Ataxia with oculomotor apraxia is a condition characterized by problems with movement that worsen over time. The hallmark of this condition is poor coordination and balance (ataxia), which is often the first symptom. Most affected people also have oculomotor apraxia, which makes it difficult to move their eyes side-to-side. People with oculomotor apraxia have to turn their head to see things in their side (peripheral) vision.

There are several types of ataxia with oculomotor apraxia, the most common of which are types 1, 2, and 4. The types are very similar but are caused by mutations in different genes.

Type 1 begins around age 4. In addition to ataxia and oculomotor apraxia, affected individuals can have involuntary jerking movements (chorea) or muscle twitches (myoclonus); these movement problems tend to disappear over time. Individuals with this type may also develop muscle wasting in their hands and feet, which further impairs movement. As in all forms of ataxia with oculomotor apraxia, nearly all people with type 1 develop nerve abnormalities (neuropathy). Neuropathy impairs reflexes and leads to limb weakness and an inability to sense vibrations. Many individuals with ataxia with oculomotor apraxia require wheelchair assistance, typically 10 to 15 years after the start of movement problems.

People with some types of ataxia with oculomotor apraxia may have characteristic blood abnormalities. Individuals with type 1 tend to have reduced amounts of a protein called albumin, which transports molecules in the blood. The shortage of albumin likely results in elevated levels of cholesterol circulating in the bloodstream. Increased cholesterol levels raise a person's risk of developing heart disease.

Ataxia with oculomotor apraxia type 2 usually begins around age 15. As in type 1, affected individuals may have chorea or myoclonus, although these movement problems persist throughout life in type 2. Neuropathy is also common in this type.

A key feature of ataxia with oculomotor apraxia type 2 is high amounts of a protein called alpha-fetoprotein (AFP) in the blood. (Raised levels of this protein are normally seen in the bloodstream of pregnant women.) Individuals with type 2 may also have high amounts of a protein called creatine phosphokinase (CPK) in their blood. This protein is normally found primarily in muscle tissue. The effect of abnormally high levels of AFP or CPK in people with ataxia with oculomotor apraxia type 2 is unknown. Although individuals with type 2 usually have normal albumin levels, cholesterol may be elevated.

Ataxia with oculomotor apraxia type 4 begins around age 4. In addition to ataxia and oculomotor apraxia, individuals with this type typically develop dystonia, which is involuntary, sustained muscle tensing that causes unusual positioning of body parts. Dystonia can be the first feature of the condition, and it tends to disappear gradually over time. Muscle wasting in the hands and feet and neuropathy are also common in individuals with type 4.

In ataxia with oculomotor apraxia type 4, albumin levels can be low, and cholesterol or AFP can be elevated. However, the amounts of these molecules are normal in many affected individuals.

Intelligence is usually not affected by ataxia with oculomotor apraxia, but some people with the condition have intellectual disability.

Mutations in the APTX, SETX, or PNKP gene cause ataxia with oculomotor apraxia types 1, 2, or 4, respectively. Mutations in another gene cause ataxia with oculomotor apraxia type 3.

The APTX, SETX, and PNKP genes provide instructions for making proteins that are involved in repairing damaged DNA. Mutations in any of these genes reduce the amount of functional protein produced from that gene. This shortage prevents the efficient repair of DNA damage, which leads to the accumulation of broken DNA strands. DNA breaks may be caused by potentially harmful molecules (called reactive oxygen species) produced during normal cellular functions, natural and medical radiation, or other environmental exposures. They may also occur when chromosomes exchange genetic material in preparation for cell division. DNA damage that is not repaired makes the cell unstable and can lead to cell death. It is thought that cell death has a particularly severe effect in the brain because the nervous system does not replace nerve cells that have been lost. The part of the brain involved in coordinating movements (the cerebellum) is especially at risk. It is thought that the loss of brain cells in the cerebellum causes the movement problems characteristic of ataxia with oculomotor apraxia.

Normal Function

The APTX gene provides instructions for making a protein called aprataxin that is involved in the repair of DNA damage in cells. Aprataxin is located in the nucleus of cells and is produced in various tissues, including the brain, spinal cord, and muscles. Different parts of the aprataxin protein allow the protein to interact with other DNA repair proteins to make repairs. At the site of the damage, aprataxin modifies the broken ends of the DNA strands so they can be joined back together correctly.

Health Conditions Related to Genetic Changes

Ataxia with oculomotor apraxia

More than 30 mutations in the APTX gene have been found to cause ataxia with oculomotor apraxia type 1. This condition is characterized by difficulty coordinating movements (ataxia) and problems with side-to-side movements of the eyes (oculomotor apraxia). Most mutations change single protein building blocks (amino acids) in aprataxin, resulting in an unstable aprataxin protein that is quickly broken down in the cell. A lack of functional aprataxin disrupts DNA repair and can lead to an accumulation of damage in cells, particularly affecting cells in the part of the brain involved in coordinating movements (the cerebellum). This accumulation can lead to cell death in the cerebellum, causing the characteristic movement problems of ataxia with oculomotor apraxia type 1.

