Ataxia with Vitamin E Deficiency

Synonyms of Ataxia with Vitamin E Deficiency

• AVED
• Familial Isolated Vitamin E Deficiency
• Isolated Vitamin E Deficiency

General Discussion

Ataxia with vitamin E deficiency (AVED) is a rare inherited neurodegenerative disorder characterized by impaired ability to coordinate voluntary movements (ataxia) and disease of the peripheral nervous system (peripheral neuropathy). AVED is a progressive disorder that can affect many different systems of the body (multisystem disorder). Specific symptoms vary from case to case. In addition to neurological symptoms, affected individuals may experience eye abnormalities, disorders affecting the heart muscles (cardiomyopathy), and abnormal curvature of the spine (scoliosis). AVED is extremely similar to a more common disorder known as Friedreich’s ataxia. AVED is inherited as an autosomal recessive trait.

Vitamin E deficiency often occurs secondary to disorders that impair the absorption of vitamin E from fat including liver disorders, disorders of fat metabolism, and disorders of bile secretion. These disorders include cholestasis (a syndrome of various causes characterized by impaired bile secretion); cystic fibrosis (primarily a lung disorder that may also affect bile secretion); primary biliary cirrhosis (a liver disorder that results in cholestasis); and abetalipoproteinemia (a digestive disorder characterized by fat malabsorption). Premature infants may have a low vitamin E reserve because only small amounts of vitamin E cross the placenta, and therefore they may become deficient if fed a formula high in unsaturated fats and low in vitamin E. In rare cases, vitamin E deficiency may be caused by a poor diet. (For more information on the above disorders, choose the specific disorder name your search term in the Rare Disease Database.)

Signs & Symptoms

AVED affects the central nervous system resulting in peripheral neuropathy and ataxia. Peripheral neuropathy is a general term that denotes a disorder of the peripheral nervous system. The peripheral nervous system consists of all the motor and sensory nerves that connect the brain and spinal cord to the rest of the body (i.e., the nerves outside the central nervous system). Individuals with AVED develop progressive weakness of the legs, which may appear as a staggering, lurching way of walking (gait) or trembling when an affected individual is standing still. Ataxia is defined as a failure of muscle coordination that generally results in an unsteady gait. Without treatment, AVED may progress to cause significant difficulties walking and, potentially over the course of many years, can result in an affected individual becoming wheelchair bound.

Additional neurological findings include partial loss of the sense of touch or sensitivity to pain and temperature may also occur. With time, reflexes in the legs may slow or be absent (areflexia), and an abnormally high-arched foot (pes cavus) may develop with overextension (hyperextension) of the big toe. Involvement of the throat muscles may lead to impaired swallowing and choking and may cause difficulty in eating. Slurred speech (dysarthria) may also be present. Some affected individuals may develop a tremor or shaking of the head (titubation). Intellect and emotions are rarely affected.

In addition to neurological symptoms, individuals with AVED may develop symptoms affecting other systems of the body including eye abnormalities such as retinitis pigmentosa (RP), which is one name for a large group of vision disorders that cause progressive degeneration of the membrane lining the eyes (retina) resulting in visual impairment. Some affected individuals may have yellow “fatty” deposits (xanthelasmata) in the retina.

Affected individuals may also develop lateral or sideways curvature of the spine (scoliosis), degenerative changes of the heart muscle (cardiomyopathy), or “fatty” deposits (xanthomas) affecting the Achilles tendon. Some individuals with AVED may experience a form of dystonia. Dystonia is the name for a group of movement disorders that is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures).

Causes

AVED is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes; one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.

Researchers have determined that AVED results from mutations of a gene on the long arm (q) of chromosome 8 (8q13.1-q13.3). The gene regulates production of a protein (alpha-tocopherol transfer protein) that binds vitamin E into fatty proteins (very-low-density lipoprotein or VLDL) produced and secreted by the liver. Individuals with AVED have an impaired ability to bind vitamin E into VLDL, which results in vitamin E deficiency in certain tissues.

