Leber Hereditary Optic Neuropathy

2019 ◽  
pp. 25-28
Author(s):  
Matthew J. Thurtell ◽  
Robert L. Tomsak
Keyword(s):  
Optic Neuropathy ◽  
Vision Loss ◽  
Treatment Options ◽  
Leber Hereditary Optic Neuropathy ◽  
Dna Mutations ◽  
History Of ◽  
Eye Involvement ◽  
Promising Treatment ◽  
Almost All ◽  
Hereditary Optic Neuropathy

Leber hereditary optic neuropathy in an important cause of acute painless monocular vision loss. It most often occurs in young men. Almost all patients develop fellow eye involvement within a few months, resulting in severe irreversible binocular vision loss. In this chapter, we begin by reviewing the differential diagnosis of acute optic neuropathy. We next discuss the genetic basis for Leber hereditary optic neuropathy and list the three common mitochondrial DNA mutations that cause it. We then review the clinical features and natural history of Leber hereditary optic neuropathy. Lastly, we discuss the treatment approach for this condition and review promising treatment options.

Hereditary Optic Neuropathy

2011 ◽  
pp. 25-28
Author(s):  
Matthew J. Thurtell ◽  
Robert L. Tomsak ◽  
Robert B. Daroff
Keyword(s):  
Optic Neuropathy ◽  
Optic Atrophy ◽  
Vision Loss ◽  
Treatment Options ◽  
Monocular Vision ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Central Vision Loss ◽  
Promising Treatment ◽  
Hereditary Optic Neuropathy

Monocular and binocular vision loss can occasionally be caused by hereditary optic neuropathy. While progressive painless binocular central vision loss is characteristic of dominant optic atrophy, acute painless monocular vision loss is characteristic of Leber’s hereditary optic neuropathy. We discuss the clinical features and evaluation of Leber’s hereditary optic neuropathy and briefly mention promising treatment options.

scholarly journals A Typical Case Presentation with Spontaneous Visual Recovery in Patient Diagnosed with Leber Hereditary Optic Neuropathy due to Rare Point Mutation in MT-ND4 Gene (m.11253T>C) and Literature Review

Medicina ◽  
2021 ◽  
Vol 57 (3) ◽  
pp. 202
Author(s):  
Rasa Liutkeviciene ◽  
Agne Sidaraite ◽  
Lina Kuliaviene ◽  
Brigita Glebauskiene ◽  
Neringa Jurkute ◽  
...  
Keyword(s):  
Optic Neuropathy ◽  
Vision Loss ◽  
European Medicines Agency ◽  
Visual Recovery ◽  
Leber Hereditary Optic Neuropathy ◽  
Diagnostic Features ◽  
Mitochondrial Respiratory Chain Complex ◽  
Male Predominance ◽  
Mtdna Mutations ◽  
Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is one of the most common inherited mitochondrial optic neuropathies, caused by mitochondrial DNA (mtDNA) mutations. Three most common mutations, namely m.11778G>A, m.14484T>G and m.3460G>A, account for the majority of LHON cases. These mutations lead to mitochondrial respiratory chain complex I damage. Typically, LHON presents at the 15–35 years of age with male predominance. LHON is associated with severe, subacute, painless bilateral vision loss and account for one of the most common causes of legal blindness in young individuals. Spontaneous visual acuity recovery is rare and has been reported in patients harbouring m.14484T>C mutation. Up to date LHON treatment is limited. Idebenone has been approved by European Medicines Agency (EMA) to treat LHON. However better understanding of disease mechanisms and ongoing treatment trials are promising and brings hope for patients. In this article we report on a patient diagnosed with LHON harbouring rare m.11253T>C mutation in MT-ND4 gene, who experienced spontaneous visual recovery. In addition, we summarise clinical presentation, diagnostic features, and treatment.

scholarly journals 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

2021 ◽  
Vol 12 ◽  
Author(s):  
Nancy J. Newman ◽  
Patrick Yu-Wai-Man ◽  
Valerio Carelli ◽  
Valerie Biousse ◽  
Mark L. Moster ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Visual Acuity ◽  
Natural History ◽  
Optic Neuropathy ◽  
Linear Mixed Model ◽  
Vision Loss ◽  
Indirect Comparison ◽  
External Control ◽  
Leber Hereditary Optic Neuropathy ◽  
Hereditary Optic Neuropathy

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies.Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control.Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss.Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences.Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4.Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p < 0.0001).Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies.Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

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

Eye ◽  
2021 ◽  
Author(s):  
Patrick Yu-Wai-Man ◽  
◽  
Nancy J. Newman ◽  
Valerio Carelli ◽  
Chiara La Morgia ◽  
...  
Keyword(s):  
Optic Neuropathy ◽  
Vision Loss ◽  
The United States ◽  
Local Regression ◽  
Leber Hereditary Optic Neuropathy ◽  
Visual Outcomes ◽  
Mtdna Mutations ◽  
Presymptomatic Stage ◽  
One Year ◽  
Hereditary Optic Neuropathy

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.

scholarly journals Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees.

Genetics ◽  
1995 ◽  
Vol 140 (1) ◽  
pp. 285-302 ◽  
Author(s):  
N Howell ◽  
I Kubacka ◽  
S Halvorson ◽  
B Howell ◽  
D A McCullough ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Optic Neuropathy ◽  
Phylogenetic Analyses ◽  
Population History ◽  
Mitochondrial Genomes ◽  
Coding Region ◽  
Leber Hereditary Optic Neuropathy ◽  
Phylogenetic Cluster ◽  
History Of ◽  
Hereditary Optic Neuropathy

Abstract The nucleotide sequences of the mitochondrial genomes from patients with Leber hereditary optic neuropathy (LHON) were used for phylogenetic analysis to study the origin and population history of pathogenic mitochondrial mutations. Sequences of both the coding region (8300 bp) and the more rapidly evolving noncoding control region (1300 bp) were analyzed. Patients with the primary LHON mutations at nucleotides 3460, 11,778, and 14,484 were included in this study, as were LHON patients and non-LHON controls that lacked these primary mutations; some of the subjects also carried secondary LHON mutations. The phylogenetic analyses demonstrate that primary LHON mutations arose and were fixed multiple times within the population, even for the small set of LHON patients that was analyzed in these initial studies. In contrast, the secondary LHON mutations at nucleotides 4216, 4917, and 13,708 arose once: the mitochondrial genomes that carried these secondary mutations formed a well-supported phylogenetic cluster that apparently arose 60,000 to 100,000 years ago. Previous studies found secondary LHON mutations at a higher frequency among LHON patients than among control subjects. However, this finding does not prove a pathogenetic role of these mutations in LHON. Instead, the increased frequency is more likely to reflect the population genetic history of secondary mutations relative to that of primary LHON mutations.

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