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Year : 2023  |  Volume : 26  |  Issue : 1  |  Page : 80-81

Diagnosing leber's hereditary optic neuropathy requires documentation of a causative mtDNA variant

Department of Neurological, Neurology and Neurophysiology Center, Vienna, Austria

Date of Submission24-Oct-2022
Date of Acceptance05-Dec-2022
Date of Web Publication17-Jan-2023

Correspondence Address:
Josef Finsterer
Postfach 20, 1180 Vienna
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.aian_863_22

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How to cite this article:
Finsterer J. Diagnosing leber's hereditary optic neuropathy requires documentation of a causative mtDNA variant. Ann Indian Acad Neurol 2023;26:80-1

How to cite this URL:
Finsterer J. Diagnosing leber's hereditary optic neuropathy requires documentation of a causative mtDNA variant. Ann Indian Acad Neurol [serial online] 2023 [cited 2023 Feb 1];26:80-1. Available from:

Letter to the Editor

With interest, we read the article by Wilson et al.[1] about a retrospective cross-sectional study on the clinical profile of 73 Indian patients with Leber's hereditary optic neuropathy (LHON) Â primary LHON mutation was detected in 23 patients but the remaining 50 patients did not carry one of the primary LHON mutations.[1] It was concluded that clinical profiles of mutation-positive and mutation-negative LHON patients did not differ.[1] We have the following comments and concerns.

A shortcoming of the study is that heteroplasmy rates of the causative mtDNA variants were not provided. Although most LHON variants occur in the homoplasmic state, individual patients or families may carry a LHON mutation in the heteroplasmic constellation.[2] Therefore, knowing the heteroplasmy rates is crucial not only for assessing the phenotype, course and outcome of the disease but also for genetic counselling.[2]

A further shortcoming is that first degree relatives, particularly, the mothers were not investigated systematically neither clinically nor genetically. Knowing the clinical and genetic status of first degree relatives is essential to assess whether the causative variants in the 23 index patients were inherited or occurred sporadically. Clinically unaffected females may carry a primary LHON mutation and may transmit it to their offspring.

A further shortcoming of the study is that nothing is reported about the treatment of the included patients. We should know how many received idebenone, other antioxidants, and in which dosage and for how long. Did any of the patients undergo gene therapy?

We disagree with the statement in the introduction that 'limited literature is available on the natural profile of LHON'.[1] On the contrary, there are ample publications about the clinical presentation, pathophysiology, diagnosis, treatment, outcome and the genetic background of LHON. When searching PubMed for the term 'Leber's hereditary optic neuropathy' more than 1800 hits can be achieved.

Because LHON mutations not only manifest with pure LHON but also with LHON plus,[3] it is crucial to prospectively examine all LHON patients for mild or subclinical involvement of organs other than the eyes. Of particular interest are the brain, heart, and skeletal muscles. We should know how many of the included patients had LHON plus and required symptomatic treatment of extra-ocular involvement.

There are a number of LHON patients in whom spontaneous regression of the visual impairment occurred.[4] We should know how many of the included patients had spontaneous recovery of visual disturbance.

Overall, the study carries obvious limitations that require re-evaluation and discussion. Clarifying these weaknesses would strengthen the conclusions and could improve the study. LHON patients require comprehensive genetic work-up to detect the underlying causative variant, they require treatment with idebenone, they should be systematically investigated for LHON plus, and their first degree relatives, particularly their mothers, should be systematically screened for clinical or genetic affection.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Wilson V, Kaur P, Singh S, Ramachandran RP, Jyothi V, Mahesh KV, et al. Clinical profile of patients with leber hereditary optic neuropathy (LHON): An ambispective study of North Indian cohorts. Ann Indian Acad Neurol 2022;25:65-9.  Back to cited text no. 1
  [Full text]  
Yu-Wai-Man P, Chinnery PF. Leber hereditary optic neuropathy. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al. editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2022. [Updated 2021 Mar 11].  Back to cited text no. 2
Nikoskelainen EK, Marttila RJ, Huoponen K, Juvonen V, Lamminen T, Sonninen P, et al. Leber's “plus”: Neurological abnormalities in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 1995;59:160-4.  Back to cited text no. 3
Liutkeviciene R, Sidaraite A, Kuliaviene L, Glebauskiene B, Jurkute N, Aluzaite-Baranauskiene L, et al. A typical case presentation with spontaneous visual recovery in patient diagnosed with leber hereditary optic neuropathy due to rare point mutation in MT-ND4 Gene (m. 11253T>C) and literature review. Medicina (Kaunas) 2021;57:202.  Back to cited text no. 4


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