FA Fact Sheet
ATAXIA: FA or FRDA ( Friedreich's Ataxia)
RELATED GENES:
FXN (protein: frataxin)
MUTATION TYPE:
FXN -> Mutation by GAA expansion (96%) and point mutation by alteration or deletion (4%)
LAST UPDATE:
Sept 24, 2025 by Marcio Galvão
LOCATION:
Gene located on chromosome 9 (9q21.11)
HERITAGE:
Autosomal Recessive
Content generated with the support of Generative AI. Review: Amália Maranhão
1. ABOUT FA
Friedreich's ataxia (FA or FRDA) is an inherited disease of the central nervous system. It is named after Nikolaus Friedreich, who first described the disease in 1863, and was the first form of inherited ataxia to be differentiated from other forms of ataxias (see History in 7. Additional Information ).
The disease is caused by mutations in the FXN gene, which encodes frataxin , a protein essential for mitochondrial iron homeostasis. The most common mutation is the anomalous expansion of GAA trinucleotide repeats in the gene's first intron, reducing frataxin expression. A deficiency causes iron accumulation in the mitochondria, increasing oxidative stress and compromising cellular energy production.
Figure 1 - Image generated by the author with the support of Artificial Intelligence
FA is a progressive and disabling disease that affects multiple systems, including the neurological, muscular, and cardiovascular. The lack of frataxin makes the nervous system, myocardium, and other organs, such as the pancreas, more vulnerable to oxidative stress caused by accumulated mitochondrial iron. As part of the therapeutic approach, some FA patients receive antioxidant supplementation, such as coenzyme Q10 and vitamin E, in an attempt to reduce damage induced by free radicals. However, the effectiveness of these treatments is still under scientific investigation.
SKYCLARYS – On February 28, 2023, the Food and Drug Administration (FDA) approved the first drug indicated for the treatment of Friedreich’s ataxia (FA): SKYCLARYS (the trade name for omaveloxolone), developed by Reata Pharmaceuticals, which was acquired by Biogen. This approval represented a significant milestone not only for FA patients—often referred to as “Fredericos” within the patient community—but also for those affected by other forms of ataxia. Although Skyclarys was approved specifically for FA, the evaluation process adopted by the FDA, which combined clinical trial data with natural history studies of the disease, established a model potentially applicable to the approval of future treatments for other hereditary ataxias. This model may encourage other pharmaceutical companies to follow similar strategies in the pursuit of faster regulatory approval of new drugs for rare neurodegenerative diseases.
2. TYPICAL SYMPTOMS
The typical symptoms of FA (Friedreich’s Ataxia) include:
-
Balance difficulties
-
Impaired motor coordination in both upper and lower limbs
-
Slurred speech (dysarthria), which is usually one of the first symptoms to appear
-
Fatigue, associated with reduced energy and loss of muscle mass
-
Skeletal deformities, such as spinal curvature (kyphoscoliosis) and high-arched feet (pes cavus)
-
Diabetes mellitus (often requiring insulin treatment)
-
Serious heart problems (hypertrophic cardiomyopathy and arrhythmias)
-
Dysphagia (difficulty swallowing)
Notes:
-
Affected individuals may experience proprioceptive deficits, meaning difficulty perceiving the position of the feet and hands in space, as well as progressive limb weakness.
-
As the disease progresses, some individuals may develop incontinence (difficulty controlling the bladder).
-
Cognitive and intellectual abilities are not affected by FA.
-
Diabetes mellitus is a metabolic disorder characterized by difficulty in regulating blood glucose levels. Although it can be managed with diet and glucose monitoring, some patients require insulin therapy.
-
Some individuals with FA develop rapid, involuntary eye movements known as square wave jerks. These differ from nystagmus by being faster.
-
Hypothyroidism may also be present in some patients.
-
The progressive loss of coordination and muscle strength may lead to the need for mobility aids. Many patients require canes, walkers, or wheelchairs by late adolescence or early adulthood.
It is important to note that these symptoms do not appear in all individuals with FA, and when they do, they can range from mild to severe. For example, diabetes occurs in about 10–20% of individuals with FA, and incontinence affects around 50% of patients in more advanced stages of the disease.
FA Ataxia is a highly complex disease.
For more technical and detailed information on clinical features and symptoms, see [1] in Section 10 (References).
