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Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G > A mutation in the MT-ND4 gene being the most common disease-causing mitochondrial DNA (mtDNA) variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G > A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary endpoint was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary endpoint). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (p < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (p < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G > A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections. [ABSTRACT FROM AUTHOR]

Hereditary optic neuropathies result from defects in the human genome, both nuclear and mitochondrial. The two main and most recognised phenotypes are dominant optic atrophy and Leber hereditary optic neuropathy. Advances in modern molecular diagnosis have expanded our knowledge of genotypes and phenotypes of inherited disorders that affect the optic nerve, either alone or in combination, with various forms of neurological and systemic degeneration. A unifying feature in the pathophysiology of these disorders appears to involve mitochondrial dysfunction, suggesting that the retinal ganglion cells and their axons are especially susceptible to perturbations in mitochondrial homoeostasis. As we better understand the pathogenesis behind these genetic diseases, aetiologically targeted therapies are emerging and entering into clinical trials, including treatments aimed at halting the cascade of neurodegeneration, replacing or editing the defective genes or their protein products, and potentially regenerating damaged optic nerves, as well as preventing generational disease transmission. [ABSTRACT FROM AUTHOR]

Leber hereditary optic neuropathy (LHON) is a devastating cause of blindness that predominantly affects young adult men. Over 90% of patients harbour one of three mitochondrial DNA point mutations, namely, m.3460G>A (MT‐ND1), m.11778G>A (MT‐ND4) and m.144484T>C (MT‐ND6). Idebenone is the only approved treatment for LHON. New evidence has refined the management guidelines for idebenone, in particular the duration of treatment and the therapeutic window of opportunity. Gene therapy using allotopic expression is an attractive strategy for LHON as it corrects the underlying mitochondrial DNA defect. Promising results have been obtained for the m.1178G>A (MT‐ND4) mutation for patients treated within 1 year of disease onset with an intravitreal injection of a modified adeno‐associated viral vector carrying the replacement gene. [ABSTRACT FROM AUTHOR]

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to progressive, bilateral vision loss. Childhood‐onset LHON has a relatively good prognosis, suggesting that age at onset influences disease progression and potential response to treatment. In LEROS, a Phase IV, open‐label interventional study (ClinicalTrials.gov NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment (IDE) were compared to those of a Natural History (NH) cohort. Methods: LEROS included patients aged ≥12 years with a disease onset ≤5 years prior. Data from 181 patients were compared to retrospective data from a NH cohort (N = 372), matched by time since symptom onset. Here, we compare the difference in least squares‐mean VA change, or delta VA, from baseline to Month 24 in treated eyes versus those in the NH cohort (a negative value favours IDE). Eyes were stratified by time since symptom onset at baseline: subacute/dynamic (≤1 year) and chronic (>1 year) phase, and by age at symptom onset (<18 years, ≥18 years). Results: In treated subacute/dynamic eyes from the <18 years group (n = 22 IDE), delta VA was +0.38 logMAR (p = 0.020) relative to the NH cohort (n = 22). In the chronic phase, delta VA was −0.08 logMAR (n = 16 IDE vs n = 37 NH eyes; p = 0.405). In subacute/dynamic eyes from the ≥18 years group, delta VA was −0.18 logMAR (n = 99 IDE vs n = 53 NH; p = 0.060). In the chronic phase, delta VA was −0.21 logMAR (n = 100 IDE vs n = 56 NH; p < 0.001). Conclusions: In eyes of patients ≥18 years at symptom onset, VA improvement at Month 24 was greater in idebenone‐treated versus untreated NH eyes. Treatment benefit was particularly apparent in the chronic phase, corresponding to >10 additional letters on the ETDRS chart. In subacute/dynamic eyes, spontaneous VA recovery was unexpectedly high in the NH cohort. In chronic eyes from patients <18 years, a non‐significant trend favouring idebenone was observed. [ABSTRACT FROM AUTHOR]

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease resulting in severe vision loss. The causative mitochondrial DNA (mtDNA) mutation impacts disease progression and prognosis. In LEROS, a Phase IV, open‐label interventional study (Clinicaltrials.gov NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment (IDE) were compared to those of an external Natural History (NH) cohort. Here, we compare VA change from baseline to Month 24 according to primary mtDNA mutation and disease stage. Methods: Eyes of patients with LHON and either a m.G11778A, m.T14484C or m.G3460A, mtDNA mutation were stratified by time since onset: subacute/dynamic (≤1 year) and chronic (>1 but ≤5 years). Data from 181 patients were compared to retrospective data from the NH cohort (N = 372), matched by time since symptom onset at baseline. We compare the difference in least squares‐mean VA change, or delta VA, from baseline to Month 24 in IDE versus NH eyes (a negative value favours IDE). Results: In treated subacute/dynamic m.G11778A eyes (n = 60 IDE), delta VA was −0.32 logMAR (p = 0.002) versus the NH cohort (n = 47). In chronic m.G11778A eyes, delta VA was −0.11 logMAR (n = 82 IDE vs n = 51 NH; p = 0.043). In subacute/dynamic m.T14484C eyes, delta VA was +0.20 logMAR (n = 35 IDE vs n = 10 NH; p = 0.285). In chronic m.T14484C eyes, delta VA was −0.52 logMAR (n = 11 IDE vs n = 18 NH; p < 0.001). In subacute/dynamic m.G3460A eyes, delta VA was +0.53 logMAR (n = 26 IDE vs n = 18 NH; p = 0.001). In chronic m.G3460A eyes, delta VA was −0.13 logMAR (n = 23 IDE vs n = 24 NH; p = 0.162). Conclusions: Idebenone improved VA in a large proportion of eyes; this benefit manifested to varying degrees depending on disease stage and mtDNA mutation. m.G11778A eyes saw a consistent benefit regardless of disease stage. m.T14484C and m.G3460A results should be interpreted with caution in some cases due to the relatively low number of eyes; further study is warranted. [ABSTRACT FROM AUTHOR]

