What is Friedreich’s ataxia?
Friedreich’s ataxia (also called FA or FRDA) is a rare inherited disease that causes nervous system damage and movement problems. It usually begins in childhood and leads to impaired muscle coordination (ataxia) that worsens over time. The disorder is named after Nicholaus Friedreich, a German doctor who first described the condition in the 1860s.
In Friedreich’s ataxia the spinal cord and peripheral nerves degenerate, becoming thinner. The cerebellum, part of the brain that coordinates balance and movement, also degenerates to a lesser extent. This damage results in awkward, unsteady movements and impaired sensory functions. The disorder also causes problems in the heart and spine, and some people with the condition develop diabetes. The disorder does not affect thinking and reasoning abilities (cognitive functions).
Friedreich’s ataxia is caused by a defect (mutation) in a gene labelled FXN. The disorder is recessive, meaning it occurs only in someone who inherits two defective copies of the gene, one from each parent. Although rare, Friedreich’s ataxia is the most common form of hereditary ataxia, affecting about 1 in every 50,000 people in the United States. Both male and female children can inherit the disorder.
What are the signs and symptoms?
Symptoms typically begin between the ages of 5 and 15 years, although they sometimes appear in adulthood and on rare occasions as late as age 75. The first symptom to appear is usually gait ataxia, or difficulty walking. The ataxia gradually worsens and slowly spreads to the arms and the trunk.
There is often loss of sensation in the extremities, which may spread to other parts of the body. Other features include loss of tendon reflexes, especially in the knees and ankles. Most people with Friedreich’s ataxia develop scoliosis (a curving of the spine to one side), which often requires surgical intervention for treatment.
Dysarthria (slowness and slurring of speech) develops and can get progressively worse. Many individuals with later stages of Friedreich’s ataxia develop hearing and vision loss.
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 hypertrophic 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. Most individuals with Friedreich’s ataxia tire very easily and find that they require more rest and take a longer time to recover from common illnesses such as colds and flu.
The rate of progression varies from person to person. Generally, within 10 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 may become completely incapacitated.
Friedreich’s ataxia can shorten life expectancy, and heart disease is the most common cause of death. However, some people with less severe features of Friedreich’s ataxia live into their sixties, seventies, or older.
How is Friedreich’s ataxia diagnosed?
A diagnosis of Friedreich’s ataxia requires a careful clinical examination, which includes a medical history and a thorough physical exam, in particular looking for balance difficulty, loss of proprioception (joint sensation), absence of reflexes, and signs of neurological problems. Genetic testing now provides a conclusive diagnosis. Other tests that may aid in the diagnosis or management of the disorder include:
- Eectromyogram (EMG), which measures the electrical activity of muscle cells,
- Nerve conduction studies, which measure the speed with which nerves transmit impulses,
- Electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,
- Eechocardiogram, which records the position and motion of the heart muscle,
- Blood tests to check for elevated glucose levels and vitamin E levels, and
- Magnetic resonance imaging (MRI) or computed tomography (CT) scans tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.
How is Friedreich’s ataxia inherited?
Friedreich’s ataxia is an autosomal recessive disease, meaning individuals only develop symptoms if they inherit two copies of the defective FXN gene, one from their father and one from their mother. A person who has only one abnormal copy of the gene is called a carrier. A carrier will not develop the disease but could pass the gene mutation on to his or her children. If both parents are carriers, 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 an abnormal FXN gene.
In 1996, an international research team identified the Friedreich’s ataxia gene on chromosome 9. The FXN gene codes for production of a protein called “frataxin.” In the normal version of the gene, a sequence of DNA (labelled “GAA”) is repeated between 7 and 22 times. In the defective FXN gene, the repeat occurs over and over again—hundreds, even up to a thousand times.
This abnormal pattern, called a triplet repeat expansion, has been implicated as the cause of several dominantly inherited diseases, but Friedreich’s ataxia is the only known recessive genetic disorder caused by the problem. Almost all people with Friedreich’s ataxia have two copies of this mutant form of FXN, but it is not found in all cases of the disease. About two percent of affected individuals have other defects in the FXN gene that are responsible for causing the disease.
The triplet repeat expansion greatly disrupts the normal production of frataxin. Frataxin is found in the energy-producing parts of the cell called mitochondria. Research suggests that without a normal level of frataxin, certain cells in the body (especially peripheral nerve, spinal cord, brain and heart muscle cells) cannot effectively produce energy and have been hypothesized to have a buildup of toxic by-products leading to what is called “oxidative stress.” It also may lead to increased levels of iron in the mitochondria.
When the excess iron reacts with oxygen, free radicals can be produced. Although free radicals are essential molecules in the body’s metabolism, they can also destroy cells and harm the body. Research continues on this subject.
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Figure 1:The graphic above represents how likely two parents carrying the abnormal FXN gene are to passing FA onto their children
Figure 2:The graphic above is a model of the FXN gene