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.
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.
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.
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. Research continues on this subject
(see section on "What research is being done?").
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.
Genetic testing is available at some specialized laboratories and can
assist with clinical diagnosis, prenatal diagnosis, and carrier status
determination. Genetic counselors can help explain how Friedreich's ataxia
is inherited and its effect on the patient and the family. Psychological
counseling and support groups for people with genetic diseases may also
help patients and their families cope with the disease.
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.
Keeping on Top of Your Condition
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NIH Neurological Institute
P.O. Box 5801
Bethesda,
Maryland 20892
(301) 496-5751
(800) 352-9424
Friedreich's Ataxia Research Alliance (FARA)
2001 Jefferson Davis
Hwy.
Suite 209
Arlington, VA 22202
(703)
413-4468
fara@frda.org
Home Page: http://www.frda.org/
National Ataxia Foundation
2600 Fernbrook Lane, Suite
119
Minneapolis, Minnesota 55447-4752
(612) 553-0020
Home Page:
http://www.ataxia.org/
Muscular Dystrophy Association
3300 East Sunrise Drive
Tucson,
Arizona 85718-3208
(520) 529-2000
(800) 572-1717
Home page: http://www.mdausa.org/
National Organization for Rare Disorders, Inc. (NORD)
55 Kenosia
Avenue
P.O. Box 1968
Danbury, CT 06813-1968
(203)
744-0100
(800) 999-6673 (voicemail only)
Fax: (203) 798-2291
Home page: http://www.rarediseases.org/
For information on genetics and genetic counseling referrals, please
contact:
Alliance of Genetic Support Groups
4301 Connecticut Avenue,
N.W., Suite 404
Washington, D.C. 20008-2304
(202) 966-5557
(800)
336-GENE (4363)
Home page: http://www.geneticalliance.org/
Prepared by
Office of Communications and Public Liaison
National
Institute of
Neurological Disorders and Stroke
National Institutes
of Health
Bethesda, Maryland 20892-2540
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