Types of FXN Gene Mutations That Affect Frataxin Production
According to the FARA website, approximately 96% of individuals with Friedreich’s Ataxia (FA) have an abnormal GAA trinucleotide repeat expansion in both alleles of the FXN gene. When the number of GAA repeats exceeds a certain threshold, it causes gene silencing, i.e., suppression of gene expression, preventing the proper synthesis of frataxin, a protein essential for normal mitochondrial function.
In the remaining 4% of cases, the GAA expansion occurs in only one allele, while the other allele contains a point mutation. This point mutation can manifest in two forms:
-
Substitution – one nucleotide (A, T, C, or G) is replaced by another
-
Deletion – a sequence of nucleotides is missing, resulting in a deleted portion of the gene
In both cases, these genetic alterations compromise the structure of the frataxin protein, impairing its biological function.
References: [1], [2], [3], [4]
Summary (see Figure 2 for reference):
-
Relationship between GAA repeats and frataxin production:
Individuals with a higher number of GAA repeats tend to produce lower levels of frataxin. -
Consequences of frataxin deficiency:
Reduced frataxin levels compromise health, as FA affects multiple tissues and systems, indicating that frataxin is essential for the proper function of various cell types. -
Importance of mitochondria:
Frataxin is predominantly located in the mitochondria, and its deficiency leads to mitochondrial dysfunction.
Nearly all cells contain mitochondria, which are essential organelles for cellular energy production. This function is especially critical in nerve and heart cells, where mitochondrial inefficiency can result in low energy levels. -
Symptoms of Friedreich’s Ataxia:
Mitochondrial dysfunction caused by frataxin deficiency gives rise to the multiple symptoms observed in FA, affecting several body systems.
Figure 2: Video from the 2024 FARA Symposium – “FAQs in Clinical Management for Friedreich’s Ataxia” – Oct 24, 2024
GAA repeat bands for genetic diagnosis of FA
As mentioned, a biallelic mutation (= both alleles of the FXN gene must have mutations) is required for AF to manifest. The size of the GAA expansion ( number of repeats ) required to cause the disease is quite technical, so we will present a summary. Those interested in a more detailed description can consult the Neuromuscular portal [1] , which contains a wealth of technical information.
Regarding the number of GAA repeats that can occur in the FXN gene, four categories into which the alleles can fit have been identified:
-
Normal alleles (no disease manifests) - Contain between 5 and 33 GAA repeats. More than 80% of alleles contain fewer than 12 repeats (small normal), and approximately 15% have 12 to 33 repeats (long normal). Normal alleles with more than 27 GAA repeats are rare.
-
"Normal mutant" alleles - Contain between 34 and 65 GAA repeats. Although the exact frequency of these alleles has not yet been formally determined, they likely occur in less than 1% of FXN gene alleles.
-
Mutant alleles with full penetrance (causing disease) - Contain 66 to approximately 1,300 GAA repeats. Most expanded alleles contain between 600 and 1,200 GAA repeats.
-
"Borderline" alleles (unclear if they cause disease) - Contain between 44 and 66 GAA repeats. The SMALLEST number of GAA repeats that causes disease (i.e., the exact demarcation between "normal allele" and "mutant allele with full penetrance") is not yet clearly determined.
Note: Source [1] has slightly different ranges.
References: [1], [2], [3], [4]
3. ONSET
The symptoms of Friedreich’s Ataxia (FA) usually appear in childhood or adolescence, typically between the ages of 5 and 25. Some sources indicate a narrower range – for example, [3] suggests between ages 5 and 18, with the average age of symptom onset occurring between 10 and 15 years. However, atypical cases have also been reported, with symptom manifestation occurring before childhood, in adults in their 30s or 40s, or even at other ages.
Note – There is an inverse correlation between the age of symptom onset and the size of the GAA trinucleotide expansion in the FXN gene. In other words, the greater the number of GAA repeats, the earlier symptoms tend to appear. Studies suggest that earlier onset may be associated with faster clinical progression and greater severity of certain symptoms. However, in addition to GAA expansion size, other factors – such as genetic, epigenetic, and environmental variables – also significantly influence symptom severity.
References: [2], [4], [5]
4. CAN ANTICIPATION OCCUR?
In Friedreich's ataxia, there is no intergenerational anticipation of symptoms; that is, descendants do not experience symptom onset at significantly earlier ages than their ancestors. This pattern is due to the recessive inheritance of the disease, which often results in the presence of asymptomatic carriers in previous generations, giving rise to the popular impression that the disease "skips generations."
