What is Friedreich ataxia?

Risk Factors

There are no environmental risk factors for Friedreich ataxia. The disease is inherited.

Etiology and Genetics

Friedreich ataxia results from a mutation in the FXN gene, which is located on the long arm of chromosome 9 at position 9q13. The protein product of this gene is known as frataxin, and it is normally produced in the mitochondria of some cells, particularly nerve and muscle cells. In the absence of normal levels of frataxin, these cells cannot efficiently produce energy in the form of adenosine triphosphate (ATP) by oxidative phosphorylation, and there is an accumulation of toxic metabolites that leads to what physicians call oxidative stress. In 98 percent of cases, the mutational event is known as a GAA triplet repeat.

In patients with Friedreich ataxia, a sequence of three deoxyribonucleic acid (DNA) bases—GAA, or guanine, adenine, adenine—near the beginning of the gene is repeated from seventy to more than one thousand times. Normal FXN genes have this triplet repeated anywhere from five to thirty times. Apparently the expanded triplet-repeat region interferes with the normal process of frataxin synthesis in cells, and a greatly reduced amount of the protein is made. In a very small percentage of cases (2 percent), the gene defect appears to be a point mutation that also drastically reduces the amount of frataxin produced.

The inheritance pattern for Friedreich ataxia is typical of other autosomal recessive conditions, in that both copies of the FXN gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected. If one parent has Friedreich ataxia and the other is a carrier, there is a 50 percent probability that each child will be affected. A simple blood test to check for carrier status is available. It is interesting to note that although triplet repeat expansions have been implicated in several diseases that show dominant inheritance, Friedreich ataxia is the only known recessive disease to have this particular molecular etiology.

Symptoms

Symptoms may vary. The onset of the disease generally occurs in individuals under the age of twenty-five, usually in their early teenage years. Early symptoms include progressive leg weakness (difficulty walking); ataxia, or incoordination and imbalance affecting limbs and gait; impaired sensation, especially “position sense” in the feet; and loss of tendon reflexes in the legs. Heart failure and diabetes develop as the disease progresses.

Later symptoms include difficulty speaking and swallowing (decreased coordination of the tongue); loss of tendon reflexes in all limbs; atrophy of muscles; scoliosis, or curving of the spine, which affects 85 percent of people with this condition; foot deformities; and foot ulcers. By age forty-five, 95 percent of those affected are confined to a wheelchair. Other symptoms include hearing loss and/or vision loss (for more than 10 percent of those affected), eye-movement abnormalities, and movement disorders such as tremor, dystonia, and chorea.

Screening and Diagnosis

The doctor will ask about a patient’s symptoms, including medical history, family history, and medications. The doctor will also perform a physical exam. If this disorder is suspected, a patient may also see a neurologist, a doctor who specializes in the nervous system.

Tests may include electromyography (EMG) and nerve-conduction studies to assess the function of the muscles and nerves; a computed tomography (CT) scan, a test that uses a computer to make cross-sectional images of the head; a magnetic resonance imaging (MRI) scan, a test that uses magnetic waves to make pictures of structures inside the brain and spinal cord; an electrocardiogram (ECG) and twenty-four-hour holter monitoring to assess the electrical activity of the heart; and an echocardiogram, a test that uses high-frequency sound waves (ultrasound) to examine the size, shape, and motion of the heart. Other tests include genetic testing for the frataxin gene, blood (diabetic testing) and urine tests, and a sural nerve biopsy.

Treatment and Therapy

There is no known cure for this condition. Long-term management is aimed at maximizing function and controlling symptoms. Management may include physical therapy and rehabilitation to cope with muscle weakness, the use of orthotics (devices that go in a patient’s shoes) to provide stability and to help with weakness, surgery for correcting foot abnormalities and scoliosis, and periodic testing for associated conditions of diabetes and cardiomyopathy.

As the exact role of the protein frataxin is clarified, treatments may emerge. Recent studies have focused on assessing the potential role of antioxidants such as coenzyme Q10
, vitamin E, and idebenone.

Prevention and Outcomes

There is no known way to prevent this condition.

Bibliography

Anzovino, A., et al. "Fixing Frataxin: 'Ironing Out' the Metabolic Defect in Friedreich's Ataxia." British Journal of Pharmacology 171.8 (2014): 2174–90. Web. 23 July 2014.

Bidichandani, Sanjay I., and Martin B. Delatycki. "Friedrich Ataxia." GeneReviews. Ed. Roberta A. Pagon et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 2 Feb. 2012. Web. 23 July 2014.

Cooper, J. M., and J. L. Bradley. “Friedreich’s Ataxia.” Mitochondrial Function and Dysfunction. Ed. Anthony H. V. Schapira. San Diego: Academic, 2002. 147–73. Print.

Daroff, Robert B., et al., eds. Bradley's Neurology in Clinical Practice. 6th ed. 2 vols. Philadelphia: Saunders, 2012. Print.

"Friedreich Ataxia." DynaMed. EBSCO, 27 June 2014. Web. 23 July 2014.

Koenig, Michel, and Alexandra Dürr. “Friedreich’s Ataxia.” Handbook of Ataxia Disorders. Ed. Thomas Klockgether. New York: Dekker, 2000. 151–62. Print.

150 Years of Friedreich Ataxia Research. Spec. issue of Journal of Neurochemistry 126.s1 (2013): 1–155. Web. 23 July 2014.

Scheinberg, Dianne, and Rimas Lukas. "Friedreich's Ataxia." Health Library. EBSCO, 7 May 2014. Web. 23 July 2014.