In this section:

Importance of early diagnosis
Tests to confirm LHON
Molecular genetic testing
Diagnostic Pathway
Referring your patient
Worried person

Importance of early diagnosis

Leber’s hereditary optic neuropathy (LHON) is a rare, complex, and life-altering disease.Footnote1 The visual prognosis in LHON is generally poor.Footnote1 The majority of patients will end up legally blind with a visual acuity of 20/200 or worse, which results in a significant detrimental impact on their quality of life.Footnote1,Footnote2

Diagnosis is often delayed because of the lack of disease awareness and the inability to differentiate LHON from other conditions with similar characteristics, especially in the absence of family history.Footnote3

Patients are taking far too long to be diagnosed

Tests to confirm LHON

LHON is often mistaken for conditions such as brain tumour, multiple sclerosis, and optic neuropathies because of nature of the LHON symptoms that develop in one eye.Footnote4,Footnote5,Footnote6,Footnote7

In addition to symptoms such as visual loss, a patient with LHON can often provide a history of visual loss in family members along the maternal line.Footnote8 Some of the tests that help confirm LHON are:

  • In LHON, there is an absence of dye leakage at the optic disc on fluorescein angiography. In the acute phase of the disease, an OCT reveals thickening of the retinal nerve fibre layer (RNFL) around the optic nerve and on subsequent examinations, in chronic phases, it reveals thinning of the RNFL.

  • This is an emerging non-invasive technique for evaluating ocular microvasculature. With this method, the peripapillary retinal and vascular circulation can be evaluated three-dimensionally. Evaluation of vascular changes in LHON using OCTA may help us understand the pathophysiology of the disease, assess disease progression, and monitor the efficacy of treatment. OCTa is used to detect significant peripapillary microvascular changes over the disease course of LHON. In addition to the peripapillary region, OCTa studies have also provided evidence of pathology associated with the macular vasculature in different disease stages of LHON.

    • An examination of the optic disc
    • An electroretinogram (ERG) to measure the electrical responses in the retina
    • A visual field test to characterise the area of vision loss (scotoma)
    • An MRI or CT scan to rule out optic nerve inflammation or other causes of optic neuritis or CNS lesions
    • A lumbar puncture may also be performed if a central nervous system infection is suspected

  • A mitochondrial DNA test (mtDNA test) traces a person’s mother-line using the DNA in their mitochondria.Footnote8,Footnote12 mtDNA is passed down by the mother unchanged to all her children. Both men and women can therefore take an mtDNA test.Footnote8,Footnote12

    LHON can usually be confirmed with an mtDNA blood test to reveal one of the three common mutations.Footnote8 Even if this test is negative, LHON may still be considered because approximately 5% of cases are not due to the three common LHON mutations.Footnote8,Footnote13 A complete mtDNA sequence analysis may be recommended if the clinical diagnosis of LHON remains a strong indication or if there’s evidence of maternal transmission of blindness.Footnote8

    DNA testing of primary LHON mutations is recommended in atypical presentations or in the absence of a clear family history of LHON.Footnote13

  • Recently, an autosomal recessive mode of inheritance for LHON was established when mutations in a nuclear encoded gene, DNAJC30, were identified.Footnote14 Given this, LHON can now be subdivided as mtLHON and arLHON, due to the important impact on genetic counselling.Footnote14 Clinical diagnosis for arLHON can be performed through patient-derived fibroblast cell lines obtained by skin biopsy.Footnote14

Molecular genetic testing

Molecular genetic testing approaches can include gene-targeted testing methods such as: targeted mtDNA analysis for pathogenic variants, multigene panel, and complete mtDNA sequencing.Footnote8

Targeted mtDNA analysisFootnote8

The first step is to perform a targeted analysis for the three common mtDNA pathogenic variants observed in ~90% of individuals with LHON.

Mitochondrial disease multigene panelFootnote8

This includes the mitochondrial genes that encode subunits of NADH dehydrogenase (MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6) known to cause LHON, and is most likely to identify the genetic cause of the condition at the most reasonable cost.

Complete mtDNA sequencingFootnote8

This is recommended if targeted testing and/or a multigene panel did not identify a pathogenic variant while clinical suspicion of LHON remains high.

Diagnostic pathway

Without a known family history of LHON the diagnosis usually requires a neuro-ophthalmological evaluation and blood testing for mtDNA assessment.Footnote8,Footnote15 It is essential to exclude other possible causes of vision loss and other system abnormalities.Footnote15

Due to its rare nature, diagnosis of LHON is a long process. It often takes weeks or months from the onset of symptoms to receiving a confirmed diagnosis.Footnote15

LHON patients are commonly misdiagnosed with optic neuritis and multiple sclerosis before they are properly diagnosedFootnote15

*The evolution of LHON in the first weeks/months is described canonically as
dynamic/subacute, depending on how rapidly the loss of visual acuity evolves.Footnote15

Referring your patient

Patients must get confirmation of an LHON diagnosis sooner to get timely help and management of their condition.Footnote15

If you encounter patients with sudden, unexplained and painless vision loss, refer them to any of the following without further delay.Footnote8,Footnote15

  • An ophthalmologist who understands LHON
  • A neuro-ophthalmologist
  • A specialist LHON clinic

    1. Theodorou-Kanakari A, et al. Adv Ther. 2018;35:1510–18. 

    2. Kirkman MA, et al. IOVS. 2009;50:3112–15. 

    3. Carelli V, et al. Hum Mol Genet. 2017:26;139–50.

    4. Meyersen C, et al. Clin Ophthal. 2015;9:1165–76. 

    5. Yu-Wai-Man P, et al. Prog Retin Eye Res. 2011 81–114.

    6. Fraser JA, et al. Surv Ophthalmol. 2010; 55:299–334. 

    7. Pfeffer G, et al. Neurology. 2013:81:2073–81.

    8. Yu-Wai-Man P and Chinnery PF. Leber Hereditary Optic Neuropathy. 2000.

    9. Sadun A, et al. Curr Treat Options Neurol. 2011:109–17.

    10. Kızıltunç PB, et al. Turk J Ophthalmol. 2020;50:313–16.

    11. Asanad S, et al. Ther Adv Ophthalmol. 2020, Vol. 12: 1–15.

    12. International Society of Genetic Genealogy Wiki. Available at: https://isogg.org/wiki/Mitochondrial_DNA_tests. Accessed (August 2021)

    13. Yu-Wai-Man P, et al. J Med Genet. 2002;39:162–69.

    14. Stenton SL, et al. J Clin Invest. 2021 Mar 15;131:e138267.

    15. Carelli V, et al. Eur Ophthalmic Rev. 2019;13(Suppl 2).

Disclaimer: The information on this website is intended only to provide knowledge of Leber’s hereditary optic neuropathy (LHON). This information should not be used in place of advice from your GP or other healthcare professional. If in doubt, please contact your doctor for advice. This website has been produced by Chiesi Pharmaceuticals. The website has been developed in accordance with industry and legal standards to provide information for healthcare professionals and the general public about LHON. Chiesi Pharmaceuticals makes every reasonable effort to include accurate and current information. However, the information provided in this website is not exhaustive.

Patient & Caregiver: In case you need to report an adverse drug reaction, please refer to your physician, asking him to fill in and submit the relevant case report to the concerned Health Authority, according to the Pharmacovigilance requirements in force in your Country. Nevertheless, please be kindly reminded that each patient can report any such cases directly to the national reporting system.

Healthcare Professional: In case you want to report an adverse drug reaction you become aware of, please report it to your Health Authority according to the requirements set by the pharmacovigilance legislation.