Natural history of patients with Leber hereditary optic neuropathy—results from the REALITY study

Abstract

Background/objectives REALITY is an international observational retrospective registry of LHON patients evaluating the visual course and outcome in Leber hereditary optic neuropathy (LHON). Subjects/methods Demographics and visual function data were collected from medical charts of LHON patients with visual loss. The study was conducted in 11 study centres in the United States of America and Europe. The collection period extended from the presymptomatic stage to at least more than one year after onset of vision loss (chronic stage). A Locally Weighted Scatterplot Smoothing (LOWESS) local regression model was used to analyse the evolution of best-corrected visual acuity (BCVA) over time. Results 44 LHON patients were included; 27 (61%) carried the m.11778G>A ND4 mutation, 8 (18%) carried the m.3460G>A ND1 mutation, and 9 (20%) carried the m.14484T>C ND6 mutation. Fourteen (32%) patients were under 18 years old at onset of vision loss and 5 (11%) were below the age of 12. The average duration of follow-up was 32.5 months after onset of symptoms. At the last observed measure, mean BCVA was 1.46 LogMAR in ND4 patients, 1.52 LogMAR in ND1 patients, and 0.97 LogMAR in ND6 patients. The worst visual outcomes were reported in ND4 patients aged at least 15 years old at onset, with a mean BCVA of 1.55 LogMAR and no tendency for spontaneous recovery. The LOESS modelling curve depicted a severe and permanent deterioration of BCVA. Conclusions Amongst LHON patients with the three primary mtDNA mutations, adult patients with the m.11778G>A ND4 mutation had the worst visual outcomes, consistent with prior reports.

Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

“…However, these registries are usually limited in size owing to the rarity of the disease, thereby limiting the statistical power of such comparisons. In our own LHON registry study, REALITY, we included a total of 44 LHON patients, of whom only 23 met the inclusion criteria of REVERSE and RESCUE trials ( 18 ). In order to reach a sufficient sample size to enable a statistically meaningful comparison with treated patients, we complemented our natural history dataset with patient-level data identified through a systematic review of the literature.…”

“…Natural history patients (those not treated with lenadogene nolparvovec, although they could have been treated with idebenone), with age and LHON genotype adjusted to those of treated patients, were used as an external control for the analysis. To this end, we created a large database containing visual outcome data from 11 studies originating from two main sources: (i) the REALITY LHON registry (NCT03295071) (18) sponsored by GenSight Biologics and (ii) 10 published studies on LHON identified after a systematic review of the literature (3,(19)(20)(21)(22)(23)(24)(25)(26)(27). Studies were included in the database only if they reported individual (patient-and eye-level) visual acuity values along with documentation of the time after vision loss in cohorts of at least five MT-ND4 patients.…”

“…For the analyses, all visual acuity values (from treated and natural history patients) were converted to logarithm of the minimal angle of resolution (LogMAR) using standard formula for onchart eyes (28) and the following conventions for off-chart eyes: patients only able to count fingers or detect hand motion were assigned LogMAR values of +2.0 and +2.3, respectively, according to the Lange scale (29); light perception and no light perception visual acuities were assigned LogMAR values of +4.0 and +4.5, respectively, to align with the equivalence used in the lenadogene nolparvovec studies and the REALITY registry (14,15,18). All eyes were assigned a LogMAR value of 0 at 1 month before the onset of vision loss, in line with the normal visual acuity of LHON mutation carriers before expression of the disease as described in the literature (30,31) and pre-symptomatic data of lenadogene nolparvovec studies and REALITY registry.…”

Mitochondrial Retinopathies

“…A definitive cure for this and other mitochondrial diseases will probably come from gene therapy. The results obtained on other diseases, such as spinal-muscle atrophy [ 177 ] are very encouraging As compared to nuclear DNA, mitochondrial DNA gene therapy poses additional problems, including the fact that (i) mitochondria are surrounded by a double membrane, (ii) with the exception of non-syndromic LHON, primary mitochondrial diseases are often multisystemic, making it difficult to reach the high titres required to target a majority of cells in all the affected organs, (iii) mammalian mtDNA has no recombination systems, preventing the use of homologous recombination-based approaches, (iv) mitochondria cannot import nucleic acids, preventing the use of CRISPR/Cas9-based techniques, and (v) last-but-not-least, mtDNA is polyplasmic instead of the diploid or haploid organization of nuclear genes, which implies an extremely high number of genomes to be targeted in each cell to produce a tangible effect [ 87 ]. Nevertheless, the recent development of approaches to shift mtDNA heteroplasmy opened great therapeutic opportunities.…”

Using Noninvasive Electrophysiology to Determine Time Windows of Neuroprotection in Optic Neuropathies

“…During the period preceding the tipping point (critical period) [ 12 , 13 , 14 ] accumulating adverse factors eventually overwhelm homeostatic mechanisms and cause irreversible and progressive cell death. The duration of the critical period of transition can be of the order of years, as in glaucoma, [ 15 ] or months, as in Leber’s Hereditary Optic Neuropathy (LHON) [ 16 ], and its identification would provide a red flag of impending disease and an opportunity to consider neuroprotective treatment in a time window where altered conditions may be still capable of reversal. While the tipping point is a well-established intuitive concept ( Figure 1 ), its identification is challenging as phenotypic expression and molecular changes occurring during the critical period overlap with those of the normal condition, and homeostatic neuroplasticity mechanisms to maintain normal vision offset pathological alteration [ 17 ].…”