Friedreich ataxia

Definition

Friedreich ataxia (FRDA or FA) is an inherited, degenerative nervous system disorder that results in muscle weakness and inability to coordinate voluntary muscle movements.

Description

Onset of FDRA is usually in childhood or early adolescence. The disorder is characterized by unsteady gait, slurred speech, absent knee and ankle jerks, Babinski responses, loss of position and vibrations senses, leg muscle weakness, loss of leg muscle mass, scoliosis, foot deformities, and heart disease. FRDA is a slowly progressive condition associated with a shortened life span, most often due to complications of heart disease.

FRDA is named for Nikolaus Friedreich, the German doctor who first described the condition in 1863. The most common form of the disorder, found in about three–quarters of patients, is referred to as "classic" or "typical" FDRA. Atypical forms of FDRA include: late onset Friedreich ataxia (LOFA), very late onset Friedreich ataxia (VLOFA), Friedreich ataxia with retained reflexes (FARR), Acadian type (Louisiana form), and spastic paraparesis without ataxia.

Demographics

FRDA is the most common inherited ataxia and affects between 3,000–5,000 people in the United States. The prevalence of FDRA in the Caucasian population is approximately one in 50,000 to one in 25,000. Prevalence appears to be highest in French Canadians from Quebec, Acadians from Louisiana, and among certain populations in southern Italy and Cyprus. Approximately 1% of Caucasian individuals carry one defective copy of the gene responsible for FRDA, known as FRDA1. FRDA is rare in people of Asian or African descent.

Causes and symptoms

FRDA is an autosomal recessive condition, which means that an affected individual has two altered or nonfunctioning FRDA1 genes, one from each parent. The FRDA1 gene is located on chromosome 9 and codes for a protein called frataxin. The most common gene alteration (or mutation), which is found in greater than 95% of affected individuals, is a triplet repeat expansion. The triplet repeat is a sequence of DNA bases called GAA. Normally the GAA sequence is repeated five to 33 times but in people with FRDA, it is repeated between 66 to 1700 times. Longer GAA triplet repeats are associated with more severe disease, but the severity of disease in a given individual cannot be predicted from the repeat length. About 4% of patients have the triplet repeat expansion in one copy of the FDRA1 gene and a different type of mutation, a point mutation, in the other FRDA1 gene. There have been a few patients with classic FDRA in which the FRDA1 gene on chromosome 9 has been shown not to be the cause.

FRDA1 gene mutations lead to loss of function of the gene and subsequently to decreased production of frataxin. Frataxin plays a role in the balance of iron in the mitochondria, the cellular energy structures. Frataxin insufficiency leads to a number of effects including excessive iron accumulation in the mitochondria and, eventually, the production of chemicals called free radicals that can damage and kill the cell. The cells most affected in FRDA are those in the brain, spinal cord, nerves, heart, and pancreas.

FRDA is a slowly progressive, unremitting, ataxia. There is variability in age of onset, presence of symptoms, rate of progression, and severity. Although onset of FRDA usually occurs before age 25, symptoms may appear as early as age two or as late as 30 to 40 years. Gait ataxia, or difficulty walking, is often the first sign of the disease. For example, an affected child might trip frequently over low obstacles. The ataxia eventually spreads to the arms within several years, resulting in decreased hand-eye coordination. Unsteadiness when standing still and deterioration of position sense is common. Other symptoms that appear early in the course of the disease are loss of knee and ankle tendon reflexes and dysarthria (slowness and slurring of speech). Over time, individuals with FRDA experience loss of sensation that begins in their hands and feet and may spread to other parts of the body. Abnormal muscle control and tone leads to problems such as scoliosis (curvature of the spine) and foot deformities such as pes cavus (high-arched feet) with extensor plantar response. Arm weakness, if it occurs, develops later in the course of the disorder. Loss of muscle control eventually necessitates use a wheelchair.

Heart disease represents a potentially significant complication of FRDA. Heart muscle enlargement with or without an abnormal heartbeat is present in about two–thirds of cases and represents a major cause of death. About one–third of patients develop diabetes, most of whom will require insulin. Other medical findings in FRDA include optic nerve atrophy, nystagmus (eye tremor), tremor, amyotrophy (loss of muscle mass), hearing loss, difficulty swallowing, and incontinence.

Diagnosis

A diagnosis of FDRA is based on clinical findings and results of genetic testing. The clinical diagnosis of Friedreich ataxia is made through physical exam and medical history. The presence of progressive ataxia, loss of position and/or vibration sense, and loss of lower limb tendon reflexes in a child or adolescent is suspicious of the diagnosis. Tests that may aid in diagnosis include electromyography , nerve conduction studies, an electrocardiogram, an echocardiogram, magnetic resonance imaging (MRI) , computed tomography (CT) scan, a spinal tap, and glucose analysis of blood and urine. Genetic testing is recommended for all individuals in whom the diagnosis of FRDA is suspected.

Genetic testing is accomplished by counting the number of GAA repeats in the FRDA gene to see if there is an expansion (66 or more repeats). For those cases in which only one FRDA gene has a triplet repeat expansion, 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 chorionic villus sampling (CVS) or amniocentesis.

