Neurology Now:
January/February 2010 - Volume 6 - Issue 1 - p 12–13
doi: 10.1097/01.NNN.0000368484.78547.a7
Departments: The Waiting Room
This Way In: Friedreich's Ataxia
Stump, Elizabeth
There is promising news on the horizon for people with Friedreich's
ataxia, a neurological disease that causes progressive muscle weakness,
difficulty walking, slurred speech, and heart problems. The discovery of
the mechanism for a potential drug treatment was reported in the
September 25, 2009 issue of the medical journal Chemistry & Biology.
A team of researchers led by Joel Gottesfeld, Ph.D., professor of
molecular biology at the Scripps Research Institute in LaJolla, CA,
discovered the specific enzyme target of a compound called 4b that stops
the progression of the disease in mice. Dr. Gottesfeld's team discovered
the compound three years ago but didn't know how it worked. Now, having
identified the particular enzyme that 4b blocks, they are developing
targets for treatment.
The term "ataxia" can refer to problems with movement and coordination
that occur with several different neurological conditions. The term also
indicates a group of degenerative and progressive diseases of the
nervous system that occur sporadically or—as in the case of Friedreich's
ataxia—through genetics.
Friedreich's ataxia affects 1 in every 20,000 to 50,000 people in the
United States. Men and women are equally affected. The cause of
Friedrich's ataxia is a defect in a gene, located on chromosome 9, that
reduces the amount of a protein called frataxin in patients. Frataxin is
found in the energy-producing parts of the cell. Without a normal level
of frataxin, certain cells in the body cannot effectively produce energy
or rid themselves of toxins, resulting in degeneration. For example, the
spinal cord becomes thinner, and nerve cells that control limb movement
lose some of their myelin sheath (the covering on all nerve cells that
helps conduct nerve impulses).
Researchers believe the genetic defect attracts a group of enzymes known
as histone deacetylases, which inactivate expression of the frataxin
gene. In 2006, Dr. Gottesfeld's team reported that 4b blocked activity
of these enzymes, jumpstarting frataxin production in white blood cells
taken from Friedreich's patients. Later work showed that a close
derivative of 4b increased frataxin production in a mouse model for
Friedreich's ataxia. The most recent work has identified the specific
histone deacetylase enzyme that is blocked by 4b.
The degeneration of nerve tissue in Friedreich's ataxia leads to muscle
weakness and wasting in the hands, feet, and lower legs, which is why
patients are often confined to a wheelchair within 10 to 20 years of the
appearance of symptoms. Typically, symptoms begin in patients ages 5 to
15. Difficulty with walking is usually the first symptom to appear. As
the disease progresses, patients may experience a gradual loss of
sensation in the extremities; rapid, involuntary eye movements; slow,
slurred speech; spinal curvature (scoliosis); and heart disease and
heart failure.
The rate of progression and the life expectancy varies from person to
person. Most people with Friedreich's ataxia die in early adulthood if
they have significant heart disease (the most common cause of death in
these patients). Some people with less severe symptoms of Friedreich's
ataxia live into their sixties or seventies.
In order to diagnose Friedreich's ataxia, neurologists perform a careful
clinical examination. They may also perform tests such as an
electromyogram (EMG), which measures the electrical activity of muscle
cells; electrocardiogram (EKG), which shows the beat pattern of the
heart; magnetic resonance imaging (MRI) or computed tomography (CT)
scan, which show a picture of the brain and spinal cord; a spinal tap to
examine the cerebrospinal fluid; nerve conduction studies, which measure
the speed with which nerves transmit impulses; blood and urine tests to
look for high glucose levels; and genetic testing to identify the
affected gene.
Adaptive devices (such as canes or walkers), therapies (such as speech
therapy to improve speech and aid swallowing), and medications for
accompanying complications (like heart problems) can assist patients.
Although there is no effective treatment or cure for Friedreich's
ataxia, researchers are hard at work.
"Idebenone has shown some efficacy in preventing or reversing the
associated heart disease, but even idebenone has failed to reverse or
slow progression of the neurological symptoms," Dr. Gottesfeld says.
"Our compounds—called histone deacetylase inhibitors—target the loss of
frataxin protein, which is the cause of the disease. They do this by
reactivating the gene that is silenced in Friedreich's ataxia."
Dr. Gottesfeld will continue to study how the enzyme blocked by 4b
controls frataxin production and its relationship to inactivating the
frataxin gene. Repligen Corporation, which was involved in Dr.
Gottesfeld's study, is doing all of the pre-clinical testing necessary
to initiate a human safety trial.
"Erythropoetin has also been found to increase the levels of frataxin
protein, and this drug is in clinical trials," Dr. Gottesfeld adds.
Genetic testing assists with prenatal diagnosis, clinical diagnosis, and
carrier status determination. Psychological counseling and support
groups may also help patients and their families cope.
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Ataxia Resources
▸ Friedreich's Ataxia Research Alliance (FARA) 703-426-1576, CureFA.org
▸ Genetic Alliance 202-966-5557 or 800-336-GENE (4363)
geneticalliance.org
▸ Muscular Dystrophy Association 520-529-2000 or 800-344-4863, mda.org
▸ National Ataxia Foundation 763-553-0020, ataxia.org
▸ National Organization for Rare Disorders (NORD) 203-744-0100 or
800-999-NORD (6673), rarediseases.org
▸ National Society of Genetic Counselors 312-321-6834, nsgc.org
Elizabeth Stump
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