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What is Friedreich’s Ataxia?
Friedreich’s ataxia is a rare hereditary disease that causes progressive damage to the nervous system, resulting in increasingly severe movement problems. It typically begins in childhood or adolescence, causing reduced muscular coordination (ataxia) that worsens over time.
To understand how this disease affects the body, it helps to consider the role of peripheral nerves. These nerves continuously carry information in two directions between the brain and the rest of the body:
- From the brain to the body: For example, initiating a step to walk toward a different location (signals from the brain to the leg muscles)
- From the body to the brain: For example, transmitting the sensation of pain when walking barefoot on a sharp object (signals from the body’s periphery to the brain)
In Friedreich’s ataxia, the nerve fibers of the spinal cord and peripheral nerves undergo progressive degeneration, becoming thinner and less functional over time. The cerebellum, the part of the brain responsible for coordinating balance and movement, also degenerates, although to a lesser extent. Together, these changes produce the hallmark features of the disease: clumsy, unsteady movements and impaired sensory function.
The disorder is named after Nikolaus Friedreich, a German physician who first described the condition in the 1860s. In addition to its neurological effects, the disease causes:
- Heart problems in approximately one third of affected individuals
- Spinal deformity (scoliosis) in many patients
- Diabetes mellitus in a proportion of cases
Importantly, Friedreich’s ataxia does not impair intellectual function: thinking, reasoning, and memory remain intact throughout the disease course.
The disease is caused by a mutation in the FXN gene, which is responsible for producing a protein called frataxin. Only individuals who inherit two defective copies of this gene (one from each parent) will develop the disease.
The rate of progression varies from person to person, but in general, within 10 to 20 years of symptom onset, most patients require a wheelchair. The disease can unfortunately reduce life expectancy, and cardiac disease is the most common cause of death. However, some patients with milder forms of the disease live into their sixties or beyond.
Causes
Although rare, Friedreich’s ataxia is the most common form of hereditary ataxia in Europe, the Middle East, South Asia (the Indian subcontinent), and North Africa, affecting approximately 1 in 40,000 individuals.
Hereditary Transmission
A gene is a segment of DNA (the genetic code) that contains the instructions for producing a specific protein. Every human being carries two copies of each gene (one inherited from each parent).
Patients with Friedreich’s ataxia have inherited two defective copies of the FXN gene (one from each parent). Individuals who inherit only one defective copy are called carriers: they do not develop any symptoms themselves, but they can pass the defective gene on to their children.
Technically, Friedreich’s ataxia is an autosomal recessive condition, meaning both copies of the gene must be defective for the disease to manifest. The inheritance pattern works as follows:
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Two carrier parents (each with one normal and one defective copy):
- 25% probability with each pregnancy that the child will inherit both defective copies and develop the disease
- 50% probability with each pregnancy that the child will be a healthy carrier (like the parents)
- 25% probability with each pregnancy that the child will inherit two normal copies and be completely unaffected
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If only one parent is a carrier and the other is not, no child will develop the disease, though 50% may be carriers.
The risk is identical for males and females.
It is important to note that many carriers are entirely unaware of their status, as they carry the gene without experiencing any symptoms themselves.
Frataxin
The FXN gene contains the instructions for producing a protein called frataxin, which is normally found within the mitochondria (the energy-producing structures within cells). Frataxin plays a critical role in mitochondrial energy metabolism and in regulating iron levels within the cell.
Without adequate levels of frataxin, certain cell types (particularly those of the peripheral nerves, spinal cord, brain, and cardiac muscle) suffer from:
- Insufficient energy production due to impaired mitochondrial function
- Accumulation of iron within mitochondria, leading to the generation of toxic free radicals
- Oxidative stress: cellular damage caused by an imbalance between harmful reactive oxygen species and the cell’s antioxidant defenses
In the normal version of the FXN gene, a specific DNA sequence called a GAA trinucleotide repeat (guanine-adenine-adenine) occurs between 7 and 22 times. In the defective version of the gene, this GAA repeat is massively expanded (occurring hundreds to over a thousand times). This abnormal expansion prevents the gene from being read correctly, dramatically reducing the amount of frataxin produced by the cell.
The age of onset and the severity of the disease are broadly correlated with the number of GAA repeats: individuals with longer repeat expansions tend to have earlier onset and more severe disease, though this relationship is not perfectly predictive at the individual level.