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a mitochondrial disease resulting in bilateral vision loss. Childhood‐onset LHON has a relatively good prognosis, suggesting that age influences disease progression and, potentially, treatment response. In LEROS, a Phase IV, open‐label interventional study (Clinicaltrials.gov NCT02774005), visual acuity (VA) outcomes following 24 months of idebenone treatment (IDE) were compared to those of an external Natural History (NH) cohort. Methods: LEROS included patients aged ≥12 years with a disease onset ≤5 years prior. Data from 181 patients were compared to retrospective data from a NH cohort (N = 372), matched by time since symptom onset. Here, we compare clinically relevant recovery (CRR) and clinically relevant worsening (CRW) from baseline to Month 24 in IDE eyes versus NH eyes, stratified by time since symptom onset at baseline: subacute/dynamic (≤1 year) and chronic (>1 year) phase, and by age at symptom onset (<18 years, ≥18 years). Results: In patients aged <18 years, VA outcomes were observed, in IDE versus NH eyes, as follows: CRR: subacute/dynamic 31.8% (7/22) vs 59.1% (13/22), p = 0.048; chronic 31.3% (5/16) vs 21.6% (8/37), p = 0.241; CRW: subacute/dynamic 26.3% (5/19) vs 21.4% (3/14), p = 0.558; chronic 8.3% (1/12) vs 19.2% (5/26), p = 0.078. In patients aged ≥18 years, the following VA outcomes were observed: CRR: subacute/dynamic 51.5% (51/99) vs 22.6% (12/53), p = 0.001; chronic 32.0% (32/100) vs 12.5% (7/56), p < 0.001; CRW: subacute/dynamic 25.7% (19/74) vs 62.9% (22/35), p < 0.001; chronic 1.8% (1/56) vs 20.6% (7/34), p = 0.003. Conclusions: Idebenone improved the ratio of positive to negative VA outcomes. Treatment benefit was particularly pronounced in patients ≥18 years at onset, with only non‐significant positive trends observed in chronic patients <18 years. Results in subacute/dynamic patients aged <18 years were limited by an unusually high recovery rate in the NH cohort, warranting further study. [ABSTRACT FROM AUTHOR]

Inherited optic neuropathies affect around 1 in 10,000 people in England; in these conditions, vision is lost as retinal ganglion cells lose function or die (usually due to pathological variants in genes concerned with mitochondrial function). Emerging gene therapies for these conditions have emphasised the importance of early and expedient molecular diagnoses, particularly in the paediatric population. Here, we report our real-world clinical experience of such a population, exploring which children presented with the condition, how they were investigated and the time taken for a molecular diagnosis to be reached. A retrospective case-note review of paediatric inherited optic neuropathy patients (0–16 years) in the tertiary neuro-ophthalmology service at Moorfields Eye Hospital between 2016 and 2020 identified 19 patients. Their mean age was 9.3 ± 4.6 (mean ± SD) years at presentation; 68% were male, and 32% were female; and 26% had comorbidities, with diversity of ethnicity. Most patients had undergone genetic testing (95% (n = 18)), of whom 43% (n = 8) received a molecular diagnosis. On average, this took 54.8 ± 19.5 weeks from presentation. A cerebral MRI was performed in 70% (n = 14) and blood testing in 75% (n = 15) of patients as part of their workup. Continual improvement in the investigative pathways for inherited optic neuropathies will be paramount as novel therapeutics become available. [ABSTRACT FROM AUTHOR]

Leber hereditary optic neuropathy (LHON) is an important cause of mitochondrial blindness among young adults. In this study, we investigated the potential of four quinone analogues (CoQ 1 , CoQ 10 , decylubiquinone and idebenone) in compensating for the deleterious effect of the m.11778G>A mitochondrial DNA mutation. The LHON fibroblast cell lines tested exhibited reduced cell growth, impaired mitochondrial bioenergetics and elevated levels of reactive oxygen species (ROS). Idebenone increased ATP production and reduced ROS levels, but the effect was partial and cell-specific. The remaining quinone analogues had variable effects and a negative impact on certain mitochondrial parameters was observed in some cell lines. [ABSTRACT FROM AUTHOR]

Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called 'plus' phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation. [ABSTRACT FROM AUTHOR]

We describe three unrelated patients presenting with a spinal cord syndrome and neuroimaging features consistent with multiple sclerosis ( MS). All harbored a pathogenic OPA1 mutation. Although the neurological phenotype resembled neuromyelitis optica ( NMO), anti-aquaporin 4 antibodies were not detected and the disorder followed a slow progressive course. The coincidental occurrence of OPA1 mutations and an MS-like disorder is likely to have modulated the phenotypic manifestations of both disorders, but unlike the previously reported association of Leber hereditary optic neuropathy and MS (Harding disease), the optic neuropathy in patients with OPA1 mutations and an MS-like disorder can be mild with a good visual prognosis. [ABSTRACT FROM AUTHOR]

Three decades have elapsed since the first reports of human disease being directly caused by defects within the mitochondrial genome, including the identification of the m.11778G > A mitochondrial DNA (mtDNA) mutation in patients with Leber hereditary optic neuropathy (LHON). LHON causes severe bilateral visual loss among young adults with an estimated prevalence of 1 in 30 000 in the general population. Most patients carry point mutations in mtDNA with the three most common pathogenic variants being m.3460G > A (MT‐ND1), m.11778G > A (MT‐ND4) and m.14484 T > G (MT‐ND6). LHON carries a poor visual prognosis and patient management remains largely supportive. However, major advances in our understanding of the mechanisms underpinning retinal ganglion cell loss in this mitochondrial disorder are paving the way for novel forms of treatment aimed at halting or reversing visual deterioration at different stages of the disease process. The eye is an ideal target organ for gene therapy given its relative ease of anatomical access, but some key issues need to be explored further, in particular, the most efficient gene delivery systems and the optimal window for therapeutic intervention in LHON. [ABSTRACT FROM AUTHOR]

Purpose: Idebenone is approved in Europe for the treatment of LHON – a rare mitochondrial disorder resulting in severe, bilateral vision loss. Controlled data beyond a 6‐month treatment duration is lacking. Here, we report primary results from LEROS, a Phase 4, externally controlled interventional study in patients with subacute/dynamic LHON treated with idebenone for up to 24 months. Methods: Patients with LHON onset ≤5 years prior were enrolled and stratified by time since onset: subacute/dynamic (≤1 year) and chronic (>1 year). Visual acuity (VA) outcomes from 181 patients, treated for up to 24 months were compared to retrospective data from an external natural history (NH) cohort (N = 372) matched by time since onset. Outcome measures, from baseline, were clinically relevant recovery (CRR): improvement from 'off‐chart' VA to at least 1.6 logMAR, or a ≥0.2 logMAR improvement if already 'on‐chart'; clinically relevant stabilization (CRS): maintenance of VA < 1.0 logMAR; and clinically relevant benefit (CRB): reaching a CRR, a CRS, or both. Results: The primary endpoint – the proportion of subacute/dynamic eyes with a CRB from baseline following 12 months of treatment, versus matched NH eyes – was met (42.3% [60/142] vs. 20.7% [40/193] [p = 0.0020]); this difference was maintained after 24 months (52.9% [64/121] vs. 36.0% [27/75] [p = 0.0297]). The difference in the CRB rate was largely driven by CRS, occurring in 64.5% (20/31) of eligible (<1.0 logMAR at baseline) treated eyes versus 22.5% (9/40) of eyes in the NH cohort at 12 months (p = 0.0005). The proportion of off‐chart patients (best VA) continuously decreased after the likely nadir at 6 months. By 24 months, a larger proportion of patients had moved into the non‐legally blind category than at BL (42.9% vs. 33.9%). Conclusions: LEROS corroborates previous idebenone efficacy results, demonstrating that long‐term treatment is well tolerated and results in prolonged clinical benefit in patients with LHON in the subacute/dynamic phase. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and safety of a bilateral injection of lenadogene nolparvovec in patients with Leber Hereditary Optic Neuropathy (LHON) carrying the m.11778G > A mutation. Methods: REFLECT is a randomized, placebo‐controlled, phase 3 study that included 98 patients with vision loss ≤1 year at enrolment. Patients received a single intravitreal injection of lenadogene nolparvovec (9E10 viral genomes per eye) in their first‐affected eye. The second‐affected eye was randomized to a second injection of gene therapy or placebo. Results: A total of 48 patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in best‐corrected visual acuity (BCVA) of the second‐affected eyes was not statistically different between the two arms (primary endpoint). Two years after injection, a statistically significant improvement in BCVA was reported from baseline in treated eyes. Mean BCVA showed an absolute difference between the arms of +6 ETDRS letters in favour of bilaterally treated patients. The improvement from nadir was +20 and +17 letters for the first‐ and second‐affected eyes treated bilaterally, and +19 and +14 letters for first‐ and second‐affected eyes treated unilaterally (all p < 0.0001). Clinically meaningful improvement from nadir ≥ +15 letters was found in the majority of bilaterally and unilaterally treated patients (73% and 66%, respectively). The main ocular adverse event related to gene therapy was intraocular inflammation, which was mostly mild and responsive to conventional treatment. Overall, the safety profile was favourable and comparable in patients treated unilaterally and bilaterally. Conclusions: The 2‐year data confirm the results observed 1.5 years after treatment: bilaterally treated patients have better improvement of BCVA than unilaterally treated patients with a favourable safety profile. Placebo eyes showed a contralateral therapeutic effect as previously observed in the RESCUE and REVERSE trials. [ABSTRACT FROM AUTHOR]

