Matthew Xavier

1015200

Dr. E. Cummings

03/20/2016

Lebers Hereditary Optic Neuropathy (LHON)

Lebers hereditary optic neuropathy (LHON), also referred to as Lebers Hereditary Atrophy, is
an inherited form of vision loss. Although the age of onset is typically between 10-30 years, rare
cases have been reported in early childhood or in the seventh of eighth decade. For some
unknown reason, males are more likely to be affected than females, with some reported ratios as
high as 9:1.
Individuals eventually diagnosed with LHON may initially be asymptomatic, or experience mild
blurring of the central visual field of one eye. Symptoms may progress from mild unilateral
visual loss to severe bilateral visual loss, usually worse than 20/200. Second eye involvement is
usually weeks to months yet the visual loss may be simultaneous. Visual field testing typically
shows a worsening central or cecocentral scotoma. Central vision is needed for detailed tasks
such as reading, driving, and recognizing faces. Peripheral vision generally remains intact so the
affected individual can still walk around independently. Examination may initially reveal normal
or pseudo-edematous optic nerves, with optic nerve pallor and atrophy appearing subsequently.
Individuals may harbor concurrent disease including cardiac conduction abnormalities, dystonia,
and multiple sclerosis-like illness. This is considered "LHON Plus" disease. Few individuals
recover vision once lost, but visual loss rarely progresses to a state of no light perception.
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of
dysfunction of the mitochondrial respiratory chain. Mutations in the MT-ND1, MT-ND4, MTND4L, or MT-ND6 gene can cause LHON. These genes are found in the DNA of mitochondria,
which convert the energy from food into a form that cells can use. Each of these genes provides
instructions for making a protein involved in normal mitochondrial function. These proteins are
part of the NADH-ubiquinone oxidoreductase chain, a large enzyme complex in mitochondria
that helps convert oxygen, fats, and simple sugars to energy. Mutations in any of the genes
disrupt this process. It remains uncertain how these genetic changes cause the death of cells in
the optic nerve, or why these cells are particularly vulnerable, however, it is thought that the
mutations impair glutamate transport and increase reactive oxygen species production, which
leads to apoptosis of retinal ganglion cells, and subsequent atrophy and demyelination of the
optic nerves, chiasm and tracts.

Matthew Xavier

1015200

Dr. E. Cummings

03/20/2016

Many mitochondrial diseases display heteroplasmy. Each cell contains numerous mitochondria,
and in 10-15% of patients with LHON mutations, only a certain percentage of these
mitochondria may have mutant DNA. Those with a "mutation load" less than threshold (60-75%
in some reports) may not exhibit a disease phenotype, and may never lose vision or have related
health problems. Environmental factors such as smoking, alcohol use and industrial toxins may
be implicated, as these have mitochondrial-toxic effects, although studies have produced
conflicting results. It is unknown why males are preferentially affected, but theories include the
presence of a 'susceptibility locus' on the Y chromosome.
LHON has a mitochondrial pattern of inheritance, also referred to as maternal or matrilineal
inheritance. The developing embryo inherits the mitochondria (and mtDNA) in the original
maternal ova and not in sperm. Therefore, a pattern of inheritance associated with alterations of
genes in mitochondrial DNA, gives a pattern of the condition affecting both male and female
offspring, but always being maternally inherited. An affected male does not pass on his
mitochondria to his children, so all his children will be unaffected.
Given that there is a clear pattern of LHON inheritance, those with a family member on the
maternal inheritance chain with LHON should expect that any sudden, painless central vision
loss is caused by LHON. Diagnosis can be confirmed by identification of a pathogenic mtDNA
variant on molecular genetic testing of DNA extracted from a blood sample. Often, however,
people who develop the features of LHON have no family history. Since a person may carry an
mtDNA mutation without experiencing any signs or symptoms, it is hard to predict which
members of a family who carry a mutation will eventually develop vision loss or other problems
associated with LHON. It is important to note, that all females with an mtDNA mutation, even
those who do not have any signs or symptoms, will pass the genetic change to their children.
Treatments for LHON include low vision aids for severe visual loss, avoidance of potential
precipitants of visual loss, antioxidants to help reduce the neurotoxic stress due to reactive
oxygen species, anti-apoptotic agents and a variety of gene therapies. Symptomatic treatments
should be considered in all patients with vision-impairing optic neuropathies to improve quality
of life, in particular to aid with reading, communication, gainful employment, navigation and
self-operation of a motor vehicle.

Matthew Xavier

1015200

Dr. E. Cummings

03/20/2016

References
. Sadun, A., Morgia, C. and Carelli, V. (2010). Lebers Hereditary Optic Neuropathy. Curr Treat
Options Neurol, 13(1), pp.109-117. Available at: http://lhon.org/lhon/LHON_101.html [Accessed
22 Mar. 2016].

. Ifond.org. (2016). Leber Hereditary Optic Neuropathy, International Foundation for Optic
Nerve Disease. [online] Available at: http://www.ifond.org/lhon.php3 [Accessed 22 Mar. 2016].

. Genetics Home Reference. (2016). Leber hereditary optic neuropathy. [online] Available at:
https://ghr.nlm.nih.gov/condition/leber-hereditary-optic-neuropathy [Accessed 22 Mar. 2016].

. Yu-Wai-Man, P. and Chinnery, P. (2013). Leber Hereditary Optic Neuropathy. University of

Washington, Seattle. [online] Available at: http://www.ncbi.nlm.nih.gov/books/NBK1174/
[Accessed 22 Mar. 2016].

. Genetics.edu.au. (2016). [online] Available at: http://www.genetics.edu.au/Publications-andResources/Genetics-Fact-Sheets/FactSheetMitochondria [Accessed 22 Mar. 2016].