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). Some affected individuals may also develop diabetes mellitus, a condition in which there is insufficient secretion of the hormone insulin. Primary symptoms may include abnormally increased thirst and urination (polydipsia and polyuria), weight loss, lack of appetite, fatigue, and blurred vision.
Friedreich's Ataxia may be inherited as an autosomal recessive trait. Cases in which a family history of the disease has not been found may represent new genetic changes (mutations) that occur spontaneously (sporadically). Friedreich's Ataxia results from mutations of a gene known as "X25" or "frataxin" located on the long arm (q) of chromosome 9 (9q13). In most affected individuals, the frataxin gene contains errors in the coded "building blocks" (nucleotide bases) that make up the gene's instructions. The symptoms and findings associated with Friedreich's Ataxia are thought to result primarily from degenerative changes of nerve fibers of the spinal cord as well as peripheral nerves, which are the motor and sensory nerves and groups of nerve cell bodies (ganglia) outside the brain and spinal cord.
The primary symptom of Friedreich’s Ataxia is progressive weakness of the legs, which may appear as a staggering, lurching way of walking (gait), or trembling when the patient is standing still. Ataxia is defined as a failure of muscle coordination that generally results in an unsteady gait. 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, and a high- arched foot 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. The intellect and emotions are rarely affected. Lateral or sideways curvature of the spine (scoliosis), diabetes mellitus, or degenerative changes in the heart (cardiomyopathy) may occur but are not necessary for a differential diagnosis.
Symptoms of Friedreich’s Ataxia are caused by the gradual deterioration (degeneration) of nerve cells on the back portion of the spinal nerves (the dorsal ganglia), spinal cord and brain.
Approximately, ten percent of individuals with Friedreich’s Ataxia develop Diabetes Mellitus. In addition, an estimated 20 percent of individuals with Friedreich’s Ataxia may develop an intolerance to carbohydrate.
Friedreich’s Ataxia may be transmitted as an autosomal recessive trait. In addition, cases in which a positive family history has not been found are thought to represent new genetic changes (mutations) that occur spontaneously (sporadically).
Human traits, including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene from 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
During genetic analysis of several affected families (kindreds), investigators identified a gene responsible for Friedreich’s Ataxia. The gene, designated as the “X25″ or “frataxin” gene, is located on the long arm (q) of chromosome 9 (9q13). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.
The frataxin gene regulates (encodes for) the production of a protein that is expressed at high levels in the heart and spinal cord. Certain mutations of the gene may result in impaired functioning or deficiency of the frataxin protein, ultimately leading to the symptoms and findings associated with Friedreich’s Ataxia.
In most affected individuals, the frataxin gene contains errors in the coded “building blocks” that make up its specific genetic instructions. The instructions within every gene consist of different arrangements of four basic chemicals (nucleotide bases) called adenine (A), cytosine (C), guanine (G), and thymine (T). In those with Friedreich’s Ataxia, the frataxin gene may contain abnormally long repeats of coded instructions consisting of guanine, adenine, and adenine (GAA trinucleotide repeat expansion). For example, individuals with the disease may have 200 to over 1,000 GAA repeats. However, individuals without the disorder tend to have about 7 to 22 GAA repeats in the gene. Expanded GAA repeats are unstable and may expand or contract with successive generations. Some investigators indicate that the variability of associated symptoms and findings may be related to the size of expanded GAA repeats. For example, shorter expansions may be associated with later symptom onset and absence of cardiomyopathy.
Researchers have determined that the protein encoded by the frataxin gene is a mitochondrial protein. Mitochondria are minute, thread-like components (organelles) outside the nuclei of cells that provide the primary source of cellular energy. Investigators suggest that the frataxin protein plays a role in regulating mitochondrial iron levels. Impaired functioning or deficiency of the protein may lead to abnormal accumulations of iron within mitochondria and increased production of certain chemical compounds (oxygen free radicals) that may cause cumulative cellular damage and impaired cellular functioning.
A variant of Friedreich’s Ataxia has been identified that is associated with deficiency of vitamin E. Associated symptoms may be indistinguishable from those associated with the classic form of the disorder. This disorder variant, known as Friedreich’s-like Ataxia with Vitamin E Deficiency or “AVED” is also transmitted as an autosomal recessive trait. 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. Those with AVED have an impaired ability to bind vitamin E into VLDL, resulting in vitamin E deficiency in certain tissues. Some investigators suggest that the classic form of Friedreich’s Ataxia may also be related to impaired vitamin E or VLDL metabolism.
Although Friedreich’s Ataxia can be present at birth, symptoms usually first appear between the ages of five and 15 years. Estimates of occurrence in the United States range from 2,000 or 3,000 cases to as many as 20,000. A more precise estimate is difficult to arrive at since many cases may be misdiagnosed. Friedreich’s Ataxia is the most common of the various forms of hereditary ataxias.
The prevalence of Friedreich ataxia is 2/100,000-4/100,000. The carrier frequency is 1/60-1/100. FRDA is the most common inherited ataxia in Europe, the Middle East, South Asia (Indian subcontinent), and North Africa. FRDA has not been documented in Southeast Asia, in sub-Saharan Africa, or among Native Americans. A lower than average prevalence of FRDA is noted in Mexico.
Treatment of Friedreich's Ataxia is symptomatic and supportive. Continuous medical supervision to avoid potential complications involving the heart, lungs, spine, bones and muscles are recommended. Prevention of pneumonia is a challenge in the care of people in the advanced stages of Friedreich's Ataxia.
Heart problems and/or diabetes associated with Friedreich's Ataxia may be treated with medication. The patient may also be more susceptible to infection. Insulin is usually effective in controlling Diabetes Mellitus. Vision and hearing problems may be alleviated with either corrective devices, drugs, or in some cases surgery. Mental functions usually remain unaffected but emotional strain can affect patients and their families. In such cases, psychological counseling may be helpful. Genetic counseling can assist many patients and families when they are affected by one of the hereditary ataxias. Prenatal diagnosis is available for pregnant women with Friedreich's Ataxia.
Physical therapy may be helpful when recommended by a physician. Various aids may assist muscular movement. Orthopedic surgery or braces may help curvature of the spine and abnormalities of the feet, but should be carefully considered after consultation with a neurologist and orthopedist.
Drugs may be useful in treating some symptoms of Friedreich's Ataxia. Propanalol may be effective against static tremors, and less often against intention tremors. Static tremors can occur when the affected individual is not moving, whereas intention tremors occur when the patient makes intentional movements. Dantrolene Sodium may help some patients with muscle spasms of the legs. These drugs should be carefully monitored by a physician to limit the possibility of toxicity. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
In 2004, the Food and Drug Administration (FDA) granted orphan drug status to the drug, Idebenone. Research on this drug to date as a possible treatment for young people with Friedreich’s ataxia has produced promising results. Additional study of this drug is needed to determine its potential in reducing the effects of Friedreich’s ataxia on young patients.
Santhera Pharmaceuticals (Switzerland) Ltd received it’s first product approval for SNT-MC17 / idebenone for the managment of Friedreich’s Ataxia, in Canada It will be launched in the market under the brand name Catena in Canada in October of 2008.
For more infromation please contact
Ms MJ Roach, General Manager,
Santhera Pharmaceuticals (USA) Inc,
40 Warren Street (3rd Floor),
Charlestown, MA 02129
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