Other Names for This Gene

• AOA
• AOA1
• APTX_HUMAN
• ataxia 1, early onset with hypoalbuminemia
• AXA1
• EAOH
• EOAHA
• FHA-HIT

Genomic Location

Normal Function

The PNKP gene provides instructions for making the polynucleotide kinase-phosphatase (PNKP) enzyme. This enzyme is critical for repairing broken strands of DNA molecules. It can help fix damage that affects one DNA strand (single-strand breaks) or both strands (double-strand breaks). At the site of the damage, the PNKP enzyme modifies the broken ends of the DNA strands so that they can be joined back together.

Health Conditions Related to Genetic Changes

Ataxia with oculomotor apraxia

At least nine PNKP gene mutations have been found to cause ataxia with oculomotor apraxia type 4. This condition is characterized by poor coordination and balance (ataxia) and problems with side-to-side movement of the eyes (oculomotor apraxia). These problems are due to the breakdown (degeneration) of nerve cells in the part of the brain that coordinates movement (the cerebellum).

PNKP gene mutations that cause ataxia with oculomotor apraxia type 4 lead to production of an unstable enzyme that is quickly broken down in the cell. Shortage of the PNKP enzyme prevents efficient repair of damaged DNA. Researchers suggest that the repair of single-strand breaks is particularly impaired in ataxia with oculomotor apraxia type 4. It is thought that single-strand DNA damage increases after birth as the brain grows. Without repair, the accumulating damage leads to a loss of nerve cell in the brain, resulting in the movement problems characteristic of ataxia with oculomotor apraxia type 4.

Microcephaly, seizures, and developmental delay

At least six mutations in the PNKP gene have been found to cause microcephaly, seizures, and developmental delay (MCSZ). This condition is characterized by problems with brain development before birth that result in an unusually small head size (microcephaly), recurrent seizures (epilepsy), and delayed development of speech and motor skills. Rarely, affected individuals also have difficulty coordinating movements (ataxia) due to degeneration of nerve cells in the cerebellum.

PNKP gene mutations that cause MCSZ lead to production of an unstable enzyme that is quickly broken down in the cell. Shortage of the PNKP enzyme prevents efficient repair of damaged DNA. Researchers suggest that, in contrast to ataxia with oculomotor apraxia type 4 (described above), the repair of double-strand breaks is particularly impaired in MCSZ. The accumulating damage is especially harmful to nerve cells. It is thought that excessive DNA damage before birth leads to the death of nerve cell precursors, impairing normal brain development and causing microcephaly and the other neurological features of MCSZ.

It is unclear why mutations in the same gene, even the same mutation in some cases, can have different effects on single-strand or double-strand DNA damage repair and cause either ataxia with oculomotor apraxia type 4 or MCSZ.

Other Names for This Gene

• AOA4
• bifunctional polynucleotide phosphatase/kinase
• DNA 5'-kinase/3'-phosphatase
• EIEE10
• Homo sapiens polynucleotide kinase 3'-phosphatase (PNKP)
• MCSZ
• PNK

Genomic Location

Normal Function

The SETX gene provides instructions for making a protein called senataxin. Senataxin is produced in a wide range of tissues, including the brain, spinal cord, and muscles. Based on the structure of senataxin, researchers believe that it is one of a class of proteins called helicases, which attach to particular regions of DNA or RNA (a chemical cousin of DNA) and temporarily unwind the strands of the molecule. By unwinding the strands, helicases allow other proteins to reach the strands to perform their function. Although senataxin's role in cells is not completely understood, it appears to be involved in the production of proteins from genes (transcription), the processing of RNA molecules, and the repair of damaged DNA.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Ataxia with oculomotor apraxia

At least 125 mutations in the SETX gene have been found to cause ataxia with oculomotor apraxia type 2. This condition is characterized by difficulty coordinating movements (ataxia) and problems with side-to-side movements of the eyes (oculomotor apraxia). Most mutations replace single protein building blocks (amino acids) in senataxin. The mutations associated with ataxia with oculomotor apraxia type 2 are thought to disrupt the helicase function of senataxin. Although it is unclear how impaired senataxin function leads to the signs and symptoms of ataxia with oculomotor apraxia type 2, some researchers suggest that it disrupts DNA repair and can lead to an accumulation of DNA damage in cells. This accumulation can lead to cell death and seems particularly harmful to cells in the part of the brain involved in coordinating movements (the cerebellum), causing the characteristic movement problems of ataxia with oculomotor apraxia type 2.

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Other Names for This Gene

• ALS4
• AOA2
• KIAA0625
• SCAR1
• Sen1
• SETX_HUMAN

Genomic Location

All types of this condition are 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.

Ataxia with oculomotor apraxia is a rare condition. Types 1 and 4 are most frequent in Portugal, and type 1 is also found in Japan. Type 2 is estimated to occur in 1 in 900,000 individuals worldwide. Type 3 has been found in only one family.