Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple <scp>mtDNA</scp> deletions

Hou, Yue; Zhao, Xutong; Xie, Zhiying; Yu, Meng; Lv, He; Zhang, Wei; Yuan, Yun; Wang, Zhaoxia

doi:10.1002/mgg3.1921

Cited by 6 publications

(2 citation statements)

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“…DNA was extracted from patients' muscle tissues, and mtDNA deletions were detected by Southern blot (6 patients) or long‐range polymerase chain reaction (LR‐PCR, 149 patients). The specific deletion endpoints were determined by Sanger sequencing of short‐cycle PCR products (121 patients) or next‐generation sequencing (NGS, 34 patients) (Grady et al., 2014; Hou et al., 2022). This study examined the MT‐CO genes, including MT‐CO1, MT‐CO2, and MT‐CO3, and the MT‐CYB genes present in the deletion fragments.…”

Section: Methodsmentioning

confidence: 99%

The clinical, myopathological, and genetic analysis of 155 Chinese mitochondrial ophthalmoplegia patients with mitochondrial DNA single large deletions

Zhao,

Hou,

Zhao

et al. 2023

Molec Gen & Gen Med

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BackgroundProgressive external ophthalmoplegia (PEO) is a common subtype of mitochondrial encephalomyopathy.ObjectiveThe study aimed to investigate the relationship between mitochondrial DNA (mtDNA) abnormalities, muscle pathology, and clinical manifestations in Chinese patients with single large‐scale mtDNA deletion presenting with PEO.MethodsThis is a retrospective single‐center study. Patients with PEO who had a single large deletion in mitochondrial DNA were included in this study. The associations were analyzed between mtDNA deletion patterns, myopathological changes, and clinical characteristics.ResultsIn total, 155 patients with mitochondrial PEO carrying single large‐scale mtDNA mutations were enrolled, including 137 chronic progressive external ophthalmoplegia (CPEO) and 18 Kearns–Sayre syndrome (KSS) patients. The onset ages were 9.61 ± 4.12 in KSS and 20.15 ± 9.06 in CPEO. The mtDNA deletions ranged from 2225 bp to 9131 bp, with m.8470_13446del being the most common. The KSS group showed longer deletions than the CPEO group (p = 0.004). Additionally, a higher number of deleted genes encoding respiratory chain complex subunits (p = 0.001) and tRNA genes (p = 0.009) were also observed in the KSS group. A weak negative correlation between the mtDNA deletion size and ages of onset (p < 0.001, r = −0.369) was observed. The proportion of ragged red fibers, ragged blue fibers, and cytochrome c negative fibers did not correlate significantly with onset ages (p > 0.05). However, a higher percentage of abnormal muscle fibers corresponds to an increased prevalence of exercise intolerance, limb muscle weakness, dysphagia, and cerebellar ataxia.ConclusionWe reported a large Chinese cohort consisting of mitochondrial PEO patients with single large‐scale mtDNA deletions. Our results demonstrated that the length and locations of mtDNA deletions may influence onset ages and clinical phenotypes. The severity of muscle pathology could not only indicate diagnosis but also may be associated with clinical manifestations beyond the extraocular muscles.

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Section: Methodsmentioning

confidence: 99%

The clinical, myopathological, and genetic analysis of 155 Chinese mitochondrial ophthalmoplegia patients with mitochondrial DNA single large deletions

Zhao,

Hou,

Zhao

et al. 2023

Molec Gen & Gen Med

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“…The nuclear genes associated with CPEO are POLG/POLG2, PEO1 (TWNK), RRM2B, SLC25A4 (ANT1), DNA2, OPA1, TYMP, MGM1, RNASEH1, TK2, and DGUOK ; mutations in these genes are usually inherited in an autosomal dominant or autosomal recessive fashion [ 1 – 4 , 7 , 8 ]. The mitochondrial transfer RNA gene implicated in CPEO is MT-TL1 ; mutations in this gene are inherited in a mitochondrial pattern.…”

Section: Introductionmentioning

confidence: 99%

Pontine stroke in a patient with Chronic Progressive External Ophthalmoplegia (CPEO): a case report

et al. 2023

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Background Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease with slowly progressive bilateral ptosis and symmetric ophthalmoplegia due to a genetic mutation that results in defective oxidative phosphorylation. Common genes that are implicated in CPEO include POLG, RRM2B, ANT1 and PEO1/TWNK. Here, we report a case of a patient diagnosed with CPEO caused by a novel mutation in PEO/TWNK after suffering a right pontine stroke. Case presentation A 70-year-old man with history of chronic progressive bilateral ptosis and ophthalmoplegia, as well as similar ocular symptoms in his father and grandfather, presented with acute onset of right hemifacial weakness and dysarthria. Brain MRI revealed an acute ischemic stroke in the right dorsal pons. The patient did not experience diplopia due to severe baseline ophthalmoplegia. Creatine kinase was elevated to 6,080 U/L upon admission and normalized over the course of one week; electromyography revealed a myopathic process. Genetic testing revealed a novel mutation c.1510G > A (p. Ala504Thr) in a pathogenic “hot spot” of the C10ORF2 gene (TWNK/PEO1), which is associated with CPEO. The mutation appears to be deleterious using several pathogenicity prediction tools. Conclusions This case report describes a patient with late-onset CPEO caused by a novel, likely pathogenic, mutation in the TWNK gene. Although the patient presented with a pontine stroke, it manifested with solely new onset facial palsy, as he had a severe underlying ophthalmoplegia secondary to his CPEO.

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Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple mtDNA deletions

Hou

Zhao

Xie

et al. 2022

Molec Gen & Gen Med

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Objectives 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). Methods 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. Results 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. Conclusions 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.

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Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple mtDNA deletions

Cited by 6 publications

References 44 publications

The clinical, myopathological, and genetic analysis of 155 Chinese mitochondrial ophthalmoplegia patients with mitochondrial DNA single large deletions

The clinical, myopathological, and genetic analysis of 155 Chinese mitochondrial ophthalmoplegia patients with mitochondrial DNA single large deletions

Pontine stroke in a patient with Chronic Progressive External Ophthalmoplegia (CPEO): a case report

Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple mtDNA deletions

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