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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 are at nucleotide positions 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.[1]
Clinically, there is an acute onset of visual loss, first in one eye, and then a few weeks to months later in the other. Onset is usually young adulthood, but age range at onset from 8-60 is reported. This typically 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.
“LHON Plus” is a name given to rare strains of the disorder with eye disease together with other conditions. [2] 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.[3] Many cases of LHON plus have been comparable to Multiple Sclerosis because of the lack of muscular control.[4]
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.[5] 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.
In Northern European populations about one in 9000 people carry one of the three primary LHON mutations.[6] [7] There is a prevalence of between 1:30,000 to 1:50,000 in Europe.
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