Ataxia with oculomotor apraxia

Ataxia with oculomotor apraxia is a condition characterized by progressive problems with movement. The hallmark of this condition is difficulty coordinating movements (ataxia), which is often the first symptom. About half of affected people have trouble moving their eyes to look side-to-side (oculomotor apraxia). People with oculomotor apraxia have to turn their head to see things in their side (peripheral) vision.

There are two types of ataxia with oculomotor apraxia. The two types are very similar but are caused by mutations in different genes. Shared features, in addition to ataxia and oculomotor apraxia, are involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). Type 1 typically has an earlier onset of symptoms (around age 7) than type 2 (around age 15). Chorea and myoclonus tend to disappear gradually in type 1 whereas these movement problems are persistent in type 2. Neuropathy is more severe in type 1 and can lead to impaired mobility, muscle and nerve degeneration (atrophy), and occasionally, limb deformities. Individuals with type 1 typically require wheelchair assistance about 10 years after the start of movement problems; those with type 2 tend to be mobile for a longer period of time. Intellectual functioning is usually not affected by either type of the disorder, but some people may have mild cognitive problems, such as difficulty concentrating or performing multi-step activities.

People with ataxia with oculomotor apraxia type 1 tend to have decreased amounts of a protein called albumin, which transports molecules in the blood, and increased amounts of cholesterol circulating in their bloodstream. Increased cholesterol levels may raise a person's risk of developing heart disease. The effects of abnormal levels of albumin are unknown. People with ataxia with oculomotor apraxia type 2 tend to have high amounts of a protein called alpha-fetoprotein (AFP) in their blood. The level of this protein is usually increased in the bloodstream of pregnant women. Affected individuals may also have high amounts of a protein called creatine phosphokinase (CPK) in their blood. This protein is found mainly in muscle tissue. The effect of abnormally high levels of AFP or CPK in people with ataxia with oculomotor apraxia is unknown.

Ataxia with oculomotor apraxia is a rare condition. Type 1 is estimated to affect 55 per million people in Portugal, where the condition was first discovered. Type 1 is a common form of ataxia in Japan. Type 2 is more common in the French-Canadian population than in other parts of the world. Outside of these populations, the incidence of both types of this condition is unknown.

Mutations in the APTX gene cause ataxia with oculomotor apraxia type 1. The APTX gene provides instructions for making a protein called aprataxin that is involved in DNA repair. Mutations in the APTX gene result in an unstable aprataxin protein that quickly gets broken down in the cell.

Mutations in the SETX gene cause ataxia with oculomotor apraxia type 2. The SETX gene provides instructions for producing a protein called senataxin. Based on the structure of senataxin, researchers believe that it is involved in DNA repair and the production of RNA, a chemical cousin of DNA. Mutations in the SETX gene cause the production of a senataxin protein that cannot perform its function in DNA repair and RNA production.

Nonfunctional aprataxin and senataxin proteins lead to the accumulation of breaks in DNA. These breaks can be caused by natural and medical radiation or other environmental exposures, and also occur when chromosomes exchange genetic material in preparation for cell division. DNA breaks that are not repaired cause the cell to be unstable and can lead to cell death. Mutations in aprataxin and senataxin particularly affect brain cells, where DNA repair is essential. The part of the brain involved in coordinating movements (the cerebellum) is especially affected. It is thought that the loss of brain cells in the cerebellum causes the movement problems characteristic of ataxia with oculomotor apraxia.

Read more about the APTX and SETX genes.

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.