Leber Hereditary Optic Neuropathy
Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder characterized by acute or subacute, painless, bilateral loss of central vision, predominantly affecting young adult males. The disease results from point mutations in mitochondrial DNA (mtDNA), most commonly affecting genes encoding subunits of complex I (NADH dehydrogenase) of the mitochondrial respiratory chain. These mutations impair oxidative phosphorylation, leading to decreased ATP production and increased generation of reactive oxygen species, which ultimately cause selective degeneration of retinal ganglion cells and atrophy of the optic nerve. The health impacts of LHON are profound, as affected individuals typically experience rapid, irreversible central vision loss, resulting in severe visual impairment or legal blindness. Although extraocular manifestations are rare, some patients may develop a multisystemic disorder known as 'LHON-plus,' which can include neurological, cardiac, or skeletal abnormalities.
This type of LHON is caused by a point mutation at nucleotide position 11778 in the mitochondrial ND4 gene. It is the most prevalent and widely studied form, accounting for approximately 50-70% of cases worldwide. The clinical course is often severe, with poor visual prognosis and a low rate of spontaneous visual recovery.
This type is associated with a mutation at nucleotide position 3460 in the ND1 gene of mitochondrial DNA. It represents about 10-15% of cases. The visual prognosis is generally poor, and this mutation is sometimes associated with a higher risk of developing 'LHON-plus' syndromes involving neurological or cardiac manifestations.
This variant results from a mutation at nucleotide position 14484 in the ND6 gene. It accounts for approximately 10-15% of LHON cases. Compared to other types, this mutation is associated with a relatively higher rate of spontaneous visual recovery, especially in younger patients.
This form refers to patients with classic LHON-associated mtDNA mutations who also present with additional neurological, cardiac, or skeletal symptoms. Manifestations may include movement disorders, peripheral neuropathy, dystonia, or cardiac conduction defects, reflecting a broader spectrum of mitochondrial dysfunction.
Leber hereditary optic neuropathy has an estimated prevalence of 1 in 30,000 to 1 in 50,000 individuals worldwide, with significant geographic and ethnic variability. The disease predominantly affects males, with a male-to-female ratio of approximately 4:1, despite maternal inheritance. Onset typically occurs between the ages of 15 and 35 years, although cases have been reported in both children and older adults. Penetrance is incomplete, with only about 50% of male and 10% of female mutation carriers developing visual loss during their lifetime. Environmental and genetic modifiers, including smoking, alcohol consumption, and mitochondrial haplogroup background, influence disease expression and severity. The three primary mtDNA mutations (11778, 3460, and 14484) collectively account for over 90% of cases, with the 11778 mutation being most common in Europe, North America, and East Asia.
The diagnosis of Leber hereditary optic neuropathy is based on a combination of clinical, ophthalmological, and molecular genetic assessments. Clinically, patients present with acute or subacute, painless, bilateral central vision loss, often preceded by mild visual blurring or color vision deficits. Ophthalmologic examination typically reveals circumpapillary telangiectatic microangiopathy, swelling of the retinal nerve fiber layer, and eventual optic disc atrophy. Visual field testing demonstrates dense central or cecocentral scotomas. Definitive diagnosis requires identification of one of the pathogenic mtDNA point mutations (11778, 3460, or 14484) through molecular genetic testing. Additional investigations, such as optical coherence tomography (OCT), may reveal thinning of the retinal nerve fiber layer, while electrophysiological studies such as visual evoked potentials (VEP) show reduced or delayed responses. Differential diagnosis includes other hereditary optic neuropathies and acquired causes of optic neuropathy, which should be excluded through appropriate clinical and laboratory evaluation.
Idebenone is an approved treatment option for Leber hereditary optic neuropathy. It is a synthetic analog of coenzyme Q10 and functions as an antioxidant, facilitating electron transfer in the mitochondrial respiratory chain and thereby bypassing the defective complex I. Clinical studies have demonstrated that idebenone can improve or stabilize visual function in a subset of patients, particularly when administered early in the disease course. The drug is generally well tolerated and is indicated for use in both pediatric and adult patients with LHON, with dosing and duration of therapy tailored to individual clinical response.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | idebenone (Rec INN; USAN) | 58186-27-9 | C19 H30 O5 | 338.439 |
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