Leber hereditary optic neuropathy: bridging the translational gap

Area of Science:

• Ophthalmology
• Genetics
• Mitochondrial Diseases

Background:

• Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) genetic disorder.
• LHON involves retinal ganglion cell (RGC) dysfunction preceding rapid vision loss.
• Pediatric cases may exhibit atypical, slow, or subclinical visual decline, causing diagnostic delays.

Purpose of the Study:

• To review the clinical evolution of Leber hereditary optic neuropathy (LHON).
• To identify secondary etiological factors contributing to vision loss in LHON.
• To discuss the development of effective LHON treatments.

Main Methods:

• Review of current literature on LHON clinical progression and etiology.
• Analysis of factors influencing disease conversion and RGC loss.
• Examination of ongoing therapeutic strategies, including gene therapy and mitochondrial replacement.

Main Results:

• LHON presents with a preclinical RGC dysfunction phase before visual deterioration.
• The LHON mtDNA mutation alone is insufficient for RGC loss; smoking and estrogen levels are implicated in disease conversion.
• Gene therapy using adeno-associated viral vectors and mitochondrial replacement therapy are under investigation.

Conclusions:

• LHON exhibits greater phenotypic heterogeneity than previously recognized.
• A complex interplay of genetic, environmental, and hormonal factors modulates vision loss risk in LHON carriers.
• Advances in disease modeling, drug screening, and genetic engineering offer potential therapeutic breakthroughs for LHON.