Treatment team

Management of FRDA requires a multidisciplinary approach. In addition to the patient's primary health care professionals, medical professionals involved in the care of patients with FRDA generally include a neurologist , a cardiologist, an orthopedic surgeon, an ophthalmologist, a speech therapist, a physical therapist, an occupational therapist, and a physiatrist. Additional specialists in endocrinology and urology may be needed. Some patients with FRDA may receive comprehensive services through a muscular dystrophy association (MDA) clinic and/or a Shriner's Hospital for Children. A genetic specialist, such as a clinical geneticist or a genetic counselor, may be helpful to the patient and family, especially at the time of diagnosis or prior to genetic testing. Psychological counseling and support groups may also assist families in coping with this condition.

Treatment

As of 2003, there is no cure for FRDA. The purpose of treatment, which is largely supportive, is to help patients optimize function and to manage any associated medical complications of the disorder. Treatment includes most if not all of the following options:

• Orthopedic intervention. Braces or surgery may be necessary to treat scoliosis and foot deformities. For example, a surgical procedure known as spinal fusion may be considered in patients with significant curvature.
• Medications. Some antioxidants (chemicals that capture free radicals) have shown benefits in patients with FRDA. Vitamin E and coenzyme Q10, which are naturally occurring substances, may be prescribed. Patients should discuss the current recommendations with their physician.
• Cardiac and diabetes care. Since cardiac disease is the most common cause of death, proper cardiac care is essential. For those cases in which there is heart disease, medications can be effective for many years. Of those individuals with diabetes mellitus, most will require insulin therapy.

Recovery and rehabilitation

Rehabilitation for Friedreich ataxia consists of speech, physical, and occupational therapy. The goal of these therapies is to make full use of the patient's existing muscular functions. For example, physical therapy can help stretch muscles to improve or maintain flexibility. Speech therapy can help to retrain certain muscles in order to improve speech and swallowing. Occupational therapy can teach patients to use adaptive techniques and devices that may help compensate for loss of coordination and strength. For example, prostheses, walking aids, and wheelchairs may be recommended to help the individual with FRDA to remain ambulatory or mobile.

Clinical trials

Research studies of idebenone, a synthetic antioxidant, have shown it to reduce hypertrophy (overgrowth) of the left ventricle of the heart in patients with FRDA. A phase I clinical trial will be conducted in the United States to establish the maximum tolerated dose of idebenone in children, adolescents, and adults with Friedreich's ataxia; as of November 2003, active patient recruitment was underway. Information on this trial can be found at <http://www.clinicaltrials.gov> or by contacting the National Institute of Neurological Disorders and Stroke patient recruitment and public liason office at 1-800-411-1222. Another substance that is being researched is an antioxidant known as mitoquinone or "MitoQ" which is a synthetic form of coenzyme Q10 that has the potential to protect the mitochondria from free radical damage. As of 2003, mitoquinone was in the developmental phase of study and not yet available to patients.

Prognosis

The rate of progression of FRDA varies. Most patients lose the ability to walk within 15 years of symptom onset, and 95% require a wheelchair for mobility by age 45. Shortened life span from FRDA 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.

Special concerns

A child with a diagnosis of Friedreich ataxia is eligible to have an Individual Education Plan (IEP). An IEP provides a framework from which administrators, teachers, and parents can meet the educational needs of a child with FRDA.

Resources

BOOKS

Nance, Martha A. Living with Ataxia, 2nd ed. Minneapolis: National Ataxia Foundation, 1997.

Parker, James N., and Philip M. Parker, eds. The Official Parent's Sourcebook on Friedreich's Ataxia: A Revised and Updated Directory for the Internet Age. San Diego, CA: ICON Health Publications, 2002.

Ruzicka, Evzen, Mark Hallett, and Joseph Jankovic, eds. Gait Disorders. Philadelphia, PA: Lippincott Williams and Wilkins, 2001.

PERIODICALS

Alper, G., and V. Narayanan. "Friedreich's Ataxia." Pediatric Neurology 28 (May 2003): 335–341.

Pilch, J., E. Jamroz, and E. Marza. "Friedreich's Ataxia." Journal of Child Neurology 17 (May 2002): 315–319.

WEBSITES

Friedreich's Ataxia Parents Group (FAPG). <http://www.fortnet.org/fapg/>.

The Muscular Dystrophy Association (MDA). Facts about Friedreich's Ataxia (FA). <http://www.mdausa.org/publications/fa-fried-qa.html>.

The National Institute of Neurological Disorders and Stroke (NINDS). Friedreich's Ataxia Fact Sheet. <http://www.ninds.nih.gov/health_and_medical/pubs/friedreich_ataxia.htm>.

ORGANIZATIONS

Friedreich's Ataxia Research Alliance (FARA). 2001 Jefferson Davis Highway, Suite 209, Arlington, VA 22202. (703) 413-4468; Fax: (703) 413-4467. [email protected]. <http://www.frda.org>.

Muscular Dystrophy Association. 3300 East Sunrise Drive, Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717; Fax: (520) 529-5300. [email protected]. <http://www.mdausa.org>.

National Ataxia Foundation (NAF). 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. (763) 553-0020; Fax: (763) 553-0167. [email protected]. <http://www.ataxia.org>.

Dawn J. Cardeiro, MS, CGC