Symptoms
Symptoms typically begin between the ages of 5 and 15, although in approximately 15% of patients onset occurs in adulthood, after the age of 25. This later-onset form is sometimes referred to as late-onset Friedreich’s ataxia (LOFA).
Neurological Symptoms
The first neurological symptom is usually difficulty walking combined with poor balance, often described by patients or their families as appearing drunk or staggering. Another early sign is a progressive change in speech: language becomes slow, slurred, and hesitant (a condition called dysarthria), making communication increasingly difficult.
The difficulty in coordinating voluntary muscle movements (ataxia) progressively worsens over time, eventually affecting:
- The legs (earliest and most prominently affected)
- The arms and hands
- The trunk and posture
As muscle weakness increases, many patients develop increased muscle tone (spasticity), which further restricts movement.
Spinal and Musculoskeletal Complications
Up to two thirds of patients develop scoliosis, an abnormal lateral curvature of the spine, which can be severe and often requires surgical correction. Additionally, many patients develop pes cavus (high-arched feet), a characteristic foot deformity associated with Friedreich’s ataxia.
Most affected individuals also develop difficulty swallowing (dysphagia), arising from impaired coordination of the tongue and throat muscles, which can pose risks of aspiration and nutritional complications.
Sensory Symptoms
In addition to movement difficulties, patients frequently experience:
- Loss of sensation in the arms and legs, which may spread to other parts of the body
- Loss of reflexes, especially at the knees and ankles (areflexia), one of the earliest and most consistent clinical signs
- Loss of proprioception (the sense of joint position and movement), contributing to the unsteadiness of gait
In advanced stages, some patients develop:
- Hearing loss (hypoacusis)
- Visual impairment, including loss of visual acuity and, occasionally, optic atrophy
Cardiac Complications
Cardiac involvement is a major cause of morbidity and mortality in Friedreich’s ataxia. Patients frequently experience palpitations and shortness of breath (dyspnea), reflecting underlying heart disease, which can include:
- Hypertrophic cardiomyopathy: Abnormal enlargement and thickening of the heart muscle, the most common cardiac manifestation
- Myocardial fibrosis: Replacement of normal heart muscle by fibrous tissue, impairing cardiac function
- Heart failure: Progressive inability of the heart to pump effectively
- Cardiac arrhythmias: Including tachycardia (rapid heartbeat) and impaired conduction of electrical impulses within the heart (heart block)
Regular cardiac monitoring is essential in all patients with Friedreich’s ataxia, as cardiac complications are the leading cause of death in this condition.
Metabolic Complications
- Approximately 50% of patients develop carbohydrate intolerance (prediabetes)
- Approximately 30% of patients develop diabetes mellitus, requiring specific management
General Symptoms
Patients commonly report:
- Excessive fatigue and the need for extended rest periods
- Prolonged recovery times from common illnesses such as colds and influenza
Key reminder: Despite all of these progressive physical and neurological symptoms, cognitive function - including thinking, memory, and reasoning - remains unaffected in Friedreich’s ataxia. Patients retain full intellectual capacity throughout the disease course.
Diagnosis
The diagnosis of Friedreich’s ataxia requires a careful and systematic clinical evaluation, combining a detailed medical history and a thorough physical examination. The physician specifically looks for:
- Gait instability and balance difficulties
- Loss of proprioception (joint position sense)
- Absent or reduced tendon reflexes (particularly at the knees and ankles)
- Signs of cerebellar dysfunction (such as finger-nose incoordination, dysmetria)
- Signs of peripheral neuropathy
Genetic testing provides the definitive diagnosis by confirming the presence of the pathological GAA repeat expansion in both copies of the FXN gene. This is now the gold standard for diagnosis confirmation.