5. INHERITANCE
Friedreich's ataxia (FA) has an autosomal recessive inheritance pattern, meaning that individuals of both sexes have an equal chance of inheriting the mutation. Symptoms of the disease manifest only when an individual inherits two mutated copies of the FXN gene—one from each parent. If an individual inherits only one mutated copy, they are considered a carrier and will not develop the disease, as the normal allele is sufficient to ensure adequate frataxin levels. In contrast, inheriting two defective copies of the FXN gene results in frataxin deficiency and, consequently, clinical manifestations of the disease throughout life. (Please see Section 3. Onset .)
Unless genetic testing is required for a family history of the disease, most carriers may be unaware of carrying a mutated FXN gene, as they have no symptoms of the disease. Therefore, it is common for parents to only discover they are carriers of the gene when one of their children is diagnosed with FA (meaning both biological parents are carriers). Because carrier parents have no symptoms of the disease, but children who inherit two mutant genes do, Friedreich's ataxia (like other autosomal recessive diseases) is said to "skip generations."
Probability of children inheriting the mutation that causes the disease
When both parents carry the mutated FXN gene, the probabilities for each child are as follows:
-
25% chance: the child inherits a mutated copy from each parent, developing the disease.
-
50% probability: the child inherits only one mutated copy (from one of the parents), becoming an asymptomatic carrier.
-
25% probability: the child does not inherit any mutated copy (neither from the father nor from the mother), neither developing the disease nor being a carrier.
Notes: "Autosomal" means the gene is located on any chromosome except the X and Y sex chromosomes. Genes, like chromosomes, typically exist in pairs (we have a pair of each gene; one copy of the gene is inherited from the mother, the other from the father). Thus, men and women are equally likely to inherit a mutated gene that can cause hereditary ataxia. "Recessive" means that two mutated copies (alleles) of the gene must be inherited (one from the biological father, the other from the mother) for a person to develop the disease.
Figure 3 - Source: MedlinePlus, US National Library of Medicine .
6. PREVALENCE
Friedreich's ataxia (FRDA) is the most common form of recessively inherited ataxia with symptoms beginning in childhood. In the United States, it is estimated that approximately 1 in 100 individuals is an asymptomatic carrier of a mutation in the FXN gene, often unaware of their condition. The prevalence of the disease in its overt form—that is, in individuals with two mutated copies of the FXN gene who are symptomatic—is estimated at 1 in 50,000 people. These prevalence figures may vary by geographic region and different ethnic groups around the world.
Note: Taking the 1/50,000 ratio as a reference, we can estimate that in Brazil, with approximately 214 million inhabitants, there are approximately 4,000 people affected by Friedreich's ataxia. For the United States, the FARA website estimates the existence of 5,000 people with FA [3] . This number will be higher if we consider that the current US population is 330 million. With a ratio of 1 case per 50,000 inhabitants, the estimated total would be closer to 6,000 people with FA.
7. ADDITIONAL INFORMATION
History of the Discovery and Research Advances in Friedreich’s Ataxia
-
In 1988, researcher Susan Chamberlain [8] and collaborators mapped the gene associated with Friedreich’s Ataxia to chromosome 9, a significant milestone that marked the first step toward understanding the genetic basis of the disease.
-
In 1996, an international team of scientists led by Dr. Massimo Pandolfo announced the identification of the gene responsible for Friedreich’s Ataxia, now known as FXN. This discovery clarified the genetic cause of the disease, accelerated research into its pathophysiology, and enabled the development of a specific genetic test for diagnosis.
-
The following year, in 1997, researchers demonstrated that frataxin, the protein encoded by the FXN gene, is located in the mitochondria, organelles essential for cellular energy production. This finding redirected efforts toward studying mitochondrial dysfunction as a therapeutic target.
-
In June 1999, a mouse model carrying the GAA repeat expansion in the FXN gene was developed, allowing experimental studies on the effects of frataxin deficiency and the impact of the mutation on cellular function.
-
In February 2023, the Food and Drug Administration (FDA) approved Skyclarys (omaveloxolone), the first medication for the treatment of Friedreich’s Ataxia, developed by Reata Pharmaceuticals, which was later acquired by Biogen.
-
In March 2024, Biogen submitted a registration application for Skyclarys to the Brazilian Health Regulatory Agency (ANVISA), seeking approval for its use in Brazil.
The Role of Frataxin
-
Studies conducted by Dr. Massimo Pandolfo’s team, among other researchers, confirm that frataxin plays a fundamental role in regulating iron metabolism within mitochondria. Iron is an essential element for cellular energy production, as it is incorporated into mitochondrial proteins involved in the respiratory chain and in the biosynthesis of iron-sulfur clusters, which are crucial for numerous biochemical reactions.