Purpose: LHON is a rare mitochondrial disorder which results in bilateral vision loss. Idebenone is approved in Europe for the treatment of LHON, but relatively little controlled data exists to support use in chronic patients. Here, we report primary results from LEROS, a Phase 4, externally controlled interventional study in patients with chronic LHON (1 to ≤5 years since onset) treated with idebenone for up to 24 months. Methods: Patients with LHON onset ≤5 years prior were enrolled and stratified by time since onset: subacute/dynamic (≤1 year) and chronic (>1 but ≤5 years). Visual acuity (VA) outcomes from 181 patients, treated for up to 24 months were compared to retrospective data from an external natural history (NH) cohort (N = 372) matched by time since onset. Outcome measures, from baseline, were clinically relevant recovery (CRR): improvement from 'off‐chart' VA to at least 1.6 logMAR, or a ≥0.2 logMAR improvement if already 'on‐chart'; clinically relevant stabilization (CRS): maintenance of VA <1.0 logMAR; and clinically relevant benefit (CRB): reaching a CRR, a CRS, or both. Results: As was observed in the subacute/dynamic phase, the frequency of a CRB from baseline at 12 months was significantly higher in treated, chronic eyes than in matched NH eyes (50.3% [72/143] vs. 38.6% [59/153] [p = 0.0087]). This difference was largely driven by a higher proportion of eyes with a CRR of visual acuity (VA) (32.9% [47/143] vs. 19.6% [30/153] [p = 0.0034]). The distribution of patients between VA categories changed over the study duration. At baseline, 34.5% of patient's best VA was off‐chart, with 35.6% between 1.0–1.68 logMAR, and 29.9% < 1.0 logMAR. By 24 months, these proportions had changed to 16.4, 41.8 and 41.8%, respectively. Conclusions: LEROS provides evidence of a significant therapeutic benefit of idebenone treatment in patients with LHON in the chronic stage up to 5 years from onset. [ABSTRACT FROM AUTHOR]

As a group, inherited optic neuropathies represent an important cause of severe irreversible visual loss among children and young adults. Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two most common forms encountered in clinical practice and several shared disease pathways have emerged that contribute to retinal ganglion cell loss, and eventually visual failure. In this review, the author critically appraises the evidence base for the various therapeutic strategies that have been put forward to treat these two mitochondrially determined optic neuropathies, including future developments. Innovative in vitro fertilization techniques to prevent female carriers of childbearing age from transmitting pathogenic mitochondrial DNA mutations to their biological children will also be discussed. [ABSTRACT FROM AUTHOR]

The 197th ENMC workshop entitled "Neuromuscular disorders of mitochondrial fusion and fission -OPA1 and MFN2 molecular mechanisms and therapeutic strategies" took place from the 26th to the 28th of April 2013 in Naarden, The Netherlands. A multidisciplinary group of 19 participants took part in this workshop, including 18 clinical and basic science researchers from six different countries (France, Germany, Italy, Spain, the United Kingdom (UK), and the United States of America), and one patient representative from CMT UK. The principal aim of this workshop was to establish an integrated research network in order to better understand the basic mechanisms responsible for the development of neuromuscular disease in patients harbouring pathogenic OPA1 and MFN2 mutations, which cause autosomal dominant optic atrophy (DOA) and axonal Charcot-Marie-Tooth disease (CMT2A), respectively. [ABSTRACT FROM AUTHOR]

Introduction: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. Methods: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. Results: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was − 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was − 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. Conclusion: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. Trial Registration Numbers: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY). [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is an idiopathic demyelinating disease which predominantly affects the optic nerve and spinal cord. Multiplex NMO pedigrees have been reported but the genetic risk factors conferring this increased familial susceptibility have not yet been determined. OPA1 mutations have recently been identified in families with progressive visual failure and spastic paraparesis, raising the possibility that OPA1 genetic variants could contribute to the aetiology of NMO. We therefore screened for OPA1 in 32 patients with NMO. No pathogenic mutations were found, and none of the 13 single-nucleotide polymorphisms identified were associated with an increased risk of developing NMO. [ABSTRACT FROM AUTHOR]

Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber’s hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber’s hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber’s hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber’s hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated. [ABSTRACT FROM PUBLISHER]

