Novel Variants in Mitochondrial Ribosomal RNA Genes MT-RNR1 and MT-RNR2 Identified in Hereditary Optic Neuropathy...

Hereditary optic neuropathy may be caused by various mitochondrial or nuclear DNA mutations affecting the mitochondrial function. A growing body of evidence shows that mutations in non-classical mitochondrial genes, including the ribosomal RNA genes MT-RNR1 and MT-RNR2, have been reported in patients with hereditary optic neuropathy, although their pathogenicity remains uncertain. Herein, we report a case initially diagnosed as normal tension glaucoma in which whole mtDNA sequencing identified 2 novel variants in MT-RNR1 and MT-RNR2.

A 36-year-old man was referred for glaucoma assessment but was found to have bilateral symmetric temporal optic disc pallor and retinal nerve fibre layer thinning that was inconsistent with a glaucomatous pattern. Intraocular pressure (IOP), Humphrey visual fields, colour vision, and pupillary responses were normal. Genetic testing was negative for the 3 primary Leber's hereditary optic neuropathy (LHON) mutations but identified MT-RNR1:m.990T>C and MT-RNR2:m.2619A>G, both at 99.5% heteroplasmy and classified as ACMG class 3. Visual function remained stable at 6-month follow-up.

Neither MT-RNR1 and MT-RNR2 variants could be definitively linked to the hereditary optic neuropathy in this patient, and they are best regarded as findings of uncertain significance. This case highlights a diagnostic pitfall as non-glaucomatous optic disc pallor can be mistaken for normal tension glaucoma and underscores the diagnostic value of whole mtDNA sequencing when primary LHON screening is negative.