The symptoms of AVED occur because of a deficiency of vitamin E, a fat-soluble vitamin that the body needs in very small amounts. It is stored in the body’s fat. Therefore, it is not necessary to consume vitamin E daily, as long as adequate amounts are stored in the body from a well balanced diet. Vitamin E is found in various foods including vegetable oils, wheat germ, whole-grain cereals, egg yolk, and liver. The liver stores the vitamin E-containing fat. Bile breaks down dietary fat in the small intestine so that vitamins can be absorbed. Vitamin E is an antioxidant, a substance used by the body to protect cells from free radicals, which are atoms that are normal by-products of metabolism. Free radicals damage the cells of the body.

Affected Populations

AVED affects males and females in equal numbers. The disorder is estimated to occur in fewer than 1 in 1 million people. In Tunisia, the disorder is estimated to occur in 1 in 100,000 people. The onset of AVED may occur during childhood or adulthood with cases reported in children as young as two and adults as old as 52. The disorder was first described in the medical literature in 1981.

Related Disorders

Symptoms of the following disorders can be similar to those of AVED. Comparisons may be useful for a differential diagnosis:

Friedreich’s ataxia is a genetic, progressive, neurologic movement disorder that typically becomes apparent before adolescence. Initial symptoms may include unsteady posture, frequent falling, and progressive difficulties walking due to an impaired ability to coordinate voluntary movements (ataxia). Affected individuals may also develop abnormalities of certain reflexes; characteristic foot deformities; increasing incoordination of the arms and hands; slurred speech (dysarthria), and rapid, involuntary eye movements (nystagmus). Friedreich’s ataxia may also be associated with cardiomyopathy, a disease of cardiac muscle that may be characterized by shortness of breath upon exertion (dyspnea), chest pain, and irregularities in heart rhythm (cardiac arrythmias). Friedreich’s Ataxia may be inherited as an autosomal recessive trait. (For more information on this disorder, choose “Friedreich’s ataxia” as your search term in the Rare Disease Database.)

Refsum syndrome is a rare disorder of lipid metabolism inherited as a recessive trait. Symptoms may include a degenerative nerve disease (peripheral neuropathy), failure of muscle coordination (ataxia), retinitis pigmentosa (a progressive vision disorder), and bone and skin changes. This disorder is believed to be due to the absence of phytanic acid hydroxylase in the blood, an enzyme needed for the metabolism of phytanic acid (found in dairy products, beef, lamb and some seafoods). Refsum syndrome is characterized by a marked accumulation of phytanic acid in the plasma and tissues. Prolonged treatment with a diet deficient in phytanic acid can be beneficial. This slowly progressive disorder is most common in children and young adults of Scandinavian heritage. Phytanic acid is a derivative of phytol, a component of chlorophyll. (For more information on this disorder, choose “Refsum” as your search term in the Rare Disease Database.)

Abetalipoproteinemia is a rare inherited disorder of fat metabolism. Abnormalities in fat metabolism result in malabsorption of dietary fat and vitamin E. Affected individuals experience progressive neurological deterioration, muscle weakness, difficulty waling and blood abnormalities including a condition where the red blood cells are malformed (acanthocytosis) resulting in low levels of circulating red blood cells (anemia). Affected individuals may also develop degeneration of the retina of the eyes potentially resulting in loss of vision (retinitis pigmentosa). Abetalipoproteinemia is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Abetalipoproteinemia” as your search term in the Rare Disease Database.)

The following disorders may be associated with AVED as secondary characteristics. They are not necessary for a differential diagnosis: cardiomyopathy, retinitis pigmentosa, and dystonia. (For more information on these conditions, choose the specific name as your search term in the Rare Disease Database.)

Diagnosis

A diagnosis of AVED is made based upon a thorough clinical evaluation, a detailed patient history and a variety of tests and characteristic findings (e.g. low levels of vitamin E with normal levels of lipoproteins and lipids and no evidence of fat malabsorption).

Standard Therapies

Treatment

Individuals with AVED are treated with vitamin E supplementation. Vitamin E treatment has often halted the progression of the disorder and, in some cases, improved existing neurological symptoms.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.