Purpose: Autosomal-dominant optic atrophy (DOA) is one of the most common inherited optic neuropathies, and it is genetically heterogeneous, with mutations in both OPA1 and OPA3 known to cause disease. Approximately 60% of cases harbor OPA1 mutations, whereas OPA3 mutations have been reported in only 2 pedigrees with DOA and premature cataracts. The aim of this study was to determine the yield of OPA1 and OPA3 screening in a cohort of presumed DOA cases referred to a tertiary diagnostic laboratory. Design: Retrospective case series. Participants: One hundred eighty-eight probands with bilateral optic atrophy referred for molecular genetic investigations at a tertiary diagnostic facility: 38 patients with an autosomal-dominant pattern of inheritance and 150 sporadic cases. Methods: OPA1 and OPA3 genetic testing was initially performed using polymerase chain reaction-based sequencing methods. The presence of large-scale OPA1 and OPA3 genomic rearrangements was assessed further with a targeted comparative genomic hybridization microarray platform. The 3 primary Leber hereditary optic neuropathy (LHON) mutations, m.3460G→>A, m.11778G→A, and m.14484T→C, also were screened in all patients. Main Outcome Measures: The proportion of patients with OPA1 and OPA3 pathogenic mutations. The clinical profile observed in molecularly confirmed DOA cases. Results: Twenty-one different OPA1 mutations were found in 27 (14.4%) of the 188 probands screened. The mutations included 6 novel pathogenic variants and the first reported OPA1 initiation codon mutation at c.1A→T. An OPA1 missense mutation, c.239A→G (p.Y80C), was identified in an 11-year-old black girl with optic atrophy and peripheral sensorimotor neuropathy in her lower limbs. The OPA1 detection rate was significantly higher among individuals with a positive family history of visual failure (50.0%) compared with sporadic cases (5.3%). The primary LHON screen was negative in the patient cohort, and additional molecular investigations did not reveal any large-scale OPA1 rearrangements or OPA3 genetic defects. The mean baseline visual acuity for the OPA1-positive group was 0.48 logarithm of the minimum angle of resolution (units mean Snellen equivalent, 20/61; range, 20/20–20/400; 95% confidence interval, 20/52–20/71), and visual deterioration occurred in 54.2% of patients during follow-up. Conclusions: OPA1 mutations are the most common genetic defects identified in patients with suspected DOA, whereas OPA3 mutations are very rare in isolated optic atrophy cases. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. [Copyright &y& Elsevier]

Abstract: Leber hereditary optic neuropathy (LHON) and autosomal-dominant optic atrophy (DOA) are the two most common inherited optic neuropathies in the general population. Both disorders share striking pathological similarities, marked by the selective loss of retinal ganglion cells (RGCs) and the early involvement of the papillomacular bundle. Three mitochondrial DNA (mtDNA) point mutations; m.3460G>A, m.11778G>A, and m.14484T>C account for over 90% of LHON cases, and in DOA, the majority of affected families harbour mutations in the OPA1 gene, which codes for a mitochondrial inner membrane protein. Optic nerve degeneration in LHON and DOA is therefore due to disturbed mitochondrial function and a predominantly complex I respiratory chain defect has been identified using both in vitro and in vivo biochemical assays. However, the trigger for RGC loss is much more complex than a simple bioenergetic crisis and other important disease mechanisms have emerged relating to mitochondrial network dynamics, mtDNA maintenance, axonal transport, and the involvement of the cytoskeleton in maintaining a differential mitochondrial gradient at sites such as the lamina cribosa. The downstream consequences of these mitochondrial disturbances are likely to be influenced by the local cellular milieu. The vulnerability of RGCs in LHON and DOA could derive not only from tissue-specific, genetically-determined biological factors, but also from an increased susceptibility to exogenous influences such as light exposure, smoking, and pharmacological agents with putative mitochondrial toxic effects. Our concept of inherited mitochondrial optic neuropathies has evolved over the past decade, with the observation that patients with LHON and DOA can manifest a much broader phenotypic spectrum than pure optic nerve involvement. Interestingly, these phenotypes are sometimes clinically indistinguishable from other neurodegenerative disorders such as Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and multiple sclerosis, where mitochondrial dysfunction is also thought to be an important pathophysiological player. A number of vertebrate and invertebrate disease models has recently been established to circumvent the lack of human tissues, and these have already provided considerable insight by allowing direct RGC experimentation. The ultimate goal is to translate these research advances into clinical practice and new treatment strategies are currently being investigated to improve the visual prognosis for patients with mitochondrial optic neuropathies. [Copyright &y& Elsevier]

Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake. [ABSTRACT FROM PUBLISHER]

