Friedreich Ataxia: A Rare Neuromuscular Disease Overview for Healthcare Professionals

Sponsored by Biogen

The importance of learning and understanding rare diseases cannot be underscored enough within the physician community, no matter one’s specialty. Yet, with the nature of rare diseases, it can be difficult to recognize symptoms and manage these conditions. If they can recognize the symptoms, primary care providers have an opportunity to identify disorders and take steps to help patients receive a formal diagnosis and, ultimately, treatment. An example of a rare disease that primary care providers seldom see is Friedreich ataxia (FA), a rare, genetic, life-shortening, debilitating and degenerative neuromuscular disorder with approximately 5,000 people living with the condition in the United States.^1-3

As rare as FA is, it is the most common inherited ataxia. It is caused by a genetic mutation of the frataxin (FXN) gene, which negatively impacts production of frataxin, resulting in cellular damage and disruption to energy production in mitochondria.¹ As the disease progresses, many people with FA often require the use of walking aids and, eventually, a wheelchair within 10-15 years following disease onset. Unfortunately, complications from FA contribute to a life expectancy of just 37 years, on average.³

As a neurologist specializing in ataxia, I have dedicated my career to understanding these disorders and getting deeply involved with the FA community. Through my clinic at the University of Chicago and role on the Advisory Board of the National Ataxia Foundation, I’m constantly working to better understand FA. Over the years, I have found that many patients I see for the first time are still searching for a confirmed diagnosis after exhibiting possible FA symptoms, even as we continue to learn more about the disease. It is critical that pediatricians and PCPs learn to identify these symptoms and drive quicker diagnoses for patients.

Diagnosing FA: What Physicians Need to Know

Diagnosing FA can be a challenge so getting familiar with signs and symptoms is critical to early identification. While every patient’s experience is unique, there are common symptoms physicians can identify early on, including frequent falls, feeling clumsy or unbalanced, as well as fatigue and loss of reflexes and sensation.^3-5 People with FA typically begin presenting symptoms around the ages of 10-15 years but symptoms can emerge at nearly at any age.³ People with late-onset FA (LOFA) begin experiencing symptoms after 25 years of age and those with very late-onset FA (VLOFA) experience symptoms after 40 years of age.⁶

Expanding beyond initial FA symptoms, additional signs that may present over the course of the disease are cardiomyopathy, which may be present in younger patients with more severe FA, loss of bulbar function that may result in patients’ slurred speech and scoliosis.³ Patients with LOFA and VLOFA may experience atypical symptoms, including spasticity, retained reflexes, severe optic atrophy and chorea.^6-8

With the rarity of FA, it is common for patients to be misdiagnosed initially, with symptoms confused for other diseases like Charcot-Marie-Tooth disease or multiple sclerosis. As many as 1 in 4 patients with FA have been misdiagnosed.⁹

An FA diagnosis can take a median of a few years following the onset of initial symptoms.⁷ I have encountered this in my own practice with patients seeking answers due to symptom progression and the lack of a confirmed diagnosis. For those looking for resources, ataxia centers of excellence across the country and patient advocacy groups, including the National Ataxia Foundation and Friedreich’s Ataxia Research Alliance, can provide information and guidance.

Ultimately, genetic testing is the only way to definitively diagnose FA. GAA triplet-repeat expansion analysis is not standard in all genetic testing panels, but is required for an FA diagnosis.¹⁰ The number of GAA triplet repeats identified may determine the severity or prognosis of FA.³

Given the symptoms of FA, I have found that physicians may choose to order an MRI scan of a patient’s spinal cord as a first step towards diagnosis versus initiating genetic testing. I can’t stress enough that genetic testing should be the standard for diagnosis if there is suspicion of FA – I find it is easier for patients, results are delivered faster, and it is less expensive than an MRI.

Following a confirmed FA diagnosis, discussions with patients and their families regarding familial genetic testing is an important next step. Genetic testing may have implications for a patient’s siblings, parents or children so they should be encouraged to participate in genetic counseling. In my experience, when a child is diagnosed with FA, parents almost immediately want to discuss the chance of siblings being diagnosed. Some families recognize that another child may have symptoms suggestive of FA but not as many, the same, or as severe symptoms as the initial sibling diagnosed with FA.

Treatment and Management

I have been seeing patients with FA in clinical practice for decades, participated in numerous research studies and kept a very close eye on the treatment landscape for new innovations. There were no U.S. FDA-approved treatments for the disease for most of my career, and focusing on symptom management was key for treating patients with FA.

