Mitochondrial abnormalities in patients with LHON-like optic neuropathies

Area of Science:

• Ophthalmology
• Genetics
• Biochemistry

Background:

• Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily affecting the optic nerve.
• LHON-like optic neuropathies present similarly to LHON but may have different underlying causes.
• Mitochondria play a crucial role in cellular energy production and are implicated in various neurodegenerative diseases.

Purpose of the Study:

• To investigate the biochemical and molecular characteristics of mitochondria in patients with LHON-like optic neuropathies.
• To identify potential mitochondrial contributors to optic nerve dysfunction in a clinical cohort.
• To differentiate between LHON and LHON-like conditions based on mitochondrial parameters.

Main Methods:

• Selected patients with LHON-like optic neuropathies from neuro-ophthalmology clinics.
• Conducted clinical examinations, neuroimaging, and assessed blood mitochondrial parameters.
• Sequenced the entire mitochondrial (mt)DNA coding region, measured relative mtDNA content, assessed mitochondrial respiratory function, and sequenced OPA1 and OPA3 genes.

Main Results:

• Patients exhibited higher levels of potentially pathogenic nonsynonymous mtDNA changes and greater relative mtDNA content compared to controls.
• Mitochondrial respiratory activity was significantly reduced in patients (P < 0.001).
• Only 17% of patients had primary LHON mutations, yet most showed mitochondrial abnormalities, indicating dysfunction beyond classic LHON.

Conclusions:

• Primary LHON mutations are less frequent in clinically identified LHON-like optic neuropathies compared to familial LHON.
• Mitochondrial dysfunction is a key factor in LHON-like optic neuropathy, irrespective of the presence of primary LHON mutations.
• Findings impact diagnostic strategies and future research into the mechanisms of optic nerve diseases.