Information about Leber's Hereditary Optic Neuropathy

Classification & external resources

ICD-10	H47.2
ICD-9	377.16
OMIM	535000
DiseasesDB	7340
MeSH	D029242

Leber’s hereditary optic neuropathy (LHON) or Leber optic atrophy is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. However, LHON is only transmitted through the mother as it is primarily due to mutations in the mitochondrial (not nuclear) genome and only the egg contributes mitochondria to the embryo. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations affect nucleotide positions 11778, 3460 and 14484, 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.

Signs & symptoms

Clinically, there is an acute onset of visual loss, first in one eye, and then a few weeks later in the other. This eventually evolves to very severe optic atrophy and permanent decrease of visual acuity. In the acute stage lasting a few weeks, the affected eye demonstrates an edematous appearance of the nerve fiber layer especially in the arcuate bundles and enlarged or telangectatic and tortuous peripapillary vessels (microangiopathy). These main features are seen on fundus examination, just before or subsequent to the onset of visual loss. Examination reveals decreased visual acuity, loss of color vision and a cecocentral scotoma on visual field examination.

Genetics

Leber hereditary optic neuropathy is a condition related to changes in mitochondrial DNA. Although 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. These genes code for the NADH dehydrogenase protein involved in the normal mitochondrial function of oxidative phosphorylation. Oxidative phosphorylation uses a large multienzyme complex to convert oxygen and simple sugars to energy. Mutations in any of the genes disrupt this process to cause a variety of syndromes depending on the type of mutation and other factors. It remains unclear how these genetic changes cause the death of cells in the optic nerve and lead to the specific features of Leber hereditary optic neuropathy.

A significant percentage of people with a mutation that causes Leber hereditary optic neuropathy do not develop any features of the disorder. Specifically, more than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related medical problems. Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome, contribute to the development of signs and symptoms.

Diagnosis & management

The diagnosis is extremely difficult and usually requires a neuro-ophthalmological evaluation and/or blood testing for DNA assessment (that is available only in a few laboratories). Hence the incidence is probably much greater than appreciated. The prognosis is almost always that of continued very severe visual loss. There is no accepted treatment for this disease.

Of note, when a patient suffering from LHON suffers a hypertensive crisis as a possible complication of the disease process, nitroprusside (trade name: Nipride) should not be used due to increased risk of optic nerve ischemia seen with the disease in response to this anti-hypertensive in particular. ^[1] This is similar to the concern for limiting the drug use in hypertensives suffering from tobacco amblyopia. ^[1]

Eponym

Leber’s hereditary optic neuropathy is sometimes confused with Leber's congenital amaurosis, which is a different disease also first described by Theodore Leber in the 19th century.^[2]

Epidemiology

• LHON has an unusually high prevalence in Western Quebec, Canada, where it is referred to as Frenchman disease.

See also

• Amaurosis
• List of eye diseases and disorders

References

External Links

• Overview of condition at NLM Genetics Home Reference
• Carelli V, Ross-Cisneros F, Sadun A: "Mitochondrial dysfunction as a cause of optic neuropathies." Prog Retinal & Eye Research. 23:53-89, 2004. PMID 14766317

•  • [ e] Pathology of the eye (primarily , )
Eyelid, lacrimal system and orbit	Stye - Chalazion - Blepharitis - Entropion - Ectropion - Lagophthalmos - Blepharochalasis - Ptosis - Xanthelasma - Trichiasis - Dacryoadenitis - Epiphora - Exophthalmos - Enophthalmos
Conjunctiva	Conjunctivitis - Pterygium - Pinguecula - Subconjunctival hemorrhage
Sclera and cornea	Scleritis - Keratitis - Corneal ulcer - Snow blindness - Thygeson's superficial punctate keratopathy - Fuchs' dystrophy - Keratoconus - Keratoconjunctivitis sicca - Arc eye - Keratoconjunctivitis - Corneal neovascularization - Kayser-Fleischer ring - Arcus senilis - Band keratopathy
Iris and ciliary body	Iritis - Uveitis - Iridocyclitis - Hyphema - Persistent pupillary membrane
Lens	Cataract - Aphakia
Choroid and retina	Chorioretinitis - Retinal detachment - Retinoschisis - Retinopathy (Hypertensive retinopathy, Diabetic retinopathy, Retinopathy of prematurity) - Macular degeneration - Retinitis pigmentosa - Retinal haemorrhage - Central serous retinopathy - Macular edema - Epiretinal membrane - Macular pucker
Optic nerve and visual pathways	Optic neuritis - Papilledema - Optic atrophy
Ocular muscles, binocular movement, accommodation and refraction	Paralytic strabismus: Ophthalmoparesis - Progressive external ophthalmoplegia - Palsy (III, IV, VI) - Kearns-Sayre syndrome Other strabismus: Esotropia/Exotropia - Hypertropia - Heterophoria (Esophoria, Exophoria) - Brown's syndrome - Duane syndrome Other binocular: Conjugate gaze palsy - Convergence insufficiency - Internuclear ophthalmoplegia - One and a half syndrome Refractive error: Hyperopia/Myopia - Astigmatism - Anisometropia/Aniseikonia - Presbyopia
Visual disturbances and blindness	Amblyopia - Leber's congenital amaurosis - Subjective (Asthenopia, Hemeralopia, Photophobia, Scintillating scotoma) - Diplopia - Scotoma - Anopsia (Binasal hemianopsia, Bitemporal hemianopsia, Homonymous hemianopsia, Quadrantanopia) - Color blindness (Achromatopsia) - Nyctalopia - Blindness/Low vision
Pupil	Anisocoria - Argyll Robertson pupil - Marcus Gunn pupil/Marcus Gunn phenomenon - Adie syndrome
Infectious diseases	Trachoma - Onchocerciasis
Other	Nystagmus - Miosis - Mydriasis - Glaucoma - Floater - Leber's hereditary optic neuropathy - Red eye - Keratomycosis - Xerophthalmia - Aniridia

•  • [ e] Mitochondrial diseases
Myopathies	MELAS - MERRF - KSS - PEO
Other	DAD - Friedreich's ataxia - LHON - Leigh's - NARP - MNGIE - PCD - PDHA - Pearson syndrome