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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Medical Genetics

Diagnosis, Genetics & Understanding Your Tests

At a Glance

Leber Hereditary Optic Neuropathy (LHON) is primarily diagnosed using targeted genetic testing for mitochondrial DNA mutations and OCT imaging to evaluate retina damage. Because LHON is inherited exclusively from the mother, men cannot pass the genetic mutation to their children.

Reaching a diagnosis for Leber Hereditary Optic Neuropathy (LHON) involves putting together several pieces of a puzzle. Doctors primarily use two high-tech tools: Genetic Testing to find the underlying cause and OCT Imaging to see the physical impact on your eyes.

Genetic Testing: Finding the Mutation

LHON is caused by mutations in your mitochondrial DNA. Since mitochondria have their own separate set of genetic instructions, standard genetic tests may miss them.

  • The “Big Three” Mutations: About 90% of people with LHON have one of three specific “point mutations” [1]:
    • m.11778G>A: The most common mutation, found in more than 50% of cases worldwide [2][3].
    • m.3460G>A: The second most common mutation.
    • m.14484T>C: This mutation is sometimes associated with a slightly higher chance of partial vision recovery [4].
  • What if the test is negative? If you have the classic symptoms of LHON but testing for the “Big Three” comes back negative, you are not necessarily in the clear. Your doctor should order Next-Generation Sequencing (NGS) of the full mitochondrial genome [1][5]. This more detailed “spell-check” can find rare mutations that the basic test misses [6].

The Role of Maternal Inheritance

Because LHON is a mitochondrial disease, its inheritance pattern is unique. We inherit all of our mitochondria from our mothers. Therefore, LHON is passed down strictly through the maternal line [1].

  • If you are a male with LHON, you cannot pass the mutation to your children.
  • If you are a female with the mutation, you will pass the mutation to all of your children (though not all carriers will develop vision loss).
    Because of this pattern, it is strongly recommended that you and your family seek genetic counseling to understand the risk to siblings and future generations [1].

OCT: Seeing the Unseen

Optical Coherence Tomography (OCT) is a non-invasive imaging test that uses light waves to take cross-section pictures of your retina. It allows doctors to see the health of your Retinal Nerve Fiber Layer (RNFL) and the Ganglion Cell Complex (GCC) [7].

In LHON, these layers change in a very specific way depending on the stage of the disease:

Stage OCT Finding: RNFL (Nerve Fibers) OCT Finding: GCC/GCIPL (Cell Bodies)
Acute (<6 months) Thickening/Swelling: The fibers appear “puffy” as they struggle to process energy [7]. Early Thinning: Interestingly, the cell bodies often start thinning before the fibers do, especially in the “nasal” area near the nose [8][9].
Chronic (>12 months) Atrophy (Thinning): The swelling disappears, and the layer becomes significantly thinner as the fibers are lost [10]. Significant Thinning: The cell layer continues to thin, which correlates with the permanent loss of central vision [10][11].

Your Diagnostic Completeness Checklist

Because LHON can look like other conditions (like Multiple Sclerosis or tumors), it is vital to ensure your diagnostic workup is complete. Use this checklist to guide your conversations with your care team:

  • [ ] MRI of the Brain and Orbits: This is essential to rule out compressive lesions (tumors) or inflammatory diseases like MS or NMOSD [12][13].
  • [ ] Genetic Testing for the “Big Three”: These are m.11778, m.3460, and m.14484 [1].
  • [ ] Full Mitochondrial Genome Sequencing: Only required if the “Big Three” are negative but clinical suspicion remains high [5].
  • [ ] Baseline OCT Scan: To measure the thickness of your RNFL and GCC for future comparison [7].
  • [ ] Baseline EKG: To screen for minor electrical issues in the heart (like pre-excitation syndrome) that can sometimes accompany LHON [14].
  • [ ] Neurology/Ophthalmology Consultation: To ensure that both the eye and the nervous system have been thoroughly evaluated [15][16].

Return to Home Page

Common questions in this guide

What are the most common genetic mutations that cause LHON?
About 90% of people with LHON have one of three specific mitochondrial DNA mutations, known as the 'Big Three': m.11778G>A, m.3460G>A, or m.14484T>C. These are the first mutations your doctor will test for.
Can men pass LHON down to their children?
No. LHON is caused by a mutation in mitochondrial DNA, which is inherited strictly from the mother. Therefore, males with LHON or the LHON mutation cannot pass it on to their children.
What if my genetic test for LHON is negative but I still have symptoms?
If your test for the 'Big Three' mutations comes back negative, your doctor should order a more comprehensive test called Next-Generation Sequencing (NGS). This test checks your entire mitochondrial genome for rarer mutations that standard tests miss.
What does an OCT scan show for LHON?
An OCT scan takes detailed, cross-sectional pictures of your retina. It allows your eye doctor to measure the thickness of your nerve fibers and cell bodies, which typically swell in the early stages of LHON and thin out as the disease progresses.
Why do I need an MRI if my vision is the only problem?
An MRI of your brain and eye sockets is essential to rule out other conditions that can mimic LHON vision loss. It helps confirm that your symptoms aren't being caused by tumors or inflammatory diseases like multiple sclerosis.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which of the three primary mutations did my genetic test identify, or was a rarer variant found?
  2. 2.Based on my OCT scan, do I have nasal-predominant thinning of the ganglion cell layer?
  3. 3.If my targeted genetic test is negative, can we proceed to full mitochondrial genome sequencing (NGS)?
  4. 4.Does my MRI show any signs of compression or inflammation that would point to a different diagnosis?
  5. 5.Can you refer me to a genetic counselor to discuss the implications of maternal inheritance for my family?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (16)
  1. 1

    Mitochondrial 13513G>A Mutation With Low Mutant Load Presenting as Isolated Leber's Hereditary Optic Neuropathy Assessed by Next Generation Sequencing.

