Friedreich ataxia (FA) is an inherited, progressive nervous system disorder causing loss of balance and coordination.
Description
Ataxia is a condition marked by impaired coordination. Friedreich ataxia is the most common inherited ataxia, affecting between 3,000–5,000 people in the United States.
Genetic profile
FA is an autosomal recessive disease, which means that two defective gene copies must be inherited to develop symptoms, one from each parent. A person with only one defective gene copy is called a carrier and will not show signs of FA, but has a 50% chance of passing along the gene to offspring with each pregnancy. Couples in which both parents are carriers of FA have a 25% chance with each pregnancy of conceiving an affected child. The gene for FA is on chromosome 9 and codes for a protein called frataxin. Normal frataxin is found in the cellular energy structures known as mitochondria, where it is involved in regulating the transport of iron.
In approximately 96% of patients with FA, both copies of the frataxin gene are expanded with nonsense information known as a "triple repeat" of a particular sequence of DNA bases called "GAA". Normally, the GAA sequence is repeated between six and 34 times, but those with FA have between 67 and 1,700 copies. About 4% of patients have been found to have the triple repeat in only one copy of the frataxin gene and a different gene change in the other. Longer GAA repeats are associated with more severe disease, but the severity of disease in a particular individual cannot be predicted from the repeat length. The extra DNA or other gene change interferes with normal production of frataxin, thereby impairing iron transport. FA is thought to develop at least in part because defects in iron transport prevent efficient use of cellular energy supplies. Extra iron builds up in the mitochondria, leading to the accumulation of damaging chemicals called free-radicals.
The nerve cells most affected by FA are those in the spinal cord involved in relaying information between muscles and the brain. Tight control of movement requires complex feedback between the muscles promoting a movement, those restraining it, and the brain. Without this control, movements become uncoordinated, jerky, and inappropriate for the desired action.
Demographics
The prevalence of FA in the Caucasian population is approximately one in 50,000 to one in 25,000. Prevalence appears to be highest in Italy. Approximately 1% of Caucasian individuals carry one defective copy of the gene for frataxin. Friedreich ataxia is very rare in people of Asian or African descent.
Signs and symptoms
Symptoms of FA usually first appear between the ages of eight and 15, although onset as early as 18 months or as late as age 25 is possible. The first symptom is usually gait incoordination. For instance, a child with FA may graze doorways when passing through or trip over low obstacles. Unsteadiness when standing still and deterioration of position sense is common. Foot deformities and walking up off the heels often results from uneven muscle weakness in the legs. Muscle spasms and cramps may occur, especially at night.
Ataxia in the arms usually follows within several years, leading to decreased hand-eye coordination. Arm weakness does not usually occur until much later. Speech and swallowing difficulties are common. The loss of reflexes in the lower legs is common. Diabetes mellitus, a condition characterized by elevated blood sugar, may also occur. One study suggested that carriers of one FAA gene with an "intermediate" sized GAA region (10 to 36 copies of GAA) are also at increased risk for diabetes, but as of 2001, other similar studies did not show this finding. Nystagmus, or eye tremor, is common in FA, along with some loss of visual acuity. Hearing loss may also occur. A side-to-side curvature of the spine (scoliosis) occurs in many cases and may become severe.
Heart muscle enlargement with or without heartbeat abnormality occurs in about two thirds of FA patients, leading to shortness of breath after exertion, swelling in the lower limbs, and frequent complaints of cold feet.
There are some atypical forms of FA. For example, the Acadian population that descended from Northern France and now live in Louisiana, have a very slow progressing disease and rarely have heart problems, leading them to live longer than most patients with FA. Other forms include late onset Friedreich ataxia (LOFA), in which symptoms begin after the age of 25 years, and Friedreich ataxia with retained reflexes (FARR). All three of these forms have been shown to result from changes in the same gene as the "classic" form. There have been a few patients with classic FA described in which the
frataxin gene on chromosome 9 has been shown not to be the cause. A form of ataxia caused by a gene change resulting in vitamin E deficiency, but having similar symptoms to FA, has been identified with changes in a different gene on chromosome 8.
In 1988, a Spanish family was reported in which several members had FA along with congenital glaucoma, a disease caused by increased pressure inside the eye. Glaucoma is not normally seen in patients with Friedreich ataxia or other types of inherited ataxia. Most of the affected family members had parents who were closely related to each other, which placed children at increased risk for autosomal recessive conditions in general. Therefore, the glaucoma and FA may have been caused by two distinct genes inherited in an autosomal recessive manner. As of 2001, there was no follow-up of this family reported, so it is not known if their unusual disease was caused by a gene other than the since-identified frataxin gene or if the glaucoma and the FA were caused by two different genes.
Direct DNA testing is available, allowing FA to be more easily distinguished from other types of ataxia. Testing is accomplished by counting the number of GAA repeats in the frataxin gene to see if there is an expansion (67 or more sets of the DNA bases GAA) and by looking for other gene changes in patients who only show a GAA expansion in one copy of the frataxin gene. As of 2001, no patient with FA has been reported to have non-GAA changes in both copies of the frataxin gene. Many of these non-GAA changes completely prevent the frataxin protein from being made, so having two copies may not be compatible with life. The same genetic test may be used to determine the presence of the genetic defect in the carrier state (i.e., one normal copy and one defective copy of the frataxin gene) in unaffected individuals, such as adult siblings, who would like to learn their chances of producing an affected child. During pregnancy, the DNA of a fetus can be tested using cells obtained from procedures called chorionic villi sampling (CVS), in which cells from the placenta are studied, and amniocentesis, in which skin cells from the amniotic fluid surrounding the baby are tested.
Treatment
As of 2001, there is no prevention or cure for FA, nor any proven treatment that can slow its progress. One recent (1999) study in three patients has suggested that a drug called idebenone can reduce heart problems. Idebenone is an antioxidant—a drug that captures free-radicals, the toxic chemicals generated by increased iron. Amantadine may provide some limited improvement in ataxic symptoms, but is not recommended in patients with cardiac abnormalities. Physical and occupational therapy are used to maintain range of motion in weakened muscles, and to design adaptive techniques and devices to compensate for loss of coordination and strength. Some patients find that using weights on the arms can help dampen the worst of the uncoordinated arm movements.
Heart problems and diabetes are treated with drugs specific to those conditions.
Prognosis
The rate of progression of FA is highly variable. Most patients lose the ability to walk within 15 years of symptom onset, and 95% require a wheelchair for mobility by age 45. Reduction in lifespan from FA complications, usually cardiac, is also quite variable. Average age at death, usually from heart problems, is in the mid-30s, but may be as late as the mid-60s. As of 2001, the particular length of the triple repeat has not been correlated strongly enough with disease progression to allow prediction of the course of the disease on this basis.
BOOKS
Isselbacher, Kurt J., et al., eds. "Spinocerebellar Degeneration (Friedreich's Ataxia)." In Harrison's Principles of Internal Medicine. New York: McGraw-Hill, 1994, p. 2285.
PERIODICALS
Delatycki, Martin B., Robert Williamson, and Susan M. Forrest. "Friedreich Ataxia: An Overview." Journal of Medical Genetics 37 (2000): 1-8.
ORGANIZATIONS
Friedreich's Ataxia Research Alliance. 2001 Jefferson Davis Highway #209, Arlington, VA 22202. (703) 413-4468. <http://www.frda.org>.
Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717. <http://www.mdausa.org>.
National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. (763) 553-0020. Fax: (763) 553-0167. naf@ataxia.org. <http://www.ataxia.org>.
National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. (301) 496-5751 or (800) 352-9424. <http://www.ninds.nih.gov>.
