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 abnormalities (7).

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 next.

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 1996.

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 DNA. http://biomedics.biomed.brown.edu/Faculty/Miller/MitochondrialDNA.html

9) Visual Impairment Service, Leber's Amaurosis. http://call-centre.cogsci.ed.ac.uk/SSC/VISPAGES/5/VIS576634.

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