Leber's Hereditary Optic Neuropathy
by Doreid Berro
Leber's Hereditary Optic Neuropathy (LHON) is a mitochodrial genetic disease
that leads to vision loss. This disease was first described by the German
eye specialist Leber in 1871(1). Leber's Hereditary Optic Neuropathy is
different from Leber's Congenital Amaurosis which is classified by cortical
blindness or congenital absence of the rods and cones or early onset of
retinitis pigmentosa (9). Leber's Hereditary Optic Neuropathy is characterized
by a delayed bilateral loss of vision which could lead to total blindness
due to degeneration of the optic nerve. Early signs include peripapillary
telangiectatic microangiopathy(5). In other words the early signs are localized
collection of distended blood capillary vessels around the start of the
optic nerve which connects the eye balls to the cortex of the occipital
lobes of the brain. With time there is a progressive optic atrophy and vision
loss. Magnetic resonance Imaging (MRI) revealed signal alterations of lenticular
nucleus parts , like the globus pallidus and the putamen. The lenticular
nucleus is part of the basal ganglia that have complex neural connections
with the cerebral cortex and the thalamus which are all involved in the
regulation of voluntary movements at a subconscious level. Based on these
alterations, one can conclude that LHON is associated with some neurological
For a period of time two aspects of the disease puzzled the scientists.
First, women only can pass the disorder to their children and children of
men with LHON never inherited the disease. Second, the disorder affects
more males and it is highly variable from causing complete blindness in
some people to causing only minor loss of vision in others (8).
Doug Wallace of Emory University in Atlanta found the answers. Using restriction
enzymes he found single DNA base change or transition point mutations in
certain locations of the 16,569 bp mitochondrial genome. Fifty to seventy
percent of the LHON patients have the point mutations at nucleotide 11,788
(G-->A) resulting in the substitution of histidine for arginine in the
ND4 subunit of complex I. Complex I is NADH- ubiqinone oxidoreductase and
it is mainly involved in the electron transfer system of the mitochondria.
In about 15% of LHON patients other point mutation at nucleotide3,460 (G-->A)
results in the replacement with threonine of the alanine residue of the
ND1 subunit of complex I. In most of the rest of the LHON patients the mutation
is at the 14,484 nucleotide (A-->G) changing methionine residue to valine
in the ND6 subunit (5). The ratio of affected males to females were 3.7
to 1 for the 11,778 mutation, 4.3 to 1 for the 3460 mutation, and 7.7 to
1 for the 14,484 mutation. Other rare mutations could also lead to the same
disorder like the mutation T-->A at nucleotide position 14,569 leading
to the substitution of a methionine for the isoleucine in the ND6 subunit
gene. Secondary mutations also occur and these are more frequent among the
LHON patients than among the non-LHON controls. These mutations produce
more conservative amino acids and thus do not have the big effect of the
primary mutations (2).
The LHON base changes affect a single codon in the gene for a protein in
the electron transport pathway. The subsequent protein still works but not
as efficient. The NADH dehydrogenase (ND)-dependent respiration decreases
by approximately 40% in the cells that carry the mutation.(4) Moreover,
there is an increase in the lactate to pyravate ratio in the ND1 and the
ND4 (6). All of this will lower the rate by which the ATP can be produced.
The neurons of the optic nerve are the first to be affected because of their
high demand for the ATP. Some of these neurons die leading to an increase
on the load of the other neurons. Those in turn could malfunction or die
resulting in total blindness (8).
Mitochondrial inheritance is maternal, thus Leber's is passed only from
the mother to the children. Having explained the mitochondrial mutations
and their impact on the electron transfer system, we are left with the task
of explaining the variability of the disease and this will be explained
More than 1000 mitochondria are in the egg before fertilization, each mitochondrion
has its own DNA that could be carrying the defect. During cell division
mitochondria are randomly split between the two daughter cells. As a result,
Leber's variability is due to the percentage of defective mitochondria carried
by the individual cell. Doug Wallace found that patients with Leber's induced
blindness carried more than 70% of defective mitochondria; on the other
hand, those with milder forms had no more than 30% of the defective mitochondria
(8). The dominance of LHON among males has been taken first as evidence
that the penetrance of the disease is influenced by X-linked loci and by
environmental effects; however, there is some evidence that the penetrance
of the disease is also affected by the secondary LHON mutations (5).
Leber's Hereditary Optic Neuropathy maternal mode of inheritance and the
variability of the symptoms among the patients makes it a distinct disease.
Many individuals carry these genetic defects in some of their mitochondria;
however, they do not develop the disease. There is no known cure for Leber's
Hereditary Optic Neuropathy and this what makes it a very serious disease.
The available information about LHON is making the job of finding a treatment
easier than before and hopefully there will be a treatment in few years.
1)Backgrnd, Leber's Hereditary Optic Neuropathy Trust. http://ourworld.compserve.com/homepages/JamesLeeder/bckgrnd.html
2)De Vries, D., Went, L., Bruyn, G., Scholte, H., Hofstra, R., Bolhuis,
P., van Oost, B., Genetic and Biochemical Impairment of Mitochondrial Complex
I Activity in a Family with Leber Hereditary Optic Neuropathy and Hereditary
Spastic Dystonia. American Journal of Human Genetics, 58(4):703-11, April
3) Harding, A., Riordan-Eva, P., Govan, G., Mitochondrial DNA Diseases:
Genotype and Phenotype in Leber's Hereditary Optic Neuropathy. Muscle &
Nerve. 3:S82-4, 1995.
4) Hofhaus,G., Johns, D., Hurko, O., Attardi, G., Chomyn, A., Respiration
and Growth Defects in Transmitochondrial Cell Lines Carrying the 11778 Mutation
Associated With Leber's Hereditary Optic Neuropathy. Journal of Biological
Chemistry. 271(22):13155-61, May 31, 1996.
5) Howell, Neil, Kubacka, I., Halvoroson, S., Phylogenetic Analysis of the
Mitochondrial Genomes from Leber Hereditary Optic Neuropathy Pedigrees.
Genetics. 140:285-302, May 1995.
6) Majander, A., Finel, M., Savotaus, M., Nikoskelaninen, E., Wikstrom,
M., Catalytic Activity of Complex I Cell Lines That Possess Replacement
Mutations in the ND genes in Leber's Hereditary Optic Neuropathy. European
Journal of Biochemistry. 239(1):201-7, July 1, 1996.
7) Meire, F.M., Van Coster, R., Cochaux, P., Obermaier-Kusser B., Martin,
J., Neurological Disorders in Members of Families with Leber's Hereditary
Optic Neuropathy (LHON) Caused by Different Mitochondrial Mutations, Ophthalmic
Genetics. 16(3):119-26, September 1995.
8) Mitochondrial DNA, The Fire Within: The Unfolding Story of Human Mitochondrial
9) Visual Impairment Service, Leber's Amaurosis. http://call-centre.cogsci.ed.ac.uk/SSC/VISPAGES/5/VIS576634.
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