Friedreich's Ataxia: Signs, Symptoms, Diagnosis, Treatment

Friedreich's Ataxia: Signs, Symptoms, Diagnosis, Treatment

What is Friedreich's ataxia?

Friedreich's ataxia is an inherited disease that causes progressive damage to the nervous system resulting in symptoms ranging from muscle weakness and speech problems to heart disease. It is named after the physician Nicholas Friedreich, who first described the condition in the 1860's. "Ataxia," which refers to coordination problems such as clumsy or awkward movements and unsteadiness, occurs in many different diseases and conditions. In Friedreich's ataxia, ataxia results from the degeneration of nerve tissue in the spinal cord and of nerves that control muscle movement in the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath - the insular covering on all nerve cells that helps conduct nerve impulses.

Friedreich's ataxia, although rare, is the most prevalent inherited ataxia, affecting about 1 in every 50,000 people in the United States. Males and females are affected equally.

Read more: Frozen Shoulder (Adhesive Capsulitis) Causes, Symptoms, Diagnosis, Treatment, Prevention

What are the signs and symptoms?

Symptoms usually begin between the ages of 5 and 15 but can, on rare occasions, appear as early as 18 months or as late as 30 years of age. The first symptom to appear is usually difficulty in walking, or gait ataxia. The ataxia gradually worsens and slowly spreads to the arms and then the trunk. Foot deformities such as clubfoot, flexion (involuntary bending) of the toes, hammer toes, or foot inversion (turning inward) may be early signs. Over time, muscles begin to weaken and waste away, especially in the feet, lower legs, and hands, and deformities develop. Other symptoms include loss of tendon reflexes, especially in the knees and ankles. There is often a gradual loss of sensation in the extremities, which may spread to other parts of the body. Dysarthria (slowness and slurring of speech) develops, and the person is easily fatigued. Rapid, rhythmic, involuntary movements of the eyeball (nystagmus) is common. Most people with Friedreich's ataxia develop scoliosis (a curving of the spine to one side), which, if severe, may impair breathing.

Other symptoms that may occur include chest pain, shortness of breath, and heart palpitations. These symptoms are the result of various forms of heart disease that often accompany Friedreich's ataxia, such as cardiomyopathy (enlargement of the heart), myocardial fibrosis (formation of fiber-like material in the muscles of the heart), and cardiac failure. Heart rhythm abnormalities such as tachycardia (fast heart rate) and heart block (impaired conduction of cardiac impulses within the heart) are also common. About 20 percent of people with Friedreich's ataxia develop carbohydrate intolerance and 10 percent develop diabetes mellitus. Some people lose hearing or eyesight.

The rate of progression varies from person to person. Generally, within 15 to 20 years after the appearance of the first symptoms, the person is confined to a wheelchair, and in later stages of the disease, individuals become completely incapacitated. Life expectancy is greatly affected, and most people with Friedreich's ataxia die in early adulthood if there is significant heart disease, the most common cause of death. However, some people with less severe symptoms of Friedreich's ataxia live much longer.

How is Friedreich's ataxia diagnosed?

Doctors diagnose Friedreich's ataxia by performing a careful clinical examination, which includes a medical history and a thorough physical examination. Tests that may be performed include:

  • electromyogram (EMG), which measures the electrical activity of muscle cells,
  • nerve conduction studies, which measure the speed with which nerves transmit impulses,
  • electrocardiogram (EKG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,
  • echocardiogram, which records the position and motion of the heart muscle,
  • magnetic resonance imaging (MRI) or computed tomography (CT) scan, which provides a picture of the brain and spinal cord,
  • spinal tap to evaluate the cerebrospinal fluid,
  • blood and urine tests to check for elevated glucose levels, and
  • genetic testing to identify the affected gene.

Can Friedreich's ataxia be cured or treated?

As with many degenerative diseases of the nervous system, there is currently no effective cure or treatment for Friedreich's ataxia. However, many of the symptoms and accompanying complications can be treated to help patients maintain optimal functioning as long as possible. Diabetes, if present, can be treated with diet and medications such as insulin, and some of the heart problems can be treated with medication as well. Orthopedic problems such as foot deformities and scoliosis can be treated with braces or surgery. Physical therapy may prolong use of the arms and legs. Scientists hope that recent advances in understanding the genetics of Friedreich's ataxia may lead to breakthroughs in treatment.

How is Friedreich's ataxia inherited?

