Leber hereditary optic neuropathy is a maternally inherited bilateral optic neuropathy that typically affects teenage males with acute vision loss first in one eye and then the other within days or weeks. There are some distinctive changes in the ocular fundus appearance at various stages of the process that make specific diagnosis possible clinically. The etiology involves mutations in the mitochondrial DNA, and penetrance is incomplete. Due to the acute sequential presentation, there is a unique opportunity to study treatments that reduce risk of symptom development. There are active clinical trials underway to study gene therapy and drug therapy.
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• Leber hereditary optic neuropathy is a disease caused by various mutations in the mitochondrial genome and, as such, is inherited only via the maternal ovum as spermatozoa do not have mitochondria.
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• It usually manifests as sequential binocular acute painless vision loss in sons of carrier mothers.
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• There is preferential involvement of retinal ganglion cells in the papillo-macular bundle producing a dense central scotoma on visual field exam with relative sparing of peripheral visual field.
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• The optic disc appears swollen in the acute phase but typically does not leak fluorescein on fluorescein angiography.
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• Peripapillary retinal telangiectasia is typical during the acute phase but regresses within days to weeks after onset of vision loss in the affected eyes.
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• Retinal venous tortuosity can persist as a lasting marker for the disease on fundus exam.
Historical note and terminology
In 1871, Theodor Leber (1840-1917), Professor of Ophthalmology at the University Göttingen, described 55 patients in 16 families with a hereditary optic neuropathy of rapid onset (75). The vast majority of his patients were male, had visual loss beginning in the late teens or early 20s, and did not recover. Although his was not the first description of such patients, it was the most complete at that time. Ensuing decades saw the description of several pedigrees with similar clinical findings, almost all of which had a peculiar mode of inheritance from mother to affected son or mother to carrier daughter. Initially thought to be a sex-linked recessive disorder, the greater-than-expected occurrence in women and less-than-expected occurrence in maternal grandfathers of affected males suggested an alternate mechanism for transmission (118). In retrospect, many apparent cases of transmission from father to child were probably other hereditary optic neuropathies. Cytoplasmic transmission was suggested in 1936 (48), and the fact that mitochondrial DNA inheritance is maternal (33) eventually led to the discovery by Wallace and colleagues that many cases of Leber hereditary optic neuropathy are due to a mutation at position 11778 of the mitochondrial genome (133). Subsequently, mutations at positions 3460 (46) and 14484 (56) have been shown to be associated with Leber hereditary optic neuropathy in multiple pedigrees.
Leber was one of the preeminent ophthalmologists of his time. Unfortunately, several disorders described by him, all of which are eponymous, have names similar to Leber hereditary optic neuropathy. Leber congenital amaurosis is a severe bilateral retinal disease that is present at birth, transmitted as an autosomal recessive trait, and diagnosed by a permanent absence of retinal electrical activity. Leber idiopathic stellate neuroretinitis is an acute sporadic inflammation of the optic nerve and macula, characterized by both disc and macular edema, the resolution of the latter leading to a macular "star," hence the name. Leber miliary aneurysms are a milder variant of congenital retinal telangiectasia (Coats disease), a unilateral disease of mostly young boys. Retinal vessels are telangiectatic and may have localized aneurysmal outpouchings. Exudative leakage from these abnormal vessels may lead to visual loss.
Because of this possibility for confusion, it is inadequate to designate a patient with Leber hereditary optic neuropathy a "case of Leber's."