Leber hereditary optic neuropathy (LHON)

Leber hereditary optic neuropathy (LHON) is an inherited optic nerve disease that leads to sudden, painless vision loss during young adult life, most commonly affecting men. It is caused by mutations in the genetic code of the mitochondria, which are small subunits that reside within the cell.

Mitochondria are also known as the “powerhouses of the cell” as they constantly convert energy locked in our food into energy that the cell can use. 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. However, it is worth noting that a significant percentage of people who possess a mutation that causes LHON do not develop any features of the disorder.

Loss of vision due to LHON can be 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. The prevalence of this condition is thought to be around 1 in 50,000 people worldwide.

Leber hereditary optic neuropathy (LHON)

Symptoms

The symptoms of Leber’s Hereditary Optic Neuropathy (LHON) typically present when a person is in their teens or twenties, although in some rarer instances, LHON has been diagnosed in young children and in older adults.

Affected individuals do not usually present any symptoms until they develop visual blurring or clouding affecting their central vision. These vision problems may begin in one eye or both simultaneously. If one eye is affected, then similar symptoms appear in the other eye on average eight weeks later.

Over time, the vision in both eyes worsens with a severe loss of sharpness and a fading of colour vision. The vision loss mainly affects central vision, which is needed for tasks such as reading, driving and recognising faces. Optic atrophy follows, in which the cells of the optic nerve (which carries the visual information from the eyes to the brain) becomes damaged or die. In a small percentage of cases, central vision loss can improve but in most cases loss of vision is permanent.

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.

Generally, vision loss is the only symptom of LHON; however, there are cases where additional neurological symptoms have been identified such as tremors, movement disorders and electrical signal abnormalities affecting the heartbeat. This is referred to as “LHON plus”.

Causes

Leber’s Hereditary Optic Neuropathy (LHON) is a genetic condition. It is caused by mutations in the DNA of the mitochondria, the powerhouses of the cell that generate energy for the cell to use in normal activity in the human body. Within this DNA, which is separate to the DNA of the cell, the genes affected by mutations include MT-ND1, MT-ND4, MT-ND4L and MT-ND6. This leads to disrupted energy production within the mitochondria. However, it remains unknown as to how these gene mutations lead to death of cells within the optic nerve, causing optic atrophy.

LHON follows a mitochondrial pattern of inheritance, which is also known as maternal inheritance. Only egg cells (and not sperm cells) contribute mitochondria to a developing embryo, therefore only females can pass mitochondrial conditions to their children. Fathers affected by LHON or carrying LHON mutations do not pass the condition to their children.

More information on genetic inheritance can be found at out Genetic Inheritance section.

Often, 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 loss.

Diagnosis

It’s often impossible to tell which type of retinal disease a person has just by looking into the eye. As such, a genetic test may be necessary to confirm the diagnosis.

The Target 5000 programme provides free genetic and clinical testing to all individuals living in Ireland with a genetic retinal degeneration, including Leber’s Hereditary Optic Neuropathy (LHON). Through genetic screening of the person awaiting diagnosis and their family members, the Target 5000 programme will provide more detailed information about the nature and inheritance pattern of the condition.

As gene-specific clinical trials and treatments become available, knowing the genetic mutation associated with a genetic retinal degeneration will become even more important. Taking part in this programme ensures participants are included on a national registry from which participants can be identified for clinical trials and treatments and from which further information about each of the genetic retinal degenerations can be defined.

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