Spinocerebellar ataxia type 6 (SCA6) is a calcium channelopathy due to a pathological CAG repeat expansion in CACNL1A4. Patients frequently describe paroxysmal vertigo early in the disease course, but it is not clear whether this is central or labyrinthine in origin. To address this issue we studied 21 SCA6 patients. Symptoms of vertigo were defined using a structured questionnaire. Signs were recorded during a standardised bed-side vestibular examination that included systematic positional testing with Frenzel goggles. Brief, recurrent attacks of vertigo occurred in 13 patients, usually preceding the onset of ataxia. Nystagmus was observed behind Frenzel goggles in 14 patients, and was induced either during positional testing, or head shaking in 20 patients. Only one patient had findings typical of benign paroxysmal positional vertigo (BPPV). Combined downbeat and horizontal gaze-evoked nystagmus (“side-pocket”) was the most common form, occurring most commonly in supine and head-hanging positions, and following horizontal head-shaking. Nystagmus beating away from the ground (apogeotropic) occurred in 9 patients as they lay on their side. In conclusion, vertigo and abnormalities on bedside vestibular examination are common in SCA6, with forms of nystagmus typical of cerebellar, rather than labyrinthine, disease. These findings demonstrate phenotypic overlap between SCA6 and episodic ataxia type 2, which are both due to mutations in CACNL1A4. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the possibility of auditory dysfunction in patients with Leber hereditary optic neuropathy (LHON). Methods: We prospectively recruited 10 affected patients from the north-east of England harbouring one of the three primary mitochondrial LHON mutations (3460G>A n = 3, 11778G>A n = 5 and 14484T>C n = 2). A detailed auditory history was taken and they were asked to complete a validated hearing questionnaire. Each patient then underwent a comprehensive topographic neuroauditory assessment to evaluate both middle- and inner-ear functions and the integrity of the brainstem auditory pathways. Results: We found no evidence of cochlear nerve dysfunction or abnormalities of the central brainstem auditory pathways in our LHON cohort and five patients had completely normal hearing tests. The remainder had mild conductive hearing loss from childhood ear infections and/or high-frequency sensorineural hearing loss from previous noise injury. Conclusion: Although further studies are required to confirm our findings, auditory dysfunction as a result of a primary LHON mutation is probably uncommon. [ABSTRACT FROM AUTHOR]

Purpose: To compare the efficacy of intracameral cefuroxime versus subconjunctival cefuroxime in reducing the rate of endophthalmitis after cataract surgery. Setting: Single-specialty eye hospital, Sunderland, United Kingdom. Methods: A retrospective analysis of all presumed infectious endophthalmitis cases from January 1, 2000, to December 31, 2006 was performed. The rate of presumed infectious endophthalmitis in patients receiving subconjunctival cefuroxime was compared with those receiving intracameral cefuroxime at the end of surgery. Results: This study included 36743 phacoemulsification cataract procedures. The mean rate of presumed infectious endophthalmitis was 0.95 per 1000 cases. The incidence of endophthalmitis was higher in the subconjunctival cefuroxime group than in the intracameral cefuroxime group; the difference was statistically significant with an odds ratio of 3.01 (95% confidence interval, 1.37-6.63). Conclusion: Intracameral cefuroxime was a safe alternative to subconjunctival cefuroxime and led to a lower rate of endophthalmitis. [Copyright &y& Elsevier]

The article discusses abnormal retinal thickening in patients with autosomal-recessive spastic ataxia of Charlevois-Saguenay (ARSACS). It comments on retinal findings in ARSACS and how it could have practical relevance as a screening tool. It mentions five patients from the North of England whose ARSACS was molecularly confirmed but had no evidence of retinal hypermyelination. It talks about retinal nerve fibre layer thickening in ARSACS and its relation to axoplasmic stasis in the long axons.

Abstract: Leber''s hereditary optic neuropathy (LHON) is a common cause of inherited blindness, primarily due to one of three mitochondrial DNA (mtDNA) mutations. LHON, which has an unexplained variable penetrance and pathology, is characterised by disruption of the mitochondrial respiratory chain ultimately resulting in degeneration of the retinal ganglion cells. Phosphorylation of the tau protein is known to cause neurodegeneration and variation in MAPT has been associated with a range of neurodegenerative disorders. Given the relationship between MAPT variation and altered mitochondrial respiratory chain function, we hypothesised that MAPT variation could contribute to the risk of blindness in LHON mtDNA mutation carriers. We studied MAPT variation in a large, well characterised LHON cohort, but were unable to find an association between MAPT genetic variation and visual failure in LHON mtDNA mutation carriers. Our findings suggest that genetic variation in MAPT is unlikely to make a major contribution to the risk of blindness among LHON mutation carriers. [Copyright &y& Elsevier]

Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology and establishing the correct diagnosis can be challenging. Although dysfunction of the anterior visual pathways is uncommon, it is the most common neuro-ophthalmological manifestation of this condition and given the potential for irreversible, severe visual loss, prompt diagnosis and treatment are essential. We describe a patient with optic perineuritis as a rare initial presentation of sarcoidosis and discuss the underlying pathophysiology and management. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS) that preferentially targets the optic nerve and the spinal cord. Due to the significant risk of permanent visual and neurological impairment in NMO, rapid diagnosis and the prompt initiation of the most appropriate treatment are essential. Antibodies against the aquaporin‐4 (AQP4) water channel and myelin oligodendrocyte glycoprotein (MOG) have been identified in patients with NMO phenotypes. In this presentation, the clinical and neuropathological features of anti‐AQP4 and anti‐MOG optic neuropathies will be reviewed with a critical appraisal of current treatment options. [ABSTRACT FROM AUTHOR]

