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LHON plus due to the variant m.3460G>A requires extensive investigation and close monitoring

Open AccessPublished:November 07, 2022DOI:https://doi.org/10.1016/j.cjco.2022.10.006

      Key words

      We read with interest the article by Hey et al. about two patients with Leber’s hereditary optic neuropathy (LHON) who also presented with hypertrophic cardiomyopathy (hCMP) [
      • Hey T.M.
      • Nielsen S.K.
      • Eriksen U.
      • Hansen F.
      • Mogensen J.
      Leber's Hereditary Optic Neuropathy and Hypertrophic Cardiomyopathy.
      ]. The underlying genetic defect was identified as the variant m.3460G>A in ND1 in both the index patient and his sister, who had a similar phenotype but no ophthalmologic impairment [
      • Hey T.M.
      • Nielsen S.K.
      • Eriksen U.
      • Hansen F.
      • Mogensen J.
      Leber's Hereditary Optic Neuropathy and Hypertrophic Cardiomyopathy.
      ]. The study is appealing but raises concerns that should be discussed.
      A limitation of the study is that heteroplasmy rates of the m.3460G>A variant were not reported [
      • Hey T.M.
      • Nielsen S.K.
      • Eriksen U.
      • Hansen F.
      • Mogensen J.
      Leber's Hereditary Optic Neuropathy and Hypertrophic Cardiomyopathy.
      ]. Knowledge of heteroplasmy rates is crucial as the amount of mutated mtDNA in a tissue can strongly determine the phenotypic expression of the variant [
      • Yang M.
      • Xu L.
      • Xu C.
      • Cui Y.
      • Jiang S.
      • Dong J.
      • Liao L.
      The Mutations and Clinical Variability in Maternally Inherited Diabetes and Deafness: An Analysis of 161 Patients.
      ]. It would be also helpful to know the patient’s haplotype and the mtDNA copy number as these factors can contribute to phenotypic expression. In this respect, sequencing of the entire mtDNA is missing.
      The discussion about LHON plus is also missing. Not only is LHON a mono-system disease affecting retinal ganglion cells, but it is increasingly recognised that LHON can affect systems/organs other than the eyes (LHON plus) [

      Lackey E, Lefland A, Eckstein C. Leber's Hereditary Optic Neuropathy Plus Causing Recurrent Myelopathy due to an MT-DN1 Mutation at G3635A. Case Rep Neurol Med. 2022 Jan 11;2022:1628892. doi: 10.1155/2022/1628892.

      ]. Organs other than the eyes that are most commonly affected by LHON plus are the myocardium and brain [
      • Finsterer J.
      • Stollberger C.
      • Gatterer E.
      Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G>A.
      ]. Cerebral imaging can show multiple sclerosis-like features, also known as Harding’s disease. We should know if cerebral MRI showed any cerebral abnormalities in addition to optic nerve demyelination.
      There is no discussion of the association between LHON due to the variant m.3460G>A and left ventricular hypertrabeculation (LVHT), also known as non-compaction [
      • Finsterer J.
      • Stollberger C.
      • Gatterer E.
      Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G>A.
      ]. In a previous report of two brothers carrying this variant, both presented with hCMP plus LVHT [
      • Finsterer J.
      • Stollberger C.
      • Gatterer E.
      Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G>A.
      ]. One of them died of sudden cardiac death (SCD) [
      • Finsterer J.
      • Stollberger C.
      • Gatterer E.
      Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G>A.
      ]. Similar to the index patient, these two brothers had Wolff-Parkinson White syndrome [
      • Finsterer J.
      • Stollberger C.
      • Gatterer E.
      Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G>A.
      ].
      Since patients with hCMP tend to develop ventricular arrhythmias, it should be discussed whether implantation of a reveal recorder would be useful in order to assess over a longer period of time whether there is an indication for the implantation of an implantable cardioverter defibrillator (ICD). Both, supra-ventricular and ventricular arrhythmias can be complicated by syncope or SCD, so we should know if the index patient’s history or family history was positive for syncope or SCD.
      Overall, the interesting study has limitations that challenge the results and their interpretation. Patients with LHON plus require comprehensive evaluation for subclinical/clinical multisystem disease and appropriate protective measures in the case of cardiac compromise.

      References

        • Hey T.M.
        • Nielsen S.K.
        • Eriksen U.
        • Hansen F.
        • Mogensen J.
        Leber's Hereditary Optic Neuropathy and Hypertrophic Cardiomyopathy.
        CJC Open. 2022 Jun 17; 4: 813-815https://doi.org/10.1016/j.cjco.2022.06.005
        • Yang M.
        • Xu L.
        • Xu C.
        • Cui Y.
        • Jiang S.
        • Dong J.
        • Liao L.
        The Mutations and Clinical Variability in Maternally Inherited Diabetes and Deafness: An Analysis of 161 Patients.
        Front Endocrinol (Lausanne). 2021 Nov 25; 12728043https://doi.org/10.3389/fendo.2021.728043
      1. Lackey E, Lefland A, Eckstein C. Leber's Hereditary Optic Neuropathy Plus Causing Recurrent Myelopathy due to an MT-DN1 Mutation at G3635A. Case Rep Neurol Med. 2022 Jan 11;2022:1628892. doi: 10.1155/2022/1628892.

        • Finsterer J.
        • Stollberger C.
        • Gatterer E.
        Wolff-Parkinson-White syndrome and noncompaction in Leber's hereditary optic neuropathy due to the variant m.3460G>A.
        J Int Med Res. 2018 May; 46: 2054-2060https://doi.org/10.1177/0300060518765846

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