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Leber Hereditary Optic Neuropathy
Leber heridary optic neuropathy (LHON) is an inherited disease of the optic nerve which causes sudden vision loss in early adulthood.
LHON has a mitochondrial pattern of inheritance and males are more affected than females, but the reason for this is not well understood. The mitochondria are referred to as “the powerhouse of the cell” and mutations in our mitochondrial DNA can affect their ability to provide us with energy from food.
Our eyes are our most energy hungry organs and a lack of energy production can lead to degeneration and death of retinal ganglion cells (RGCs), which are the nerve cells that communicate visual information to the brain. Loss of these cells leads to subsequent degeneration of the optic nerve and visual loss. Loss of vision due to LHON does not cause any eye pain, but it is quite an alarming experience as the loss of central vision presents suddenly and can progress quite quickly, leaving only peripheral vision. This means that the majority of people with LHON retain independent mobility but cannot focus on anything straight ahead or see fine detail.
What are the symptoms of LHON?
The symptoms linked with LHON usually become apparent in early adulthood and vision loss is generally the only symptom associated with the condition. The most common first sign is blurred central vision and may begin in one eye or both eyes simultaneously. If one eye is affected, then similar symptoms generally appear in the other eye on average eight weeks later.
As the disease progresses, visual acuity and colour vision deteriorate and tasks involving central vision, such as reading and driving become very challenging. This vision loss is caused by deterioration of the optic nerve, which carries visual signals from the eyes to the brain.
The severity of symptoms may vary from one affected individual to another, even within the same family, due to a ‘dosage’ effect. This is due to the fact that we have many mitochondria in each cell. In one individual, if only a small proportion of mitochondria in each cell have the mutation, symptoms will be mild. In another individual, if a higher proportion of mitochondria in each cell carry the mutation, symptoms will be more severe.
What Causes LHON?
LHON is caused by mutations in genes within the mitochondrial DNA, such as MT-ND1, MT-ND4, MT-ND4L, or MT-ND6. Under normal conditions, these genes produce proteins which help to convert our food (fats, simple sugars) to energy but the reason for the death of cells in the optic nerve is not clear.
As LHON is passed down through generations in a mitochondrial pattern of inheritance and because only the egg cells contribute mitochondria (sperm cells don’t), only females pass the mitochondrial mutations to their children. Often times, people who develop LHON have no family history of the condition. However, it is currently impossible to predict which members of a family who carry a mutation will eventually develop vision loss. More than 50% of men and more than 85% of women with a mitochondrial mutation will never experience vision loss1.
What treatments are available?
Raxone® is a treatment indicated for visual impairments caused by LHON and contains idebenone, an antioxidant compound initially developed for the treatment of Alzheimer’s disease and acts by improving the energy production of the mitochondria. This treatment has been approved by the European Medicines Agency (EMA) as an orphan drug (drug for rare diseases) and is thought to be most effective during the earliest phase of symptoms to protect from further retinal ganglion cell loss. Other antioxidants are currently being examined for their protective effects on the retina.
Environmental factors such as smoking and excessive alcohol consumption can influence LHON onset in some people who are more susceptible and people living with LHON are strongly advised to avoid smoking and alcohol intake to manage their condition.
A number of research teams are investigating gene-based therapies for the treatment of LHON. However, progress in LHON has been slower as there is a need to deliver such a therapy targeted to the mitochondria, of which there may be hundreds or thousands within a single cell.
General eye check-ups are still very important for people with LHON, as they are still at risk for other kinds of eye problems that can affect the general population and may be treatable.
References
1. National Institute of Health. Available at https://ghr.nlm.nih.gov/condition/leber-hereditary-optic-neuropathy#inheritance. Accessed April 2020.