Leber’s hereditary optic neuropathy

Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited degeneration of retinal ganglion cells and their axons.

It is a condition related to changes in mitochondrial DNA.

Most DNA is packaged in chromosomes within the nucleus, mitochondria have a distinct mitochondrial genome composed of mtDNA.

Mutations in the MT-ND1, MT-ND4, MT-ND4L, and MT-ND6 genes cause Leber hereditary optic neuropathy.

The LHON ND4 G11778A mutation is the primary mutation in most of the world with 70% of Northern European cases and 90% of Asian cases.

LHON ND6 T14484C mutation accounts for 86% of LHON cases in Quebec, Canada.

Three mutations account for over 95% of cases: the 11778 mutation accounts for 50-70% of cases, the 14484 mutation for 10-15% and the 3460 mutation for 8-25%.

The degeneration of retinal ganglion cells and their axons leads to an acute or subacute loss of central vision.

It affects predominantly young adult males.

In Northern European populations about one in 9000 people carry one of the three primary LHON mutations.

There is a prevalence of between 1:30,000 to 1:50,000 in Europe.

LHON is only transmitted through the mother.

It is primarily due to mutations in the mitochondrial genome, and only the egg contributes mitochondria to the embryo.

Mutations in mitochondrial genes and coding the NADHD dehydrogenase subunits and causes decreased activity of complex 1 of the mitochondrial electron transport chain.

Three mutations account for more than a 95% of cases: 11778§G toA is the most common.

The mutations lead to decreased ATP production.

Most LHON-related mutations are homoplasmic, and the mitochondrial DNA can be tested in the blood for diagnosis.

LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations: These mutations are 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria.

Men cannot pass on the disease to their offspring.

Patients present with an acute onset of visual loss, first in one eye, and then a few weeks to months later in the other.

Both eyes become affected either simultaneously in 25% of cases, or sequentially in 75% of cases,with a median delay of 8 weeks.

Rarely only one eye os affected.

Onset is usually young adulthood.

Range of onset from 7-75 years is reported.

The age of onset is slightly higher in females, mean 31.3 years, than males, mean 24.3.

The male to female ratio varies between mutations: 3:1 for 3460 G>A, 6:1 for 11778 G>A and 8:1 for 14484 T>C.

It evolves to very severe optic atrophy and a permanent decrease of visual acuity.

More than 50 percent of males and more than 85 percent of females with a mutation never experience vision loss or related medical problems.

Acutely, a stage that last few weeks, the eye demonstrates edema at the nerve fiber layer especially in the arcuate bundles and enlarged and tortuous peripapliarry vessels.

A pupillary defect may be visible in the acute stage.

Eye examination reveals decreased visual acuity, loss of color vision and a central scotoma on visual field examination.

LHON Plus refers to a rare variant of the disorder with eye disease together with other conditions, such as the loss of the brain’s ability to control the movement of muscles, tremors, and cardiac arrhythmias.

LHON is related to alterations in mitochondrial DNA.

LHON genes code for the NADH dehydrogenase protein involved in the normal mitochondrial function of oxidative phosphorylation.

The eye abnormality is limited to the retinal ganglion cell layer, especially the maculopapillary bundle.

Degeneration occurs from the retinal ganglion cell bodies to the axonal pathways leading to the lateral geniculate nuclei.

Evidence suggests impaired glutamate transport and increased reactive oxygen species causing apoptosis of retinal ganglion cells.

Diagnosis usually requires a neuro-ophthalmological evaluation and blood testing for mitochondrial DNA.

Untreated LHON results in continued visual loss in both eyes.

Fundus photography can monitor nerve fiber layer swelling.

Optical coherence tomography can study of retinal nerve fiber layer thickness.

Red green color vision testing may detect losses.

Contrast sensitivity may be diminished, and could be an abnormal electroretinogram or visual evoked potentials.

Avoiding tobacco and alcohol, optic nerve toxins is advised.

Ethambutol has been implicated as triggering visual loss in carriers of LHON.

Toxic and nutritional optic neuropathies may have overlaps with LHON in symptoms, mitochondrial mechanisms of disease and management.

Nitroprusside should not be used due to increased risk of optic nerve ischemia in patients with LHON.

Idebenone has modest benefit in about half of patients, with those most likely to respond have early onset disease.

A vitamin E metabolite, α-Tocotrienol-quinone, has had some success in reversing early onset vision loss.

Idebenone is a short-chain benzoquinone that interacts with the mitochondrial electron transport chain to enhance cellular respiration., and success of its use has been reported in a small number of patients.

The particular mutation type may predict the likelihood of penetrance, severity of illness and probability of vision recovery in the affected: a woman who harbors a homoplasmic primary LHON mutation has a ~40% risk of having an affected son and a ~10% risk of having an affected daughter.

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