Ataxia with vitamin E deficiency is a disorder that impairs the body's ability to use vitamin E obtained from the diet. Vitamin E is an antioxidant, which means that it protects cells in the body from the damaging effects of unstable molecules called free radicals. A shortage (deficiency) of vitamin E can lead to neurological problems, such as difficulty coordinating movements (ataxia) and speech (dysarthria), loss of reflexes in the legs (lower limb areflexia), and a loss of sensation in the extremities (peripheral neuropathy). Some people with this condition have developed an eye disorder called retinitis pigmentosa that causes vision loss. Most people who have ataxia with vitamin E deficiency start to experience problems with movement between the ages of 5 and 15 years. The movement problems tend to worsen with age.

Mutations in the TTPA gene cause ataxia with vitamin E deficiency. The TTPA gene provides instructions for making the α-tocopherol transfer protein (αTTP), which is found in the liver and brain. This protein controls distribution of vitamin E obtained from the diet (also called α-tocopherol) to cells and tissues throughout the body. Vitamin E helps cells prevent damage that might be done by free radicals.

TTPA gene mutations impair the activity of the αTTP protein, resulting in an inability to retain and use dietary vitamin E. As a result, vitamin E levels in the blood are greatly reduced and free radicals accumulate within cells. Nerve cells (neurons) in the brain and spinal cord (central nervous system) are particularly vulnerable to the damaging effects of free radicals and these cells die off when they are deprived of vitamin E. Nerve cell damage can lead to problems with movement and other features of ataxia with vitamin E deficiency.

Normal Function

The TTPA gene provides instructions for making the α-tocopherol transfer protein (αTTP), which is found in the liver and brain. This protein controls the distribution of vitamin E obtained from the diet (also called α-tocopherol) to cells and tissues throughout the body. Vitamin E is an antioxidant that protects cells in the body from the damaging effects of unstable molecules called free radicals. Normally, vitamin E derived from food is absorbed in the intestine and then transported into the liver on molecules called chylomicrons.

After a meal, chylomicrons are formed to transport fat-soluble vitamins (such as vitamin E), dietary fats, and cholesterol from the intestine to the liver. Once in the liver, αTTP transfers vitamin E from chylomicrons to very low-density lipoproteins (VLDLs), which carry fat, fat-soluble vitamins, and cholesterol from the liver to other tissues throughout the body. The VLDLs are then released into the bloodstream so the accompanying vitamin E can be used in the body. The αTTP protein is also thought to transport vitamin E to nerve cells (neurons) in the brain.

Health Conditions Related to Genetic Changes

Ataxia with vitamin E deficiency

More than 20 mutations in the TTPA gene have been found to cause ataxia with vitamin E deficiency. This condition is characterized by the development of neurological problems including difficulty coordinating movements (ataxia) due to a buildup of harmful molecules called free radicals. Some of these mutations cause no functional protein to be made, while others change a single protein building block (amino acid) in the αTTP protein, reducing its function. As a result, the body cannot retain or use dietary vitamin E, which leads to reduced levels of this vitamin in the blood and the accumulation of free radicals.

One TTPA gene mutation that is found in the Japanese population changes the amino acid histidine to the amino acid glutamine at position 101 in the αTTP protein (written as His101Glu or H101Q). This mutation is associated with the development of an eye disorder called retinitis pigmentosa that causes vision loss in people with ataxia with vitamin E deficiency.

Mutations in the TTPA gene that cause no functional αTTP protein to be made are associated with a severe form of ataxia that begins at a young age. Mutations that reduce but do not eliminate the protein's function are associated with milder ataxia that occurs at a later age and progresses more slowly.

Other Names for This Gene

• alpha-tocopherol transfer protein
• alphaTTP
• ataxia (Friedreich-like) with vitamin E deficiency
• ATTP
• AVED
• tocopherol (alpha) transfer protein
• TTP1
• TTPA_HUMAN

Genomic Location

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.

AVED may be suspected in individuals who have the following findings at the beginning of puberty:

• Progressive ataxia
• Clumsiness of the hands
• Loss of the ability to know where one's body is in space (proprioception)
• Absent reflexes (areflexia)
• The inability to perform rapid, alternating movements (dysdiadochokinesia)
• A tendency to sway or fall while standing upright with the feet together, arms stretched out and the eyes closed (positive Romberg sign)
• A nodding movement of the head (titubation)
• Decreased visual sharpness (acuity)
• Positive Babinski sign (upward movement of the big toe and fanning of the feet after the sole of the foot has been firmly stroked)
• Macular atrophy (wasting away of the cells that form the part of our eye responsible for central vision)
• Retinitis pigmentosa (eye disease in which there is damage to the retina)

Laboratory studies typically show a reduced plasma vitamin E concentration but normal levels of lipoproteins (proteins that combine with and transport fat or other lipids in the blood). Other studies that may be useful include: nerve conduction studies, brain imaging, and studies of nerve tissues.

Although no universal diagnostic guidelines are available, researchers suggest that diseases that cause fat malabsorption, such as abetalipoproteinemia should be ruled out. Genetic testing finding two TTPA gene mutations may be useful to confirm the diagnosis.

Ataxia with vitamin E deficiency is a rare condition; however, its prevalence is unknown.