This open-label study included 9 patients with I ND4 i -LHON who were first followed for 12 months, then received a single IVT injection of gene therapy in their worse-seeing eye at a dose of 5E9 viral genomes (vg) if they were below the age of 12, and 1E10 vg if they were older. Leber hereditary optic neuropathy (LHON) is a rare, blinding, maternally inherited mitochondrial genetic disease in need of effective treatment. A rapid and significant improvement of BCVA (by at least -0.3 logMAR) was reported within 3 days in at least 1 eye of 54/149 (36.2%) of patients and in both eyes in 17/147 (11.4%) of patients.[50] Although patient age at onset is not indicated, the reported mean age at study enrollment of 19±7.1 years would imply that a fair proportion of patients treated in this open-label clinical trial were children. The ongoing REFLECT study evaluates the efficacy and safety of bilateral IVT injection of rAAV2/2 I ND4 i (9E10 vg/eye) in I ND4 i -LHON patients with bilateral vision loss within 1 year. [Extracted from the article]

Viral vectors can be utilised to deliver therapeutic genes to diseased cells. Adeno‐associated virus (AAV) is a commonly used viral vector that is favoured for its ability to infect a wide range of tissues whilst displaying limited toxicity and immunogenicity. Most humans harbour anti‐AAV neutralising antibodies (NAbs) due to subclinical infections by wild‐type virus during infancy and these pre‐existing NAbs can limit the efficiency of gene transfer depending on the target cell type, route of administration and choice of serotype. Vector administration can also result in de novo NAb synthesis that could limit the opportunity for repeated gene transfer to diseased sites. A number of strategies have been described in preclinical models that could circumvent NAb responses in humans, however, the successful translation of these innovations into the clinical arena has been limited. Here, we provide a comprehensive review of the humoral immune response to AAV gene therapy in the ocular compartment. We cover basic AAV biology and clinical application, the role of pre‐existing and induced NAbs, and possible approaches to overcoming antibody responses. We conclude with a framework for a comprehensive strategy for circumventing humoral immune responses to AAV in the future. [ABSTRACT FROM AUTHOR]

Background: ATXN2 is the causative gene of spinocerebellar ataxia type 2 (SCA2) and has been implicated in glaucoma pathogenesis. Therefore, studying ocular changes in SCA2 could uncover clinically relevant changes. Objective: The aim was to investigate optic disc and retinal architecture in SCA2. Methods: We evaluated 14 patients with SCA2 and 26 controls who underwent intraocular pressure measurement, fundoscopy, and macular and peripapillary spectral domain optical coherence tomography (SD‐OCT). We compared SD‐OCT measurements in SCA2 and controls, and the frequency of glaucomatous changes among SCA2, controls, and 76 patients with other SCAs (types 1, 3, 6, and 7). Results: The macula, peripapillary retinal nerve fiber and inner plexiform layers were thinner in SCA2 than in controls. Increased cup‐to‐disc ratio was more frequent in SCA2 than in controls and other SCAs. Conclusions: Ocular changes are part of SCA2 phenotype. Future studies should further investigate retinal and optic nerve architecture in this disorder. [ABSTRACT FROM AUTHOR]

The aim of this review was to provide an evidence-based approach to frequently asked questions relating to the risk of transmitting a maternally inherited mitochondrial disorder (MID). We do not address disorders linked with disturbed mitochondrial DNA (mtDNA) maintenance, causing mtDNA depletion or multiple mtDNA deletions, as these are autosomally inherited. The review addresses questions regarding prognosis, recurrence risks and the strategies available to prevent disease transmission. The clinical and genetic complexity of maternally inherited MIDs represent a major challenge for patients, their relatives and health professionals. Since many of the genetic and pathophysiological aspects of MIDs remain unknown, counselling of affected patients and at-risk family members remains difficult. MtDNA mutations are maternally transmitted or, more rarely, they are sporadic, occurring de novo (~25%). Females carrying homoplasmic mtDNA mutations will transmit the mutant species to all of their offspring, who may or may not exhibit a similar phenotype depending on modifying, secondary factors. Females carrying heteroplasmic mtDNA mutations will transmit a variable amount of mutant mtDNA to their offspring, which can result in considerable phenotypic heterogeneity among siblings. The majority of mtDNA rearrangements, such as single large-scale deletions, are sporadic, but there is a small risk of recurrence (~4%) among the offspring of affected women. The range and suitability of reproductive choices for prospective mothers is a complex area of mitochondrial medicine that needs to be managed by experienced healthcare professionals as part of a multidisciplinary team. Genetic counselling is facilitated by the identification of the underlying causative genetic defect. To provide more precise genetic counselling, further research is needed to clarify the secondary factors that account for the variable penetrance and the often marked differential expressivity of pathogenic mtDNA mutations both within and between families. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Orbicularis oculi muscle biopsies for mitochondrial DNA analysis in suspected mitochondrial myopathy," by A. M. Roefs and colleagues, published online in the August 14, 2012 issue.

