Author: Katharina Valentin (Austria)
Co-authors: Haleh Aminfar, Thomas Georgi, Jutta Berglöff, Mona Schneider
Leber hereditary optic neuropathy (LHON) is a mitochondrial inherited disease causing a degeneration of retinal ganglion cells and a severe bilateral reduction of visual acuity. For 90% of LHON cases three primary mtDNA (m.G3460A, m.G11778A und m.T14484C) mutations are responsible. Besides primary mutations there exists multiple polymorphisms of the mitochondrial genome leading to the phenotypic development of LHON. Currently, 37 point mutations that may cause LHON have been described. Secondary mutations can be found together with primary mutations in LHON patients at a higher frequency than in normal controls. Without primary mutations, they have a lower risk to result in LHON. If a secondary mutation occurs together with a primary or other secondary mutation, it may influence the expression of LHON or increase the penetrance. In a randomized placebo-controlled trial with patients with Leber´s hereditary optic atrophy, Klopstock et al. showed that patients may benefit from the Raxone® treatment. On basis of this trial and an early-access-program of the company Santhera Pharmaceuticals GmbH, the European Medicines Agency has approved idebenone as Raxone® for the treatment of LHON.
Since 2013 at the Department of Ophthamology of the Medical University of Graz the diagnosis LHON was confirmed molecular genetically in 14 patients. In six patients the secondary homoplasmic mutation m.T3394C was found. Five of them were treated with a standardized dose of idebenone (900mg per day). We present our results of this five patients in a retrospective case series.
In these five patients the clinical progress was evaluated through following examinations: best-corrected visual acuity (BCVA), colour vision measured with Ishihara plates, contrast vision using Lea Hyvärinen charts, retinal nerve fibre layer measured with Heidelberg Spectral OCT and/or OCT-A, visual field using 30-2 program of Octopus perimetry (Haag-Streit Germany GmbH) and/or Goldmann perimetry with three isopteres with stimulus size III/4 (outer perimeter), II/2 (scotoma detection) and I/2 (central isopter). At the baseline examination clinical history, including environmental factors like constant consume of nicotine and alcohol was assessed. Baseline (BL) was defined as the time of initiation of idebenone treatment.
Two male und three female patients with m.T3394C were included in this analysis. Mean age of onset was 38.8 years (range 23-66 years). Treatment duration varied from 2 to 29 months. Patient (P) 2 and P4 had a history of daily alcohol and nicotine consumption. In P2 multiple sclerosis was diagnosed during follow-up. No systemic side effects were observed. We defined stabilization of visual acuity as change up to +/- 0.1 logMAR since BL and deterioration/improvement as change more than +/- 0.1 logMAR. In our case series we have observed a stabilization of visual acuity in both eyes of P1, P2, P4, P5 and in the right eye of P3 from BL until the end of treatment and/or observation period. The left eye of P3 decreased by to lines. In our case series idebenone treatment was also associated with stabilization or improvement of Goldmann or Octopus perimetry in P1, P3, P4 and P5.
Until now the point mutation m.T3394C was found in haplogroups in the asian region. Currently, there exists only one report about the appearance of m.T3394C in Finland. Our case series is the second report describing the appearance of m.T3394C in Europe and the first to describe the clinical course of LHON caused by this mutation only. We observed a higher incidence of the secondary mutation m.T3394C diagnosed since 2013 in our Department than reported in previous publications. Regional distinctions, but also environmental factors or noxae such as nicotine or alcohol are main factors leading to the phenotype of LHON. This could play a role in our case series. Other factors that influence the penetrance of LHON are specific mtDNA haplogroups and nuclear modifier genes. Patients treated with idebenone showed a stable BCVA.
Reimbursement for travel provided by Santhera Pharmaceuticals Holding AG, no other funding applies to this publication.