Use of Idebenone for the Treatment of Leber's Hereditary Optic Neuropathy

Abstract Leber's hereditary optic neuropathy (LHON) is one of the most frequent mitochondrial disorders. It is caused by mutations in genes of the mitochondrial DNA coding for subunits of the respiratory chain and leads to severe bilateral vision loss, from which spontaneous recovery is infrequent. Retinal ganglion cells show a selective vulnerability to mitochondrial dysfunction in LHON. Idebenone is the first medication approved for LHON. It is a short-chain benzoquinone, which is an analogue of coenzyme Q10, but with distinct properties and mechanisms of action. Idebenone is a potent antioxidant and inhibitor of lipid peroxidation. Importantly, it facilitates electron flux directly to complex III, bypassing the dysfunctional complex I of the mitochondrial respiratory chain, thereby increasing adenosine triphosphate (ATP) production. In the Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) randomized placebo-controlled clinical trial, 85 patients with LHON were enrolled, in the first 5 years after symptom onset, and randomized to either idebenone 900 mg/d for 6 months or placebo. Idebenone was well tolerated, and although the prespecified primary end point (best recovery in visual acuity [VA]) did not reach statistical significance, all secondary end points (change in best VA, change of VA of best eye at baseline, and change of VA in all eyes) showed a trend toward visual recovery in favor of idebenone. An increasing body of evidence shows that idebenone is effective and safe for the treatment of patients with LHON, including a large retrospective open-label study, several case reports and case series, an expanded access program, and ongoing post-authorization clinical studies. Here, we review the literature on idebenone for the treatment of patients with LHON.

Mitochondrial DNA Content and the MTND4 Gene Expression in Leber's Hereditary Optic Neuropathy / 대한진단검사의학회지

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is characterized by acute or subacute bilateral visual loss, primarily caused by a mitochondrial DNA (mtDNA) point mutation. However the pathogenic mechanism of visual loss has not been clearly unraveled. We investigated the pathogenetic mechanism of LHON by the analysis of mtDNA content and the MTND4 expression. METHODS: mtDNA contents were absolutely quantified in 17 patients, 8 carriers and 47 normal subjects using real-time PCR. All patients and carriers had the 11778G>A mutation of mtDNA. For real-time PCR assay of mtDNA content, the reference ranges were established by age groups and the reproducibility was assessed by intra-run and inter-run assays. We also quantified the expression of two mitochondrial genes (MTND4 harboring 11778G>A and MTCYB) relative to a nuclear gene (GAPDH) in the three subject groups. RESULTS: The mean mtDNA contents in the patients, carriers and normal subjects were 894.9 (+/- 186.9), 848.5 (+/-221.7) and 1148.6 (+/-406.9) copies/cell, respectively. Patients and carriers had significantly lower mtDNA contents than normal subjects (P=0.001 and P=0.048, respectively). The RNA expression of both MTND4 and MTCYB tended to be lower in patients and carriers than in normal subjects (statistically insignificant), but MTND4/MTCYB ratios were similar among the three groups. CONCLUSIONS: mtDNA content and the MTND4 expression are decreased in LHON patients and carriers, and it may be caused by mitochondrial depletion. The mitochondrial depletion may be an additional cause of respiratory defect.

Leber's Hereditary Optic Neuropathy with Dystonia Caused by mtDNA 11778 Mutation

Several mtDNA mutations have been reported in Leber's hereditary optic neuropathy (LHON) associated with dystonia since it was identified as having the 14459 mutation. We report a patient with LHON and dystonia and his family. The patient presented with a slowly progressive bilateral visual loss and generalized dystonia. Brain MRI showed abnormal signal changes in both putamina. The 11778 mutation was confirmed by a Sfa I restriction digestion test. We found, in the literature, only one case of the 11778 mutation associated with dystonia, although it is one of the most common mutations in LHON. Our case suggests that the 11778 mutation should be taken into consideration in the pathogenesis of LHON associated with dystonia.

Leber's hereditary optic neuropathy(LHON) and leber's plus with mtDNA 11778 mutation: Clinical manifestations and a genealogic study

Leber's hereditary optic neuropathy (LHON) is an important cause of bilateral optic neuropathy in youth and occasionally associated with other neurological abnormalities (Leber's plus). The authors recently found out one family of LHON and another patient of Leber's plus with mitochondrial DNA (mtDNA) 11778 mutation. The presence of a point mutation of mtDNA was investigated by restriction length fragment polymorphism. Among 14 patients who had mtDNA 11778 mutation in the family, only two men had bilateral optic neuropathy. The other was a man of optic neuropathy with myelopathy. The age at onset of visual loss ranged from 14 to 25 (average 19.7). The time delay between involvement of the two eyes was I to 3 months Central visual field defect was observed in each of all affected eyes and worse in the earlier affected. The brain MRI and CSF studies revealed no abnormality. This study showed that the clinical manifestations and genealogical features of LHON in our patients are similar to those of previously reported cases in other countries.

Carbon monoxide poisoning as an epigenetic factor for Leber's hereditary optic neuropathy

A 45-year-old Korean woman visited our hospital complaining of poor vision after carbon monoxide (CO) poisoning. We have confirmed the presence of a point mutation at position 11778 in the ND4 gene of mitochondrial DNA. This case suggests that CO poisoning may precipitate the clinical expression of Leber's hereditary optic neuropathy (LHON). To our knowledge, this would be the first case report of clinical expression of LHON precipitated by CO poisoning.