Lebers hereditary optic atrophy
Lebers hereditary optic atrophy is a painless loss of central vision (blurring of objects and colors appearing less vivid) that usually begins between the ages of 25 and 35 (but can occur at any age) and leads to legal blindness. Other minor problems may be present such as tremors, numbness or weakness in arms and legs, or loss of ankle reflexes. It was first described in 1871 by Theodore Leber and is the most common cause of optic atrophy.
Lebers hereditary optic atrophy is also called Lebers hereditary optic neuropathy or LHON. The beginning of visual blurring in both eyes is called the acute phase of LHON. In about half the patients, both eyes are affected at the same time. In the remainder of patients, central vision is lost in one eye over a period of a few weeks, then a month or two later, the second eye is affected. Once both eyes are affected, a few weeks usually pass before the eyesight stops getting worse. Other less common patterns of central vision loss in LHON can be very sudden loss in both eyes, or very gradual loss occuring over several years. After the acute phase, there is rarely any significant change in eyesight during the remainder of the person's life. People with LHON are usually left with some peripheral vision, which is seeing around the edges, or out of the corner of the eye. This final phase is called the atrophic phase because the optic discs are atrophic (cells have wasted away) and rarely change.
The optic disc is the center part of the retina (back of the eye) and is where the clearest vision—both in detail and color—comes from. The retina is what interprets what a person sees and sends this message to their brain, along the pathway known as the optic nerve. In LHON, both the retina and the optic nerve stop working properly. The rest of the eye works normally, so that light enters the eye through the pupil (black circle in the center of the iris, the colored part of the eye) as it should. However, even though the light is focused on the retina properly, in LHON, this information isn't converted into signals for the brain to process. When a person wears prescription glasses, the purpose is to help focus light properly on the retina. In LHON, light is already focused as it should be, so glasses will not improve vision. Magnifying glasses and telescopes do help, however, because they make things look bigger. When a person looks through a magnifier or telescope they use more of their retina to see, and some undamaged cells of the retina may be able to provide some information to the brain.
Suddenly losing vision is a shock. Patients diagnosed with LHON may feel they have no useful sight left, and often, their family and friends treat them as the stereotypic blind person. In reality, LHON usually leaves an affected person with some useable vision. A variety of visual aids are available to enhance this.
In 60% of patients with LHON, there is a positive family history of LHON, while the remaining cases are considered sporadic (occur by chance), where only one person in the family has LHON. In 1988 it was discovered that LHON is caused by a mutation in a mitochondrial gene. Mitochondria are the energy producing organelles (structures) of cells. They have their own genetic material called mitochondrial DNA, which is separate from the usual genetic material contained in the center of the cell (or nucleus). Each mitochondria has several copies of its' circular DNA. DNA is the chemical that makes up genes. Genes code for certain traits, and in some cases, can code for disease. Mutations in the DNA of a mitochondria may be present in all copies (called homoplasmy), or may be present in a portion of the mitochondria's DNA (called heteroplasmy). About 15% of individuals with LHON are heteroplasmic, which means some of their mitochondrial DNA has a mutation, and some does not. This may have a bearing on the chance to develop symptoms, and on the risk of transmission.
There are three specific DNA changes or mutations that are found in the majority (90-95%) of LHON cases. The remaining LHON patients have other various mitochondrial mutations. In genetics, mutations are designated in such a way as to tell a scientist where they are located in the mitochondrial DNA and what the DNA alteration is:
- G11778A (i.e., mutation is located at position 11778; DNA change is G [guanine] to A [adenine]—a change in the base pairs that make up DNA)
Not all persons who have one of these mutations will develop LHON, since it is thought that additional genetic or environmental factors are necessary to develop central vision loss. In general, males with one of these mutations have a 40% lifetime risk to develop symptoms of LHON, while females have a 10% risk, although the actual risk varies slightly from mutation to mutation. In addition, the older a person in whom a mutation has been identified becomes without symptoms, the less likely they will lose their vision at all. If a person is going to experience vision loss from LHON, the majority of people with a mutation will express symptoms by the age of 50 years.
Environmental factors that can reduce the blood supply to the retina and optic nerve, and 'trigger' the vision loss in LHON to begin, include heavy drinking or smoking, exposure to poisonous fumes such as carbon monoxide, high levels of stress, and certain medications. A person in whom a mutation has been identified is considered more susceptible to some of these exposures and are advised not to smoke and to moderate their alcohol intake if they are asymptomatic.
The other important concept to understand in relation to mitochondrial disease is that mitochondria are only inherited from the mother. Therefore, a woman with a mitochondrial mutation (whether she has symptoms or not) will pass it to all of her offspring. Sons who inherit the mutation will not pass it to any of their children, while daughters who inherit the mutation will pass it to all of their children. This is in contrast to nuclear DNA, where half the genetic material is inherited from each parent.
Males have LHON more often than females, however, females may develop LHON at a slightly older age and may have more severe symptoms, including a multiple sclerosis-like illness. Multiple sclerosis is a progressive degeneration of nerve cells that causes episodes of muscle weakness, dizziness, and visual disturbances, followed by remission. The onset of LHON usually occurs by 50 years if a mitochondrial DNA mutation is present, although it can present as late as the sixth or seventh decade of life.
Signs and symptoms
Symptoms of LHON include a painless sudden loss of central vision, both in visual detail and color, in both eyes over a period of weeks to months. Peripheral vision (seeing out of the corner of the eye) remains. Additional symptoms involving the neurological system may be present such as tremors, numbness or weakness in arms or legs, or loss of ankle reflexes. Symptoms vary by gender and type of mutation present. The following mutations are frequently identified and well understood:
- G11778A—the most common mutation and usually the most severe vision loss
- T14484C—usually has the best long term prognosis or outcome
- G3460A—has an intermediate presentation
Persons who have a multiple sclerosis-like illness can have any of the three mutations. This phenomena–where different mutations give different clinical outcomes–is called a genotype-phenotype correlation. The word genotype describes the specific findings in DNA, while the word phenotype is used to describe the clinical presentation.
Suspicion of LHON is usually made by an ophthlamologist after a complete eye examination. Genetic testing for the presence/absence of mitochondrial mutations can then be performed from a small blood sample. After a symptomatic person with LHON in a family has been identified to have a mitochondrial mutation, other asymptomatic at-risk relatives can also be tested. At-risk relatives would include the affected persons' mother, siblings, and the offspring of any females found to have the mutation. Testing for asymptomatic children who are at-risk is not currently offered since no treatment is available for LHON; these individuals could opt for testing upon becoming a legal adult (i.e. reaching 18 years of age). Prenatal diagnosis for LHON is presently not available in the United States, but may be offered elsewhere. With genetic testing for LHON, it is important to remember that the presence of a mitochondrial mutation does not predict whether the condition will occur at all, the age at which it will begin, the severity, or rate of progression.
Treatment and management
There is no proven treatment available for LHON, although some studies report benefit from various vitamin therapies or other medications. Management of LHON is supportive, utilizing visual aids such as magnifiers.
The loss of central vision tends to remain the same (legally blind) over a lifetime once a person with LHON has reached the atrophic phase.
International Foundation for Optic Nerve Disease. PO Box 777, Cornwall, NY 12518. <http://www.ifond.org>.
United Mitochondrial Diseases Foundation. PO Box 1151, Monroeville, PA 15146-1151. <http://www.umdf.org>.
Leber's Optic Neuropathy. <http://www.leeder.demon.co.uk/pages/lhonhome.htm>.
Catherine L. Tesla, MS, CGC