Leber's hereditary optic neuropathy plus dystonia caused by the mitochondrial ND1 gene m.4160 T > C mutation

Background Leber's hereditary optic neuropathy (LHON) is a common mitochondrial disease. More than 30 variants in the mitochondrial DNA (mtDNA) have been previously described in LHON. However, the pathogenicity of some variants remains unclear. Herein, we report a 19-year-old boy presenting unique LHON plus dystonia syndrome with the rare m.4136A > G and m.4160 T > C variants and elucidate the molecular pathomechanisms of the m.4160 T > C mutation. Methods We performed clinical, molecular genetic analysis, and biochemical investigation in the patient's different tissues and cybrid cell lines. Results The optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) of the patient showed typical pathological changes-a significant decrease in the 17 thickness of the retinal nerve fiber layer (RNFL) and the ganglion cell complex (GCC). Brain magnetic resonance imaging (MRI) found noteworthy abnormal signals in the basal ganglia region. The genetic analysis revealed that the m.4160 T > C variant was heteroplasmic in the blood ( 80.2%), urine sediment (90.8%), and oral mucosal (81.7%) samples of the patient. In contrast, the m.4136A > G variant was homoplasmic in all available tissues. Biochemical and bioenergetic investigations showed decreased mitochondrial protein levels and mitochondrial respiration deficiency in cybrid cells harboring these variants. Conclusions This research provided more comprehensive data to help gain insight into the pathogenicity of the m.4160 T > C variant and broaden our view on the LHON plus phenotype.

Automated summary

In this study, we report a unique case of Leber's hereditary optic neuropathy (LHON) with the rare m.4136A > G and m.4160 T > C variants. We elucidate the molecular pathomechanisms of the m.4160 T > C mutation and provide comprehensive data to further understand the pathogenicity of this variant.