20.500.12556/DiRROS-24062 Atypical Leber Hereditary Optic Neuropathy (LHON) associated with a novel MT-CYB:m.15309T>C(Ile188Thr) variant Background: The study presents a detailed examination and follow-up of a Slovenian patient with an Leber Hereditary Optic Neuropathy (LHON)-like phenotype and bilateral optic neuropathy in whom genetic analysis identified a novel variant MT-CYB:m.15309T>C (Ile188Thr). Methods: We provide detailed analysis of the clinical examinations of a male patient with bilateral optic neuropathy from the acute stage to 8 years of follow-up. Complete ophthalmological exam, electrophysiology and optical coherence tomography (OCT) segmentation were performed. The genotype analysis was performed with a complete screening of the mitochondrial genome. Furthermore, proteomic analysis of the protein structure and function was performed to assess the pathogenicity of a novel variant of unknown significance. Mitochondrial function analysis of the patient’s peripheral blood mononuclear cells (PBMCs) was performed with the objective of evaluating the mutation effect on mitochondrial function using flow cytometry and high-resolution respirometry. Results: The patient had a profound consecutive bilateral visual loss at 19 years of age due to optic neuropathy with characteristics of LHON; however, unlike patients with typical LHON, the patient experienced a fluctuation in visual function and significant late recovery. He had a total of three visual acuity deteriorations and improvements in the left eye, with concomitant visual loss in the right eye and a final visual acuity drop reaching nadir 9 months after onset. The visual loss was characterized by centrocecal scotoma, abnormal color vision and abnormal VEP, while deterioration of PERG N95 followed with a lag of several months. The OCT examination showed retinal nerve fiber layer thinning matching disease progression. Following a two-year period of legal blindness, the patient’s visual function started to improve, and over the course of 5 years, it reached 0.5 and 0.7 Snellen (0.3 and 0.15 LogMAR) visual acuity (VA). Mitochondrial sequencing identified a presumably pathogenic variant m.15309T>C in the MT-CYB gene at 65% heteroplasmy, belonging to haplogroup K. Mitochondrial function assessment of the patient’s PBMCs showed a lower respiration rate, an increase in reactive oxygen species production and the presence of mitochondrial depolarization, compared to an age- and sex-matched healthy control’s PBMCs. Conclusions: A novel variant in the MT-CYB:m.15309T>C (Ile188Thr) gene was identified in a patient with optic nerve damage and the LHON phenotype without any additional systemic features and atypical presentation of the disease with late onset of visual function recovery. The pathogenicity of the variant is supported by proteomic analysis and the mitochondrial dysfunction observed in the patient’s PBMCs. LHON gene electrophysiology retinal segmentation VA improvement mitochondrial disfunction proteomic analysis true false true Angleški jezik Ni določen Neznano 2025-11-10 14:17:45 2025-11-10 14:17:45 2025-11-13 04:02:52 0000-00-00 00:00:00 2025 0 0 Nasl. z nasl. zaslona; Opis vira z dne 17. 6. 2025; str. 1-17 iss. 1, [article no.] 108 Vol. 16 2025 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 0000-00-00 61:575 2073-4425 10.3390/genes16010108 239673347 RAZ_Petrovic_Pajic_Sanja_2025.pdf RAZ_Petrovic_Pajic_Sanja_2025.pdf 1 3C00D0233976B2D04AE9EE2EE4D01B21 8e685e29e5d4f8a960997876957e405db9f145c271a1c33ce4648fe45b69e8d7 e2072791-be37-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=35766 https://www.mdpi.com/2073-4425/16/1/108 0 f69ce757-bfb2-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=35839 Univerzitetni klinični center Ljubljana 0 0 0