Background: Early diagnosis of Parkinson's disease and mild cognitive impairment is important to enable prompt treatment and improve patient welfare, yet no standard diagnostic test is available. Metabolomics is a powerful tool used to elucidate disease mechanisms and identify potential biomarkers.Objectives: The objective of this study was to use metabolic profiling to understand the pathoetiology of Parkinson's disease and to identify potential disease biomarkers.Methods: This study compared the serological metabolomic profiles of early-stage Parkinson's patients (diagnosed < 12 months) to asymptomatic matched controls using an established array based detection system (DiscoveryHD4™, Metabolon, UK), correlating metabolite levels to clinical measurements of cognitive impairment.Results: A total of 1434 serological metabolites were assessed in early-stage Parkinson's disease cases (n = 41) and asymptomatic matched controls (n = 40). Post-quality control, statistical analysis identified n = 20 metabolites, predominantly metabolites of the fatty acid oxidation pathway, associated with Parkinson's disease and mild cognitive impairment. Receiver operator curve assessment confirmed that the nine fatty acid oxidation metabolites had good predictive accuracy (area under curve = 0.857) for early-stage Parkinson's disease and mild cognitive impairment (area under curve = 0.759).Conclusions: Our study indicates that fatty acid oxidation may be an important component in the pathophysiology of Parkinson's disease and may have potential as a diagnostic biomarker for disease onset and mild cognitive impairment. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Purpose: For patients with LHON, preservation of functional visual acuity (VA) and/or recovery of lost VA are desirable outcomes. Beyond this, prevention of further VA worsening is also important. In LEROS, VA outcomes following 24 months of idebenone treatment were compared to an external, matched, natural history (NH) cohort. Here, we report results from a cumulative frequency analysis to understand the impact of idebenone across the range of possible VA outcomes. Methods: Patients with LHON onset ≤5 years prior were enrolled and stratified by time since onset: subacute/dynamic (≤1 year) and chronic (>1 year). Data from 181 patients treated up to 24 months were compared to retrospective data from an external natural history (NH) cohort (372 patients), matched by time since onset. In a cumulative frequency analysis, VA change was assessed from baseline to month 24. A change of ≥0.2 logMAR was considered a clinically relevant recovery or worsening, depending on the direction of change. Results: In subacute/dynamic eyes treated with idebenone for 24 months, 47.9% (58/121) experienced a recovery of VA, and 25.8% (24/93) experienced VA worsening. This compared to 33.3% (25/75), and 51.0% (25/49) of untreated subacute/dynamic eyes displaying a recovery or worsening, respectively. In chronic eyes, recovery was observed in 31.9% (37/116) that had undergone treatment versus 16.1% (15/93) when untreated. A VA worsening was observed for 2.9% (2/68) of treated chronic eyes versus 20.0% (12/60) of untreated. The majority of treatment emergent adverse events were considered of mild to moderate intensity, with only 11.3% considered to be related to idebenone treatment. Conclusions: In both the subacute/dynamic and chronic stages of LHON, idebenone treatment was able to boost VA recovery and prevent further VA deterioration. Consistent with previous findings, idebenone was well tolerated with no new safety concerns observed. [ABSTRACT FROM AUTHOR]

Purpose: In LEROS, visual acuity (VA) outcomes in idebenone‐treated patients with LHON were compared to an external, matched, natural history (NH) cohort. Here, we report results from a cumulative frequency analysis to understand the impact of idebenone on carriers of each of the primary mitochondrial DNA (mtDNA) mutations. Methods: Patients with LHON and a confirmed primary mtDNA mutation (11 778, 14 484 or 3460) were enrolled and stratified by time since onset: acute (≤1 year) and chronic (>1 but ≤5 years). Data from 181 patients treated up to 24 months were compared to retrospective data from the NH cohort (372 patients), matched by time since onset. In a cumulative frequency analysis, VA change was assessed from baseline to month 24. A change of ≥0.2 logMAR was considered a clinically relevant recovery or worsening, depending on the direction of change. Results: For carriers of the 11 778 mutation, VA outcomes were observed, in treated versus untreated eyes, as follows: recovery: 38.3% (23/60) vs. 14.9% (7/47) [acute], 24.4% (20/82) vs. 13.7% (7/51) [chronic]; worsening: 24.4% (10/41) vs. 66.7% (20/30) [acute], 4.4% (2/45) vs. 31.6% (6/19) [chronic]. For 14 484 carriers VA outcomes were as follows: recovery: 74.3% (26/35) vs. 70.0% (7/10) [acute], 90.9% (10/11) vs. 16.7% (3/18) [chronic]; worsening: 2.9% (1/35) vs. 22.2% (2/9) [acute], 0.0% (0/8) vs. 16.7% (3/18) [chronic]. For 3460 carriers, outcomes were as follows: recovery: 34.6% (9/26) vs. 61.1% (11/18) [acute], and 30.4% (7/23) vs. 20.8% (5/24) [chronic]; worsening: 76.5% (13/17) vs. 30.0% (3/10) [acute], and 0.0% (0/15) vs. 13.0% (3/23) [chronic]. Conclusions: Idebenone can improve the ratio of positive to negative VA outcomes in a large proportion of patients with LHON, although these benefits seem to manifest to varying degrees dependent on disease stage and/or causative mtDNA mutation. Carriers of the most prevalent mutation, 11 778, saw a consistent treatment benefit regardless of disease stage. [ABSTRACT FROM AUTHOR]