Over 30 years have elapsed from the landmark finding of the first point mutation in mitochondrial DNA (mtDNA) associated with Leber's hereditary optic neuropathy (LHON) by Doug Wallace and his team in 1988. 1 Twelve years later came the identification of the nuclear OPA1 gene, which encodes for a mitochondrial dynamin-like protein, whose pathogenic mutations cause Dominant Optic Atrophy (DOA). 2,3 This was a predictable convergence, as both nuclear and mtDNA mutations may cause a similar mitochondrial disorder resulting in vision loss, identifying DOA as a mitochondrial disease similar to LHON. 4,5 We are delighted to have compiled this special issue of Overall, the field of hereditary optic neuropathies remains extremely dynamic and lively. By presenting the "tip of the neurodegeneration iceberg" in this special issue we hope to demonstrate the importance of these diseases as an informative model to make key observation of relevance to other neurodegenerative disorders. 9 From the genetic foundation, to the clinical and preclinical research, and ultimately ending with new therapeutic strategies, we look forward to further groundbreaking progress in hereditary optic neuropathies, leading to the ultimate goal of an effective cure for these patients, preserving vision.
Abstract: Leber Hereditary Optic Neuropathy (LHON) stands as a distinctive maternally inherited mitochondrial disorder marked by painless, subacute central vision loss, primarily affecting young males. This review covers the possible relationship between LHON and multiple sclerosis (MS), covering genetic mutations, clinical presentations, imaging findings, and treatment options. LHON is associated with mutations in mitochondrial DNA (mtDNA), notably m.11778G>A, m.3460G>A, and m.14484T>C, affecting complex I subunits. Beyond ocular manifestations, LHON can go beyond the eye into a multi-systemic disorder, showcasing extraocular abnormalities. Clinical presentations, varying in gender prevalence and outcomes, underscore the nature of mitochondrial optic neuropathies. Hypotheses exploring the connection between LHON and MS encompass mitochondrial DNA mutations triggering neurological diseases, immunologically mediated responses inducing demyelination, and the possibility of coincidental diseases. The research on mtDNA mutations among MS patients sheds light on potential associations with specific clinical subgroups, offering a unique perspective into the broader landscape of MS. Imaging findings, ranging from white matter alterations to cerebrospinal fluid biomarkers, further emphasize shared pathological processes between LHON-MS and classical MS. This comprehensive review contributes to the understanding of the complex relationship between LHON and MS. Keywords: visual impairment, mitochondrial DNA, demyelination diseases, neuro-ophthalmology
PurposeTo evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).DesignRESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial.ParticipantsSubjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included.MethodsEach subject’s right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye.Main Outcome MeasuresThe primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4–treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96.ResultsEfficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4–treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4–treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from −0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4–treated and sham-treated eyes was −0.01 logMAR (P = 0.89); the primary end point of a −0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4–treated and sham-treated eyes, respectively.ConclusionsAt 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes. To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial. Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included. Each subject’s right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye. The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4–treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96. Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4–treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4–treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from −0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4–treated and sham-treated eyes was −0.01 logMAR (P = 0.89); the primary end point of a −0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4–treated and sham-treated eyes, respectively. At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.
Introduction: Leber’s hereditary optic neuropathy (LHON) is a rare mitochondrial disease which preferentially affects the optic nerve. A genetic defect in the mitochondrial DNA encoding complex I of the respiratory chain underlies this genetic disorder. Patients typically present with subacute vision loss in one eye followed by the loss of vision in the second eye approximately 6 weeks later, ultimately leading to blindness.Areas covered: In this review, we discuss failed and active therapies as well as the future of clinical trials in LHON. A review of the literature was performed and articles were identified using PubMed. The search terms LHON and treatment were used. These publications were paired to the clinical trials listed on the clinicaltrials.gov website.Expert opinion: Several therapies have been tested to treat LHON; however, so far, no double-blind placebo-controlled clinical trial has been successful in the treatment of LHON. Avoidance of triggers which generate reactive oxygen species and treatment with idebenone is the best currently available therapy for LHON.
The COVID-19 pandemic has led to the identification of new disease phenotypes associated with infection by the SARS-CoV-2 virus. This includes multiple neuro-ophthalmological sequelae, which have been associated with COVID-19 infection and administration of COVID-19 vaccines. Some of these associations have a plausible pathophysiological link to the infection or vaccination but true causation has yet to be established. We review the literature for associations reported between COVID-19 infection or vaccination and neuro-ophthalmic sequelae and review the potential pathophysiological processes that may underlie these associations.
We present the case of a 19-year-old female with a history of Down syndrome (DS) who was referred to our neuro-ophthalmology clinic for evaluation of Leber's hereditary optic neuropathy (LHON). The patient's family history was significant for a known G11778A mutation in a maternal relative, consistent with LHON. The patient was also positive for the G11778A mutation; however, the genotype demonstrated low penetrance in the pedigree, with only 1 out of 10 adult male offspring showing signs or symptoms of the disease. Mitochondrial mutations implicated in LHON have been shown to impair complex I of the electron transport chain and thereby reducing the effective generation of adenosine triphosphate and increasing the production of toxic reactive oxygen species. Although the partial or complete triplicate of chromosome 21 constitutes the etiology of DS, some of the pleiotropic phenotypes of the syndrome have been attributed to oxidative stress and mitochondrial dysfunction. Given the low penetrance of the mutation and the patient's sex, this case illustrates the possibility that the mitochondrial mutation demonstrated increased penetrance due to pre-existing mitochondrial dysfunction related to DS.
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