Leber's hereditary optic neuropathy

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. (This is not stictly true. In approximately 1 in 100,000 fertilisations, mitochondria, (and its DNA) from the sperm can enter the fertilised egg through the Zona Pellucida.) 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.

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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.^[1] 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. ^[2] This is similar to the concern for limiting the drug use in hypertensives suffering from tobacco amblyopia.

Minocycline has been proposed as a possible treatment.^[3]

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.^[4][5]

Epidemiology

• LHON has an unusually high prevalence in Western Quebec, Canada,^[6] where it is referred to as Frenchman disease.

"LHON Plus"

"LHON Plus" is a name given to rare strains of the disorder. The symptoms of this higher form of the disease include loss of the brain's ability to control the movement of muscles, tremors, and cardiac arrythmia.^[7] Many cases of LHON plus have been comparable to Multiple Sclerosis because of the lack of muscular control.^[8]

See also

• Amaurosis
• List of eye diseases and disorders

References