Exploring rare mitochondrial DNA in Leber hereditary optic neuropathy

IF 3.4

Advances in ophthalmology practice and research Pub Date : 2025-08-22 DOI:10.1016/j.aopr.2025.08.001

Shanshan Cao , Yong Liu , Mingming Sun , Yuan Zhang , Yonghua Sun , Quangang Xu , Shihui Wei , Huanfen Zhou

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Abstract

Background

Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder primarily caused by mutations in MT-ND1, MT-ND4, and MT-ND6, leading to retinal ganglion cell degeneration and severe vision loss. While 90%–95% of cases involve three common mutations (m.11778G > A, m.3460G > A, m.14484T > C), the genetic and clinical profiles of rare mutations remain poorly characterized, contributing to diagnostic challenges.

Methods

This cohort study analyzed 26 genetically confirmed LHON patients harboring rare mitochondrial DNA (mtDNA) mutations. Patients underwent best-corrected visual acuity (BCVA), optical coherence tomography (OCT) measurements (peripapillary retinal nerve fiber layer [pRNFL] and macular ganglion cell layer [GCL] thickness), and neuroimaging findings. Prognostic outcomes were compared between pediatric (≤16 years) and adult (>16 years) subgroups.

Results

The cohort (male:female = 4.2:1) exhibited a median onset age of 17 years (range:4–42), with 30.77% unilateral involvement. Rare mutations were distributed in MT-ND4(34.62%,m.11696G > A), MT-ND1(34.62%,including m.3733G > A/m.3866T > C), and MT-ND6 (23.08%, m.14502T>C), with 26.92% harboring dual mutations. Younger patients showed significantly better visual recovery (59.09% vs. 22.73% achieving BCVA ≥ 0.3, P = 0.014), despite comparable baseline vision and structural OCT parameters (pRNFL/GCL thickness, all P > 0.05). T2 hyperintensity in the optic nerve magnetic resonance imaging (MRI) was present in 38.46% of cases.

Conclusions

Our study probes into the clinical and genetic diversity of LHON with rare mtDNA mutations, revealing varied clinical presentations, such as more frequent unilateral involvement and enhanced optic nerve T2 MRI signals. Visual recovery was significantly better in the younger cohort. These results suggest the need for broader genetic testing in atypical LHON cases and offer insights into better prognostic strategies for new therapies.

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Leber遗传性视神经病变罕见线粒体DNA的研究

leber 's遗传性视神经病变（LHON）是一种母系遗传性线粒体疾病，主要由MT-ND1、MT-ND4和MT-ND6突变引起，可导致视网膜神经节细胞变性和严重视力丧失。虽然90%-95%的病例涉及三种常见突变（m.11778G >； A, m.3460G >； A, m.14484T >； C），但罕见突变的遗传和临床特征仍然很差，这给诊断带来了挑战。方法本队列研究分析了26例遗传证实的线粒体DNA （mtDNA）突变的LHON患者。患者接受最佳矫正视力（BCVA）、光学相干断层扫描（OCT）测量（乳头周围视网膜神经纤维层[pRNFL]和黄斑神经节细胞层[GCL]厚度）和神经影像学检查。比较儿童（≤16岁）和成人（≤16岁）亚组的预后。结果该队列（男：女= 4.2:1）中位发病年龄为17岁（范围：4-42岁），单侧受累30.77%。MT-ND4中有罕见突变(34.62%；11696G >； A), MT-ND1(34.62%，其中m. 3733g > A/m；3866T >；C)和MT-ND6 (23.08%, m.14502T>；C)，其中26.92%携带双突变。尽管基线视力和OCT结构参数（pRNFL/GCL厚度，均P >； 0.05）相似，但年轻患者的视力恢复明显更好（59.09% vs. 22.73% BCVA≥0.3,P = 0.014）。视神经磁共振成像（MRI） T2高信号发生率为38.46%。结论我们的研究探讨了罕见mtDNA突变的LHON的临床和遗传多样性，揭示了其不同的临床表现，如单侧受累更频繁，视神经T2 MRI信号增强。在年轻的队列中，视力恢复明显更好。这些结果表明需要在非典型LHON病例中进行更广泛的基因检测，并为新疗法的更好预后策略提供见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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