||Andrew G. Lee, MD, Chairman, Department of Ophthalmology, The Methodist Hospital, Houston, TX, Professor of Ophthalmology, Weill Cornell Medicine; Dhanatcha Sadetaporn, Baylor College of Medicine, Class of 2022
||Summary: • Leber Hereditary Optic Neuropathy: mitochondrially inherited o Does not manifest at birth, typically presents in young adult male patient o Unclear why males more affected than females who also inherit maternal mitochondrial deletion -Possible exogenous factors i.e. Nuclear cofactor, hormonal cofactor, smoking, alcohol • May be more prominent in males than females and precipitate mitochondrial threshold effect in Leber o;Passed on by mothers, so affected males cannot pass mitochondrial deletion on to descendants while females can o Mutations at positions 11778, 3460, and 14484 account for 95% of mutations in Leber patients -Remaining 5% found by sequencing entire mitochondrial DNA • Presentation: typically, young male o Acute unilateral -bilateral sequential or simultaneous central vision loss -Central or cecocentral scotoma -Initially- slightly hyperemic optic disc, pseudo edema -No leaking with fluorescein angiogram o Over time, development of optic atrophy and loss of maculopapular bundle • Diagnosis: o Imaging to rule out optic neuritis and NMO o Screen 11778, 3460, and 14484 -14484- most likely to recover -11778- most common but least likely to recover -3460- somewhere in between • Treatment: no real treatment for Leber Hereditary Optic Neuropathy o Mitochondrial supplements including Coenzyme Q10 o Study on idebenone with modest effects but not available in United States o Avoid mitochondrial precipitants- smoking, alcohol, marathon running, etc. o Ongoing clinical trial recruiting for adeno-associated viral vector gene therapy -In very early stages o Genetic counseling- male patients cannot pass mitochondrial deletion on to descendants but must inform maternal line relatives of their risk [Transcript of video] "Leber Hereditary Optic Neuropathy. Leber Hereditary Optic Neuropathy is a hereditary optic neuropathy. Even though the patients are born with it, it doesn't manifest usually until they're older. And so, the patient typically is a young adult male. Even though it is mitochondrially inherited, it's not clear why males are more affected than females because all of the patients on the maternal line are going to have the mitochondrial deletion. So, probably there's some exogenous factor perhaps a nuclear cofactor or hormonal cofactor or smoking or alcohol which are higher prevalence in males that precipitates the mitochondrial threshold effect in Leber Hereditary Optic Neuropathy. Because it is mitochondrially inherited, it means that it is passed through the mother. So, the mother as you know provides the egg, and that means it is the mother who is providing the cytoplasm and the mitochondria to all of her descendants. Cannot be passed through the paternal line so even if you have an affected son this affected son cannot pass the mitochondrial deletion on to his descendants. However, the females can pass. So, the three most common Leber Hereditary Optic Neuropathy mutations are at positions 11778, 3460, and 14484. This accounts for 95% of the mitochondrial mutations that we see in Leber. However, if you really think that the patient has Leber, we can get the extra 5% by doing the entire mitochondrial DNA. So, it typically presents in a young male and their complaint is going to be acute unilateral but then bilateral either sequential or simultaneous vision loss with a central scotoma or cecocentral scotoma. So, it's going to be a bilateral sequential or simultaneous loss of center vision. Initially, the disc may look a little hyperemic and might have pseudo edema, but if you do fluorescein angiogram it doesn't leak. And over time optic atrophy develops and loss of maculopapular bundle. There's no real treatment for Leber Hereditary Optic Neuropathy although mitochondrial supplements have been used including Coenzyme Q10. There's been a study on idebenone which shows some modest benefit but it's not available in the United States. So, we generally let our patients get the CoQ10 equivalent in the United States over the counter. We tell them to avoid the mitochondrial precipitants smoking, alcohol, marathon running, etc. but there's no real effective treatment. There's an ongoing clinical trial recruiting for adeno-associated viral vector gene therapy but it's in the very earlier stages of trial. The most important thing to know about this is young male acute unilateral optic neuropathy. We're going to image that, make sure it's not optic neuritis or NMO but if everything's negative, we're going to be thinking about Leber. We order the three mutations, the screening mutations 11778, 3460, and 14484. 14484's the most likely to recover, 11778 is the most common mutation but it's the least likely to recover. 3460 kind of in between. Once you've established that it's mitochondrial, you have to counsel the patient genetically. The patient themselves cannot pass the mitochondrial gene but the maternal line is at risk. And so, the main job is telling the maternal line relatives about their risk. And it's mitochondrial and sure you should be thinking about it in many patients with central scotoma or cecocentral scotoma, think about Leber Hereditary Optic Neuropathy."