    Sun CB, Bai HX, Xu DN, et al.

    Frontiers in neurology 2021; (12()):601307 doi:10.3389/fneur.2021.601307.

    PMID: 33746872
  2. 2

    Leber's Hereditary Optic Neuropathy with Mitochondrial DNA Mutation G11778A: A Systematic Literature Review and Meta-Analysis.

    Yuan J, Zhao J, Ye C, et al.

    BioMed research international 2023; (2023()):1107866 doi:10.1155/2023/1107866.

    PMID: 36743514
  3. 3

    The first genetically authenticated case of Leber hereditary optic neuropathy in Sri Lanka: a case report and review of the literature.

    Gunawardena K, Dissanayake VHW, Chang T

    Journal of medical case reports 2023; (17(1)):34 doi:10.1186/s13256-023-03763-x.

    PMID: 36737829
  4. 4

    International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy.

    Carelli V, Carbonelli M, de Coo IF, et al.

    Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society 2017; (37(4)):371-381 doi:10.1097/WNO.0000000000000570.

    PMID: 28991104
  5. 5

    Whole mitochondrial genome sequencing in individuals with Leber hereditary optic neuropathy negative for the common pathogenic mitochondrial DNA variants.

    Srilekha S, Ambika S, Hemavathy N, et al.

    Frontiers in neurology 2025; (16()):1584748 doi:10.3389/fneur.2025.1584748.

    PMID: 40969215
  6. 6

    Mitochondrial Genetic Heterogeneity in Leber's Hereditary Optic Neuropathy: Original Study with Meta-Analysis.

    Jha RK, Dawar C, Hasan Q, et al.

    Genes 2021; (12(9)) doi:10.3390/genes12091300.

    PMID: 34573281
  7. 7

    Leber's hereditary optic neuropathy: Update on current diagnosis and treatment.

    Esmaeil A, Ali A, Behbehani R

    Frontiers in ophthalmology 2022; (2()):1077395 doi:10.3389/fopht.2022.1077395.

    PMID: 38983564
  8. 8

    Nasal-Predominant Ganglion Cell-Inner Plexiform Layer Thinning Distinguishes Early-Stage Leber Hereditary Optic Neuropathy From Acute Optic Neuritis.

    Takai Y, Yamagami A, Inoue K, et al.

    Clinical & experimental ophthalmology 2026; doi:10.1111/ceo.70130.

    PMID: 42140845
  9. 9

    Initial Macular Ganglion Cell Changes During Conversion of Leber Hereditary Optic Neuropathy.

    Hedges TR, Dombrovsky D, Onwuka O, et al.

    Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society 2026; (46(2)):183-187 doi:10.1097/WNO.0000000000002384.

    PMID: 40797292
  10. 10

    Variation in retinal nerve fiber layer thickness at different stages of Leber's hereditary optic neuropathy in patients with the ND4 G11778A mutation.

    Tian Z, Li X, Zheng W, et al.

    Seminars in ophthalmology 2022; (37(4)):496-501 doi:10.1080/08820538.2021.1986078.

    PMID: 34702118
  11. 11

    Ganglion Cell Complex Thickness and Visual Function in Chronic Leber Hereditary Optic Neuropathy.

    Hedström J, Nilsson M, Engvall M, et al.

    Investigative ophthalmology & visual science 2024; (65(12)):4 doi:10.1167/iovs.65.12.4.

    PMID: 39365263
  12. 12

    [Brain magnetic resonance imaging features in Leber's hereditary optic neuropathy].

    Murakhovskaya YK, Sheremet NL, Eliseeva DD, Bryukhov VV

    Vestnik oftalmologii 2024; (140(5)):146-153 doi:10.17116/oftalma2024140051146.

    PMID: 39569788
  13. 13

    [Leber hereditary optic neuropathy: differential diagnosis].

    Orssaud C

    Journal francais d'ophtalmologie 2022; (45(8S1)):S9-S16 doi:10.1016/S0181-5512(22)00445-4.

    PMID: 36529477
  14. 14

    Cardiac Disorders in Patients With Leber Hereditary Optic Neuropathy.

    Orssaud C

    Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society 2018; (38(4)):466-469 doi:10.1097/WNO.0000000000000623.

    PMID: 29384800
  15. 15

    [Leber's hereditary optic neuropathy].

    Takai Y, Yamagami A, Ishikawa H

    Rinsho shinkeigaku = Clinical neurology 2024; (64(5)):326-332 doi:10.5692/clinicalneurol.cn-001924.

    PMID: 38644210
  16. 16

    Recognizing Leber's Hereditary Optic Neuropathy to avoid delayed diagnosis and misdiagnosis.

    La Morgia C, Cascavilla ML, De Negri AM, et al.

    Frontiers in neurology 2024; (15()):1466275 doi:10.3389/fneur.2024.1466275.

    PMID: 39364415

This page explains LHON diagnostic tests and genetics for educational purposes only. Always consult your ophthalmologist or genetic counselor to accurately interpret your specific test results.

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