Simply Stated: What is Friedreich’s Ataxia (FRDA)?

Friedreich’s ataxia (FRDA) is an inherited neuromuscular disease that primarily impacts the nervous system and heart and affects about one in 50,000 people worldwide. FRDA typically appears in people before the age of 25 years and is characterized by a slow, progressive loss of limb coordination (ataxia) and effects on speech and swallowing.

While there is currently no cure of FRDA, multidisciplinary care can improve the quality of life of people living with this disease and research advances provide hope for therapeutic breakthroughs.

Symptoms of FRDA

People with FRDA typically begin experiencing symptoms between 5 to 15 years of age. Disease symptoms and progression can vary greatly in each person with the disease, however, the primary symptom of FRDA is progressive ataxia. Ataxia can result in an unsteady gait when walking and poor control of fine movements of the limbs. The majority of individuals with FRDA also experience weakness in the muscles of the mouth and throat eventually leading to dysarthria (slow or slurred speech) and dysphagia (impaired swallowing).

Over the course of the disease, people with FRDA experience muscle weakness and thinning in various parts of the body, particularly in the feet, lower legs, and hands. Deformities of the foot are a characteristic symptom. Spasticity (abnormal muscle tightness) in the lower limbs, loss of tendon reflexes in the knees and ankles, and loss of sensation in the fingers and toes, are also common. More than two-thirds of individuals with FRDA eventually develop scoliosis (spine curvature). As the clinical features of FRDA continue to progress, people with FRDA often require the use of a wheelchair for mobility. Their cognitive function, however, typically remains intact throughout the course of disease.

Approximately 25% of individuals with FRDA have an “atypical” presentation, with later onset that begins after 26 years of age or with longer-lasting (more than 10 years) retention of tendon reflexes.

For more information about the signs and symptoms of FRDA, a clinical overview can be found here.

Complications of FRDA

FRDA is often associated with a number of mild to serious complications. About one-third of people with FRDA develop diabetes mellitus (a disorder in which blood sugar levels are abnormally high). Bladder and lower urinary tract symptoms are also commonly reported. Some people with FRDA may experience visual impairments or hearing loss.

Approximately two-thirds of individuals with FRDA develop cardiomyopathy, a disease of the heart muscles that may lead to irregularities in heart rhythm (arrhythmias) or heart failure. Heart problems typically develop in the later stages of FRDA and are the most common cause of mortality.

Causes of FRDA

FRDA was first described by German physician Nikolaus Friedreich in 1863. About 120 years later, researchers identified the genetic cause for FRDA, mutations in the frataxin (FXN) gene.

In most cases, FRDA is caused by abnormal expansion of a repeated DNA sequence (GAA) within the FXN gene. The FXN gene encodes frataxin protein, which is important for the proper functioning of mitochondria, the energy producing structures in our cells. In people with FRDA, abnormal expansions in the FXN gene results in reduced production of frataxin protein. This affects the function and integrity of nerve and heart cells, which are dependent on high levels of energy production, causing them to degenerate. In FRDA, the nerve fibers of the spinal cord and the peripheral nerves, which send messages from the brain/spinal cord to the rest of the body, are particularly affected.

Normally, people will have less than 30 GAA DNA repeats in the FXN gene. People with FRDA, however, may have ~100-1300 of these repeats in one or both copies of the FXN gene, with the majority of affected people containing more than 400 repeats in both copies. The number of repeats that a person with FRDA has typically correlates with the range and severity of symptoms. Shorter expansions (less than 400 GAA repeats) are often associated with later age of onset, slower progression, and mild to no cardiomyopathy. In rare cases, an affected person may have one FXN gene copy with expanded GAA repeats and the other FXN gene copy with another type of genetic defect.

FRDA is inherited in an autosomal recessive manner, meaning that two copies of the abnormal FXN gene, one from each parent, are required to cause the disease. Individuals with one normal copy and one defective copy of the FXN gene are known as carriers for the disease. Carriers do not typically show symptoms of FRDA. Every pregnancy between two carrier parents has a 25% risk of producing a child affected by FRDA.

Current management of FRDA

Though there is currently no cure for FRDA, multidisciplinary care of affected individuals can help manage symptoms and improve quality of life. Treatment is based on each person’s symptoms and may include:

• Rehabilitation medicine: prostheses, walking aids, wheelchairs, and physical therapy to maintain an active lifestyle
• Occupational therapy: design of a safe home and work environment
• Pharmacological intervention: use of agents such as baclofen and botulinum toxin to manage spasticity and/or bladder dysfunction
• Orthopedic interventions: surgical and non-surgical interventions to manage scoliosis and foot deformities
• Speech therapy and/or assistive devices: to augment communication ability
• Nutrition: dietary modification or use of feeding tube to manage dysphagia
• Cardiac care: use of medications, anticoagulants, and implanted devices (e.g., pacemaker) to reduce the risk of heart disease or failure
• Pulmonary care: continuous positive airway pressure (CPAP) to manage sleep apnea
• Treatment of diabetic complications: dietary modification, medication to manage hypoglycemia, insulin
• Psychological care: counseling and/or pharmacologic support for individuals with FRDA and family members

Care recommendations developed by physician and scientist experts in FRDA (Corben, et al, 2014 and www.curefa.org) are available to guide physicians in evidence-based treatment of people living with FRDA.

Evolving research and treatment landscape

While the standard of care is still symptom management, research advances and the promise of better therapeutics on the horizon offer hope for people living with FRDA.

Researchers are currently investigating therapeutic strategies that may reverse some of the abnormal processes that occur within the cells of people with FRDA. Deficiency of frataxin causes a number of specific defects, including accumulation of iron in the mitochondria and overproduction of molecules known as “free radicals” that can damage cells. Chelation therapy has been studied as a method to soak up excess iron within cells. Antioxidant therapies, which are designed to neutralize damaging free radicals within cells, have shown promise in clinical trials.

Also under active investigation are methods to increase frataxin levels and gene replacement therapy approaches to correct the underlying defect in FRDA. An overview of therapies under investigation is available through the Freidreich’s Ataxia Research Alliance (FARA).

To learn more about clinical trial opportunities in FRDA, visit clinicaltrials.gov and search for “Freidreich’s ataxia” in the condition or disease field.

MDA’s work to further cutting-edge FRDA research

In recent years, MDA has supported research in FRDA through various mechanisms. From 2016-2019, MDA awarded a Development Grant to the early-stage investigator Michael Huang from the University of Sydney to study the role of mitochondria in the pathogenesis of FRDA. Over the past five years, MDA has also awarded four Research Grants to established investigators studying underlying defects in and potential therapeutic solutions for FRDA. The funded investigators and projects include:

• David Lynch, Children’s Hospital of Philadelphia – Study of impaired signaling between nerve cells in FRDA (2018-2021)
• Vijayendran Chandran, University of Florida – Use of new, high-throughput approaches to identify biomarkers in FRDA (2017-2020)
• Manuela Corti, University of Florida – Study of adeno-associated virus (AAV)-delivered gene therapy to treat FRDA (2017-2020)
• Marek Napierala, University of Alabama at Birmingham – Use of small fragments of genetic material (oligonucleotides) to increase frataxin levels in FRDA (2016-2019)

Through MDA’s Venture Philanthropy program (MVP), MDA has also funded the biotechnology company AavantiBio, which is developing an AAV-based gene transfer therapy to correct the underlying defect in FRDA. If successful, this therapy could treat the neurological and cardiac symptoms of FRDA, and potentially lead to a cure.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about Freidreich’s ataxia, open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.