In addition to clinical assessment and genetic testing, the following investigations are important both for diagnosis and for ongoing monitoring of disease progression and complications:
- Electromyography (EMG): Measures the electrical activity of muscle cells and helps characterize the pattern of muscle involvement
- Nerve conduction studies: Measure the speed at which nerves transmit electrical impulses, typically showing reduced sensory nerve conduction in Friedreich’s ataxia
- Electrocardiogram (ECG): Provides a graphic representation of the electrical activity and rhythm of the heart, identifying arrhythmias and conduction abnormalities
- Echocardiogram: Ultrasound imaging that assesses the structure and function of the heart muscle, detecting cardiomyopathy
- Blood tests: Including fasting blood glucose to detect hyperglycemia and diabetes, and vitamin E levels (useful to distinguish Friedreich’s ataxia from ataxia with vitamin E deficiency, AVED, a condition that can closely mimic it)
- MRI or CT scan: Imaging of the brain and spinal cord, primarily used to exclude other neurological conditions that may produce similar symptoms, and to document the degree of spinal cord atrophy over time
Treatment
As with many degenerative diseases of the nervous system, there is currently no cure or disease-modifying treatment for Friedreich’s ataxia that can halt or reverse the underlying neurodegeneration. However, in 2023, the U.S. Food and Drug Administration (FDA) approved omaveloxolone (Skyclarys): the first drug specifically approved for the treatment of Friedreich’s ataxia in patients aged 16 and older. This represents a significant milestone, though it does not constitute a cure and its long-term impact on disease progression continues to be evaluated.
Beyond this recent development, management remains focused on treating and managing the individual symptoms and complications of the disease to help patients maintain the best possible quality of life for as long as possible.
A multidisciplinary approach is considered essential, ensuring that all aspects of the disease receive adequate expert attention:
- Diabetes management: Typically through oral hypoglycemic medications and/or insulin therapy, with regular monitoring of blood glucose levels
- Cardiac management: Including antiarrhythmic medications, treatments for heart failure, and, in selected cases, implantable devices (such as pacemakers or defibrillators); regular cardiology follow-up is essential for all patients
- Orthopedic management: Surgical correction of scoliosis when it is severe and progressive; orthotic devices (ankle-foot orthoses) for foot deformities; surgical correction of pes cavus in selected cases
- Physical and occupational therapy: Tailored exercise programs to maintain muscle strength, functional mobility, and independence for as long as possible; assessment and provision of mobility aids (walking frames, wheelchairs) as needed
- Speech and language therapy: Addressing both communication difficulties (dysarthria) and swallowing problems (dysphagia); provision of augmentative and alternative communication strategies as speech deteriorates
- Hearing rehabilitation: Hearing aids or other assistive listening devices for patients who develop significant hearing loss
- Nutritional support: Particularly important in patients with significant dysphagia, who may require dietary modifications or, in advanced cases, assisted nutrition
Research and Emerging Therapies
Several investigational therapeutic approaches are currently under active clinical investigation for Friedreich’s ataxia, including:
- Gene therapy: Aimed at delivering a functional copy of the FXN gene to affected cells
- Frataxin protein replacement: Strategies to increase frataxin protein levels within mitochondria
- Antioxidant therapies: Targeting oxidative stress caused by mitochondrial iron accumulation
- Epigenetic therapies: Aimed at unsilencing the defective FXN gene to increase frataxin production
Patients and families are encouraged to discuss participation in clinical trials with their treating specialist, as these represent an opportunity to access emerging treatments while contributing to scientific progress.
Psychological and Social Support
Living with a progressive, life-limiting neurological disease has profound psychological and social consequences. Patients and their families should have access to:
- Psychological counseling and psychotherapy to address depression, anxiety, and grief responses to progressive disability
- Support groups for patients and caregivers (national organizations such as the Friedreich’s Ataxia Research Alliance (FARA)provide invaluable resources and community support)
- Social services to assist with disability benefits, home adaptations, and care planning
Sources and Bibliography
- National Institute of Neurological Disorders and Stroke (NINDS) - NIH: Friedreich’s Ataxia
- NORD - National Organization for Rare Disorders: Friedreich’s Ataxia
- Pandolfo M. Friedreich ataxia: the clinical picture. Journal of Neurology. 2009;256(Suppl 1):3-8.
- Koeppen AH. Friedreich’s ataxia: pathology, pathogenesis, and molecular genetics. Journal of the Neurological Sciences. 2011;303(1-2):1-12.
- Bhidayasiri R, Perlman SL, Pulst SM, et al. Late-onset Friedreich ataxia: phenotypic analysis, magnetic resonance imaging findings, and review of the literature. Archives of Neurology. 2005;62(12):1865-1869.
- Dürr A, Cossée M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. New England Journal of Medicine. 1996;335(16):1169-1175.
- U.S. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. February 2023. Available at: https://www.fda.gov/
- Friedreich’s Ataxia Research Alliance (FARA). Available at: https://www.curefa.org/
