Exploring rare mitochondrial DNA in Leber hereditary optic neuropathy

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.