Why this review matters
Leber hereditary optic neuropathy (LHON) is a mitochondrial optic neuropathy that can cause severe, often rapid loss of central vision. For people living with LHON and their families, obtaining a clear genetic answer is important: it can help explain the cause of vision loss, support timely care, and shape discussions about available and emerging treatment options.
A 2026 review in Documenta Ophthalmologica examines an increasingly important challenge in LHON: not every affected person has one of the three mitochondrial DNA (mtDNA) variants traditionally considered the primary causes of the condition. Rare variants in mtDNA—and, in some cases, nuclear DNA—may contribute to LHON-like disease or related mitochondrial optic neuropathies. The authors argue that diagnosis needs to move beyond a narrow testing approach and toward broader, more comprehensive genetic evaluation.
The biological problem: energy failure in vulnerable retinal cells
Mitochondria are often described as the cell’s energy-producing structures. They generate adenosine triphosphate (ATP), a molecule cells use to power essential functions. Many LHON-associated genetic changes disrupt oxidative phosphorylation, the mitochondrial process that produces ATP.
When this process is impaired, cells may produce less energy and more reactive oxygen species. Retinal ganglion cells—the nerve cells that carry visual information from the eye to the brain—appear particularly vulnerable to this combination of reduced energy production and oxidative stress. Damage to these cells can lead to optic nerve dysfunction and the characteristic visual consequences of LHON.
The review emphasizes that this biology is not limited to the best-known LHON variants. Rare mitochondrial and nuclear genetic changes may disrupt similar pathways. Some may be associated with LHON itself, while others may occur in related mitochondrial disorders, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leigh syndrome.
Why rare variants are difficult to identify
The presence of a rare genetic variant does not automatically establish that it is disease-causing. Interpreting these findings can be especially challenging in mitochondrial disease because the clinical picture can vary substantially between individuals.
One reason is heteroplasmy. A person can carry a mixture of mitochondrial DNA molecules, some with a variant and some without it. The proportion of altered mtDNA may differ among tissues and may influence how disease appears. This variability can complicate efforts to connect a specific variant with a person’s symptoms.
The review also highlights phenotypic heterogeneity: the same or related genetic changes may be associated with different clinical presentations. Some individuals may have a presentation strongly suggestive of LHON, while others may have features that overlap with other mitochondrial conditions. These differences create real diagnostic obstacles, particularly when routine testing is negative or when a person’s clinical course is atypical.
Targeted tests designed mainly to look for the three primary LHON-associated mtDNA variants can miss less common causes. The authors therefore support the growing role of comprehensive next-generation sequencing. Broader sequencing can assess mtDNA more fully and, when appropriate, evaluate nuclear genes that may be relevant to mitochondrial optic neuropathy.
A changing diagnostic framework
Historically, molecular diagnosis of LHON centered largely on the three primary pathogenic mtDNA variants. This review describes a shift toward a broader framework that recognizes the potential importance of rare mtDNA and nuclear DNA changes.
For patients with an inconclusive result from conventional testing, full mtDNA sequencing may be particularly valuable. Integrating mitochondrial and nuclear genomic information could provide a more complete assessment, especially in people with unusual symptoms or a family history that does not fit a straightforward pattern.
The authors also identify artificial intelligence-based approaches as a potential future tool. Such methods may help researchers and clinicians analyze complex genetic and clinical data, improving the classification of rare variants and clarifying their likely significance.
What this means for treatment now and in the future
A more precise genetic diagnosis may become increasingly important as treatment strategies develop. The review discusses both genotype-specific and genotype-independent approaches.
Genotype-specific therapy aims to address a particular genetic cause. One example discussed is adeno-associated virus serotype 2 (AAV2)-mediated allotopic expression, a gene therapy approach designed around specific mitochondrial genetic defects. These approaches underscore why identifying the underlying variant matters: a therapy designed for one molecular cause may not be appropriate for another.
The review also discusses idebenone as a genotype-independent therapy. Unlike an approach directed at one specific variant, this type of treatment is intended to address disease mechanisms more broadly. The authors envision multifaceted strategies that may ultimately combine a deeper understanding of each person’s genetic findings with treatments targeting shared consequences of mitochondrial dysfunction.
Looking ahead: toward individualized LHON care
The central message of this review is that rare variants deserve careful attention rather than being overlooked after standard testing is negative. Better identification, classification, and interpretation of these variants could shorten the path to diagnosis and help prevent further visual decline through more timely treatment initiation.
For the LHON community, this evolving research landscape offers a clearer direction: broader genomic testing, stronger evidence for interpreting rare findings, and therapies designed around both individual genetic causes and common disease pathways. As molecular technologies continue to advance, the definition of LHON may become more genetically detailed—and the opportunity for individualized care may grow with it.