-
Cells acquire iron from the environment and control its uptake through regulatory mechanisms at the cell membrane. Once inside the cell, a portion of the iron is directed to the mitochondria, where it serves essential functions. However, iron also needs to be exported from the mitochondria to other parts of the cell to prevent harmful accumulation.
-
Frataxin is likely involved in mitochondrial iron export, facilitating its storage in appropriate cellular compartments for later redistribution. Frataxin deficiency leads to pathological iron accumulation within mitochondria, which may result in oxidative stress due to the excessive formation of free radicals. These radicals are highly reactive molecules that can cause oxidative damage to proteins, lipids, and mitochondrial DNA, impairing cellular function.
-
In addition to direct damage to mitochondria, there is evidence that cellular iron homeostasis is also indirectly affected. Since iron becomes trapped within the mitochondria, cellular sensors may fail to detect sufficient iron levels, triggering a compensatory increase in iron uptake. This vicious cycle may further amplify mitochondrial accumulation and oxidative stress, worsening cellular dysfunction.
-
Potential therapeutic strategies include drugs that remove iron from mitochondria (iron chelation) or drugs that neutralize free radicals (antioxidants, such as coenzyme Q10).
See Section 8 – Therapies and Medications.
Reference: [9]
8. THERAPIES AND MEDICATIONS
Figure 4 Image adapted from [10] by the author. The arrow indicates a timeline, showing how close the medicine or therapy is to reaching the market (in the US, in this case).
In addition to SKYCLARYS, which improves mitochondrial function and reduces oxidative stress and is already FDA-approved, several other drugs and therapies are under investigation aiming for FDA approval.
Below is a summary of the main ongoing clinical trials (September 2025):
1. Already approved by the FDA (available to patients in the U.S.)
-
SKYCLARYS (omaveloxolone) — Biogen (Reata): approved on Feb 28, 2023 for FA patients ≥16 years old. Already commercially available in the U.S.
2. Already submitted to the FDA (but not yet approved)
-
Vatiquinone (PTC-743) - PTC Therapeutics. Submitted to the FDA, but in August 2025 the agency rejected approval (issued a “CRL,” requesting additional studies). The program continues, but it is not yet available to patients.
3. Phase II clinical trials (testing efficacy and safety in patient groups)
-
NAD+ and Exercise in FA — study conducted at the Children’s Hospital of Philadelphia (CHOP).
-
Leriglitazone (MIN-102), Minoryx Therapeutics — Phase II study completed.
-
Dimethyl Fumarate — study conducted at the University of Federico II, Italy.
-
Nomlabofusp (CTI-1601), Larimar Therapeutics — frataxin replacement therapy. Phase II studies ongoing, including in children.
4. Phase I/II trials (first-in-human studies, testing doses and early effects)
-
Elamipretide (Children’s Hospital of Philadelphia) — pilot study conducted at CHOP.
-
LX2006 Gene Therapy — Lexeo Therapeutics: gene therapy program that has received special FDA designations (Fast Track, RMAT, and Breakthrough). Phase I/II studies are ongoing.
5. Phase I (first human safety studies)
-
ASP2016 (Astellas Gene Therapies): a gene therapy project for FA-related cardiomyopathy. The study was discontinued by the company in February 2025.
6. Preclinical stage (laboratory testing, not yet in human trials)
-
DT-216P2 (Design Therapeutics): began Phase I/II outside the U.S. in June 2025. In the U.S., the FDA placed the program on “clinical hold.”
-
PPL-001 (Papillon Therapeutics): still in preclinical (laboratory) testing.
-
NBIB-223 - Neurocrine Biosciences / Voyager Therapeutics AAV-Gene Therapy: preclinical gene therapy program; lead candidate selected in 2024.
-
SGT-212 (UPenn) — In 2025 received FDA regulatory approval (IND cleared) to begin human trials. No human results have been published yet. Currently in transition from preclinical to clinical stage.
Please see the FARA (Friedreich's Ataxia Research Alliance) FA Symposium 2024 videos below for more information.
9. TREATMENTS
Friedreich's ataxia still has no cure, but its symptoms can be treated.
-
The drug SKYCLARYS has the potential to slow the progression of the disease .
-
Monitoring heart health in patients with Friedreich's Ataxia is important because of the risks of hypertrophic cardiomyopathy and arrhythmias.
-
The same applies if you develop Diabetes mellitus, which may require insulin treatment.