Friedreich's ataxia is an autosomal recessive disease, which means the patient must inherit two affected genes, one from each parent, for the disease to develop. A person who has only one abnormal copy of a gene for a recessive genetic disease such as Friedreich's ataxia is called a carrier. A carrier will not develop the disease but could pass the affected gene on to his or her children. If both parents are carriers of the Friedreich's ataxia gene, their children will have a 1 in 4 chance of having the disease and a 1 in 2 chance of inheriting one abnormal gene that they, in turn, could pass on to their children. About one in 90 Americans of European ancestry carries one affected gene.

Humans have two copies of each gene - one inherited from the mother and one from the father. Genes are located at a specific place on each of an individual's 46 chromosomes, which are tightly coiled chains of DNA containing millions of chemicals called bases. These bases - adenine, thymine, cytosine, and guanine - are abbreviated A, T, C, and G. Certain bases always "pair" together (A with T; C with G), and different combinations of base pairs join in sets of three to form coded messages.

These coded messages are "recipes" for making amino acids, the building blocks of proteins. By combining in long sequences, like long phone numbers, the paired bases tell each cell how to assemble different proteins. Proteins make up cells, tissues, and specialized enzymes that our bodies need to function normally. The protein that is altered in Friedreich's ataxia is called frataxin.

In 1996, an international group of scientists identified the cause of Friedreich's ataxia as a defect in a gene located on chromosome 9. Because of the inherited abnormal code, a particular sequence of bases (GAA) is repeated too many times. Normally, the GAA sequence is repeated 7 to 22 times, but in people with Friedreich's ataxia it is repeated 800 to 1,000 times. This type of abnormality is called a triplet repeat expansion and has been implicated as the cause of several dominantly inherited diseases. Friedreich's ataxia is the first known recessive genetic disease that is caused by a triplet repeat expansion. Although about 98 percent of Friedreich's ataxia carriers have this particular genetic triplet repeat expansion, it is not found in all cases of the disease. A very small proportion of affected individuals have other gene coding defects responsible for causing disease.

The triplet repeat expansion apparently disrupts the normal assembly of amino acids into proteins, greatly reducing the amount of frataxin that is produced. Research suggests that without a normal level of frataxin, certain cells in the body (especially brain, spinal cord, and muscle cells) cannot manage the normal amounts of "oxidative stress" which the mitochondria, the energy-producing power plants of cells, produce. This clue to the possible cause of Friedreich's ataxia came after scientists conducted studies using a yeast protein with a chemical structure similar to human frataxin. They found that the shortage of this protein in the yeast cell led to a toxic buildup of iron in the cell's mitochondria. When the excess iron reacted with oxygen, free radicals were produced. Although free radicals are essential molecules in the body's metabolism, they can also destroy cells and harm the body.

What research is being done?

Within the Federal government the National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH), has primary responsibility for sponsoring research on neurological disorders. As part of this mission, the NINDS conducts research on Friedreich's ataxia and other forms of inherited ataxias at its facilities at the NIH and supports additional studies at medical centers throughout the United States.

Researchers are optimistic that they will soon be closer to understanding the causes of the disease, which will assist in the diagnosis of patients, aid those who counsel families, and eventually help scientists develop effective treatments and prevention strategies for Friedreich's ataxia.

The studies using yeast proteins with a chemical structure similar to human frataxin (see section on "How is Friedreich's ataxia inherited?") led to further studies in mice and humans. These studies revealed that frataxin - like the yeast protein - is a mitochondrial protein that should normally be present in the nervous system, the heart, and the pancreas. Yet in patients with the disease, the amount of frataxin in affected cells of these tissues is severely reduced. Further evidence that frataxin may function similarly to the yeast protein was the finding of abnormally high levels of iron in the heart tissue of people with Friedreich's ataxia. It is believed that the nervous system, heart, and pancreas may be particularly susceptible to damage from free radicals (produced when the excess iron reacts with oxygen) because once certain cells in these tissues are destroyed by free radicals they cannot be replaced. Nerve and muscle cells also have metabolic needs that may make them particularly vulnerable to free radical damage. Free radicals have been implicated in other degenerative diseases such as Parkinson's and Alzheimer's diseases.

Armed with what they currently know about frataxin and Friedreich's ataxia, scientists are working to better define frataxin's role, clarify how defects in iron metabolism may be involved in the disease process, and explore new therapeutic approaches for the disease. The discovery by NINDS-supported researchers of the genetic mutation that causes Friedreich's ataxia has added new impetus to research efforts on this disease.