In February 2023, the FDA approved SKYCLARYS^® (omaveloxolone), an oral, once-daily medication indicated for the treatment of FA in adults and adolescents aged 16 years and older.¹¹

SKYCLARYS is the first and only FDA-approved treatment for FA in adults and adolescents aged 16 years and older. In a clinical trial (the MOXIe trial), treatment with SKYCLARYS (n=40) resulted in 2.41 lower modified Friedreich Ataxia Rating Scale (mFARS) scores (the mFARS is a clinical assessment tool to assess patient function, which consists of 4 domains to evaluate bulbar function, upper limb coordination, lower limb coordination, and upright stability), meaning less impairment, relative to patients on placebo (n=42) at Week 48 (-1.56 vs +0.85; P=0.0138).¹¹ Results numerically favored SKYCLARYS over placebo in all four components of the mFARS assessment and in patient subgroups, including age, sex, GAA repeat length, ambulatory status, or presence of pes cavus. The MOXIe trial was not powered to detect a statistically significant difference among subgroups.²

Treatment with SKYCLARYS can cause an elevation in hepatic transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). The incidence of elevations of ALT or AST above 5 times and 3 times the upper limit of normal (ULN) was 16% and 31%, respectively, in patients treated with SKYCLARYS. Monitor ALT, AST, and total bilirubin prior to initiation of SKYCLARYS, every month for the first 3 months of treatment, and periodically thereafter. Additionally, SKYCLARYS can cause an increase in B-type natriuretic peptide (BNP), a marker of cardiac function. A total of 14% of patients treated with SKYCLARYS had an increase from baseline in BNP value above the ULN (100 pg/mL), compared to 4% of patients who received placebo. Elevations in BNP may indicate cardiac failure and should prompt an evaluation of cardiac function. Check BNP prior to initiation of SKYCLARYS. Monitor patients for the signs and symptoms of fluid overload. Treatment with SKYCLARYS can cause changes in cholesterol. In the clinical trial, 29% of patients treated with SKYCLARYS reported elevated cholesterol above ULN at one or more time points. Assess lipid parameters prior to initiation of SKYCLARYS and monitor periodically during treatment. Manage lipid abnormalities according to clinical guidelines.¹¹

The most common adverse reactions in the clinical trial (≥20% and greater than placebo) were elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain.¹¹

Please see Important Safety Information below and click for full Prescribing Information and Patient information for more information about SKYCLARYS.

SKYCLARYS has a strong recommendation in the Clinical Management Guidelines for FA to treat individuals aged 16 and older, as opposed to no treatment. The recommendation, which was updated in November 2024, is based on a moderate level of evidence and is aligned with FDA approved-labeling. The guidelines also consider the progressive nature of FA and limited treatment options, reinforcing the importance of considering treatment with patients.¹²

The FA community is tight knit and extremely well informed when it comes to updates related to clinical research. Following the approval of SKYCLARYS, many patients initiated treatment discussions and of those for whom I have prescribed SKYCLARYS, some have noted positive experiences.

It’s important to note that FA symptom management should be considered despite treatment availability. FA is a complex disease that requires a multidisciplinary care team (MDT) involving the patient’s pediatrician or PCP and neurologist, along with other specialists, such as cardiologists, endocrinologists and orthopedists.¹³ We have a responsibility as providers to help patients build this MDT and work together to ensure they feel supported in managing their disease and respective symptoms.

Looking Ahead

Awareness of FA among the physician community, especially among pediatricians and PCPs, is key for the patient community and will help both expedite diagnoses and avoid misdiagnosis. With the availability of treatment, like SKYCLARYS, it is even more imperative there is awareness among the community.

Progress like this gives me hope – my father was also a neurologist, and I took over as the provider for one of his FA patients as a part of my practice. It’s encouraging that treatments like SKYCLARYS, and the collective action and momentum around recognizing and treating rare diseases, will ultimately help improve care and create a more supportive community for those living with these diseases.

INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATION

• SKYCLARYS^® (omaveloxolone) is indicated for the treatment of Friedreich ataxia in adults and adolescents aged 16 years and older

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Elevation of Aminotransferases

• Treatment with SKYCLARYS can cause an elevation in hepatic transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). The incidence of elevations of ALT or AST above 5 times and 3 times the upper limit of normal (ULN) was 16% and 31%, respectively, in patients treated with SKYCLARYS. There were no cases of concomitant elevation of transaminases and total bilirubin observed. Maximum increases in ALT and AST occurred within 12 weeks after starting SKYCLARYS. Increases in serum aminotransferases were generally asymptomatic and reversible following discontinuation of SKYCLARYS
• Monitor ALT, AST, and total bilirubin prior to initiation of SKYCLARYS, every month for the first 3 months of treatment, and periodically thereafter. If transaminases increase to levels greater than 5 times the ULN, or greater than 3 times the ULN with evidence of liver dysfunction (e.g., elevated bilirubin), immediately discontinue SKYCLARYS and repeat liver function tests as soon as possible. If transaminase levels stabilize or resolve, SKYCLARYS may be reinitiated with an appropriate increased frequency of monitoring of liver function

Elevation of B-Type Natriuretic Peptide

• Treatment with SKYCLARYS can cause an increase in B-type natriuretic peptide (BNP), a marker of cardiac function. A total of 14% of patients treated with SKYCLARYS had an increase from baseline in BNP value above the ULN (100 pg/mL), compared to 4% of patients who received placebo. The incidence of elevation of BNP above 200 pg/mL was 4% in patients treated with SKYCLARYS. Cardiomyopathy and cardiac failure are common in patients with Friedreich ataxia. Whether the elevations in BNP are related to SKYCLARYS or cardiac disease associated with Friedreich ataxia is unclear
• Elevations in BNP may indicate cardiac failure and should prompt an evaluation of cardiac function. Check BNP prior to initiation of SKYCLARYS. Monitor patients for the signs and symptoms of fluid overload, such as sudden weight gain (3 pounds or more of weight gain in one day, or 5 pounds or more of weight gain in a week), peripheral edema, palpitations, and shortness of breath. If signs and symptoms of fluid overload develop, worsen, or require hospitalization, evaluate BNP and cardiac function, and manage appropriately. Management of fluid overload and heart failure may require discontinuation of SKYCLARYS