See the videos for more information on AF symptom management in Section 10. References .
Here are some best practices for managing AF symptoms.
-
Neurofunctional physiotherapy and exercises are recommended (within the possibilities of each patient).
-
To reduce the risk of falls due to balance difficulties when walking, you can use canes, walkers or wheelchairs, depending on the stage of the disease.
-
Occupational physical therapy and some adaptations at home and in daily habits can help (e.g., installing grab bars in hallways and bathrooms, a shower chair, lights for nighttime illumination, repositioning furniture to facilitate mobility, removing rugs to avoid tripping, using cups with lids and straws, shoes with non-slip soles that are easy to put on, etc.).
-
Rest whenever necessary, and it's important to get a good night's sleep. If you have trouble sleeping, consult your doctor, as there are medications that can help.
-
Maintain a healthy diet and good hydration.
-
Consult a neuro-ophthalmologist if visual symptoms appear.
-
For dysarthria, if such a symptom manifests, specialized speech therapy (speech therapy) is recommended.
-
For dysphagia, if it occurs, a consultation with a speech therapist is also recommended - there are exercises that can help with swallowing, reducing the risk of choking that can cause aspiration pneumonia.
-
If necessary, there are medications available to manage anxiety and depression. Consult your doctor to discuss the most appropriate options.
See information about medications for ataxia symptoms .
See information about treatments and care for patients .
See information about those who have recently been diagnosed .
See information about Support Groups for patients and caregivers.
Attention! For a comprehensive source on symptoms and clinical care (management) of patients with Friedreich’s Ataxia, consult the FARA (Friedreich's Ataxia Research Alliance) document:
Clinical Management Guidelines for Friedreich Ataxia (FRDA) – 2022.
The content is in English, but it is possible to enable subtitles and configure automatic text translation into Portuguese.
As complementary reading, we recommend the website:
Understanding FA – NAVIGATING THE FRIEDREICH’S ATAXIA JOURNEY,
which is available in different languages, including Portuguese.
10. REFERENCES
The references below include academic sources and specialized organizations that supported the information in this fact sheet, including peer-reviewed articles, genetic repositories (OMIM), literature summaries (GeneReviews), and informational materials from ataxia foundations. For more information, see the ataxia.info References list .
Articles
Ref #1
Source:
NEUROMUSCULAR DISEASE CENTER (Alan Pestronk, MD)
Washington University, St. Louis, MO - USA
Language:
English
Date:
Last Updated: Please see https://neuromuscular.wustl.edu/rev.htm
Ref #2
Source:
FRDA Fact Sheet
NAF (National Ataxia Foundation)
Language:
English
Date:
Last Updated: Oct 2024
Ref #3
Source:
FARA
Friedreich's Ataxia Research Alliance
Language:
English (the page can be displayed in several languages, including Portuguese)
Date:
Last Updated: 2024
Ref #4:
Source:
Sanjay I Bidichandani, MBBS, PhD and Martin B Delatycki, MBBS, FRACP, PhD.
Copyright © GeneReviews. GeneReviews ® is a registered trademark of the University of Washington, Seattle.
Language:
English
Date:
Last Updated: June 1, 2017
Ref #5:
Source:
FARA Portal
Leveraging research to treat Friedreich's Ataxia
Language:
English (the page can be displayed in different languages, including Portuguese)
Date:
2024
Ref #6
Source:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
English
Date:
Last Updated: February 2023
Ref #7:
Source
OMIM ® - An Online Catalog of Human Genes and Genetic Disorders.
Copyright © Johns Hopkins University.
Language:
English
Date:
Edit history: alopez: 01/26/2024
Ref #8:
Source
Susan Chamberlain et al
Nature
Language:
English
Date:
Published: July 21, 1988
Ref #10:
Source
FARA website
Drug development pipeline
Language:
English (the page can be displayed in several languages, including Portuguese)
Date:
2024
Ref #10:
Source
FARA website
Drug development pipeline
Language:
English (the page can be displayed in several languages, including Portuguese)
Date:
2024
Videos
Video:
Author/site:
NAF (National Ataxia Foundation) - Dr. Marek Napierala
Language:
English. You can enable subtitles and configure automatic translation of subtitles into Portuguese.
Date:
March 17th, 2023
Video:
Author/site:
NAF (National Ataxia Foundation) - Dr. David Lynch
Language:
English. You can enable subtitles and configure automatic translation of subtitles into Portuguese.
Date:
March 6th, 2023