear gene variations in patients with multiple mtDNA deletions.
A total of 40 Chinese PEO patients (10 males and 30 females) from 20 families were found to have multiple mtDNA deletions in this study, and the median age at onset was 35 (1-70) years. PEO and positive family history were the two prominent features of these patients, and ataxia, neuropathy, and hypogonadism were also present as onset symptoms in some patients. Fifteen of 20 probands with multiple mtDNA deletions were identified to carry nuclear gene variants; eight (40.0%) probands had variants within POLG, two (10.0%) within TWNK, two (10.0%) within RRM2B, two (10.0%) within TK2, and one (5.0%) within POLG2. A total of 24 variants were found in these five nuclear genes, of which 19 were novel. The causal nuclear genetic factors in five pedigrees remain undetermined.
The POLG gene is the most common disease-causing gene in this group of PEO patients with multiple mtDNA deletions. While inherited PEO is the most prominent symptoms in these patients, genotypic and phenotypic heterogeneity still exist, for example in onset age, initial symptoms, and accompanying manifestations.
本研究旨在探讨中国常染色体遗传性线粒体进行性眼外肌麻痹（PEO）伴多发性 mtDNA 缺失患者的临床和遗传谱。
对 274 个无关家系的肌肉 mtDNA 进行长距离聚合酶链反应和线粒体基因组高通量测序，以检测缺失情况。然后，对多发性 mtDNA 缺失患者进行靶向下一代测序，以检测核基因突变。
本研究共发现 40 例来自 20 个家系的中国 PEO 患者（10 名男性，30 名女性）存在多发性 mtDNA 缺失，发病中位年龄为 35（1-70）岁。PEO 和阳性家族史是这些患者的两个突出特征，一些患者还存在共济失调、神经病和性腺功能减退等起病症状。20 名多发性 mtDNA 缺失先证者中有 15 名携带核基因突变；8 名（40.0%）先证者的突变位于 POLG 基因内，2 名（10.0%）位于 TWNK 基因内，2 名（10.0%）位于 RRM2B 基因内，2 名（10.0%）位于 TK2 基因内，1 名（5.0%）位于 POLG2 基因内。这五个核基因共发现 24 个变异，其中 19 个是新发现的。五个家系的致病核遗传因素仍未确定。
在这组多发性 mtDNA 缺失的 PEO 患者中，POLG 基因是最常见的致病基因。虽然遗传性 PEO 是这些患者最突出的症状，但仍存在基因型和表型异质性，例如发病年龄、初始症状和伴随表现。