Lipid Abnormalities

• Treatment with SKYCLARYS can cause changes in cholesterol. In Study 1, 29% of patients treated with SKYCLARYS reported elevated cholesterol above ULN at one or more time points. Mean increases were observed within 2 weeks of initiation of SKYCLARYS and returned to baseline within 4 weeks of discontinuing treatment. A total of 16% of patients treated with SKYCLARYS had an increase in low-density lipoprotein cholesterol (LDL-C) from baseline, compared to 8% of patients who received placebo. The mean increase in LDL-C for all SKYCLARYS treated patients was 23.5 mg/dL at 48 weeks. A total of 6% of patients treated with SKYCLARYS had decreases in high-density lipoprotein cholesterol (HDL-C) from baseline compared to 4% of patients who received placebo. The mean decrease in HDL-C for all SKYCLARYS-treated patients was 5.3 mg/dL at 48 weeks
• Assess lipid parameters prior to initiation of SKYCLARYS and monitor periodically during treatment. Manage lipid abnormalities according to clinical guidelines

ADVERSE REACTIONS

• The most common adverse reactions in Study 1 (≥20% and greater than placebo) were elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain.

DRUG INTERACTIONS

• Avoid concomitant use of SKYCLARYS with moderate or strong CYP3A4 inhibitors. If use cannot be avoided, dosage modifications are recommended
• Avoid concomitant use of SKYCLARYS with moderate or strong CYP3A4 inducers
• Refer to the prescribing information for dosing instructions for concomitant use of CYP3A4 and CYP2C8 substrates and monitor for lack of efficacy of the concomitant treatment
• Advise patients to avoid concomitant use with combined hormonal contraceptives, implants, and progestin only pills

SPECIFIC POPULATIONS
Pregnancy

• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SKYCLARYS during pregnancy. Healthcare providers are encouraged to enroll pregnant patients, or pregnant women may register themselves in the program by calling 1-866-609-1785 or by sending an email to [email protected]
• There are no adequate data on the development risks associated with the use of SKYCLARYS in pregnant women

Lactation

• There are no data on the presence of omaveloxolone or its metabolites in human milk. The effects on milk production and the breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SKYCLARYS and any potential adverse effects on the breastfed infant from SKYCLARYS or from the underlying maternal condition

Hepatic Impairment

• Avoid treatment with SKYCLARYS in patients with severe hepatic impairment, including those who develop severe hepatic impairment
• Reduced dosage in patients with moderate hepatic impairment with close monitoring for adverse reactions is recommended

Please see full Prescribing Information.

References

1. National Institute of Neurological Disorders and Stroke. Friedreich Ataxia. Updated March 26, 2025. Accessed September 11, 2025. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.
2. Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann Neurol. 2021;89(2):212-225.
3. Parkinson MH, Boesch S, Nachbauer W, et al. Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J Neurochem. 2013;126(suppl 1):103-117.
4. Fogel BL, Perlman S. Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol. 2007;6(3):245-257.
5. Friedreich’s ataxia. National Organization of Rare Disorders. Revised April 7, 2025. Accessed September 11, 2025. https://rarediseases.org/rare-diseases/friedreichs-ataxia/.
6. Cook A, Giunti P. Friedreich’s ataxia: clinical features, pathogenesis and management. Br Med Bull. 2017;124(1):19-30.
7. Indelicato E, Nachbauer W, Eigentler A, et al. Onset features and time to diagnosis in Friedreich’s ataxia. Orphanet J Rare Dis. 2020;15(1):198.
8. Lynch DR, Farmer JM, Balcer LJ, Wilson RB. Friedreich ataxia: effects of genetic understanding on clinical evaluation and therapy. Arch Neurol. 2002;59(5):743-747.
9. Donoghue S, Martin A, Larkindale J, Farmer J. A meta-analysis study to evaluate time to diagnosis of Friedreich’s ataxia in the U.S. Friedreich’s Ataxia Research Alliance; 2018.
10. Wallace SE, Bird TD. Molecular genetic testing for hereditary ataxia: what every neurologist should know. Neurol Clin Pract. 2018;8(1):27-32.
11. Skyclarys. Prescribing information. Biogen; 2024.
12. Wilmot G, Mariotti C, Lynch D, Tai G, Pandolfo M. Clinical Management Guidelines for Friedreich Ataxia (FRDA). 2022. Updated November 2024. Accessed September 11, 2025. https://frdaguidelines.org/2-3/.
13. Lynch DR, Schadt K, Kichula E, et al. Friedreich ataxia: multidisciplinary clinical care. J Multidiscip Healthc. 2021;14:1645-1658.