Recognizing Friedreich Ataxia: Diagnosis and Management

As physicians, our understanding of rare diseases is constantly evolving. Due to their low prevalence and, at times, heterogenous nature, it can be difficult to identify symptoms of, diagnose and treat these conditions. One such disease is Friedreich ataxia (FA), a rare, genetic, life-shortening, debilitating and degenerative neuromuscular disorder that affects approximately 5,000 people in the United States.^1,2

FA, the most common inherited ataxia, is caused by mutations in the FXN gene, which negatively impact 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.³ Unfortunately, complications from FA contribute to a life expectancy of just 37 years, on average.³

After meeting my first patient living with FA, I knew it was important to fully understand the biochemistry of the disease to help people and their families. I have since dedicated my career, from fellowship to my current role as a clinical professor in the Neurogenetics division at the David Geffen School of Medicine at UCLA, to treating FA and driving research forward to better understand the disease. Early on, information on FA was sparse, but researchers have made great strides, including the identification of the key genetic biomarker – GAA expansion pattern. Still, more education on FA is needed to help improve patient care and outcomes.

Diagnosing FA

Patients with FA typically begin experiencing symptoms around the ages of 5-15 years, although it can also present in young adulthood or later.¹ About one third of people with FA are diagnosed after age 20.⁴

There is a classic presentation of neurological signs in FA, including gait instability, posterior column sensory loss, absent deep tendon reflexes and bilateral upgoing toes (Babinski response).^1,5 These symptoms may help to identify FA; however, symptoms may vary from person to person. Patients may present with cardiac changes, as well.³ Patients with late-onset FA and very late-onset FA may experience atypical symptoms, including spasticity, retained reflexes, severe optic atrophy and chorea.^6-8 FA is a progressive neuromuscular disease so, over time, patients will see an effect on upright stability, standing and walking, with upper extremity clumsiness becoming more apparent. Patients will also experience changes in speech, swallowing, vision and hearing.¹

It is common for even the classic presentation of FA to be misdiagnosed initially, with symptoms confused for other diseases like Charcot-Marie-Tooth disease or multiple sclerosis.⁴ The rarity of this disease and the fact that symptoms can be confused with other conditions demonstrate how critical it is for FA to be more widely discussed among the physician community; in many medical school texts, FA is a footnote and not largely discussed at all.

Genetic Testing and FA

Genetic testing is the only way to definitively diagnose FA – a tool that was not established in practice when I began to treat patients with FA.¹

To obtain a definitive diagnosis of FA, the panel must include GAA triplet-repeat expansion analysis, which is not standard in all genetic testing panels.⁹ The number of GAA triplet repeats identified may determine the severity of FA. Higher numbers of repeats have been linked to an earlier age of onset and increased FA symptoms.³

With FA so often misdiagnosed and the average time to diagnosis being a few years following the onset of initial symptoms, the importance of utilizing appropriate genetic testing cannot be underscored enough.^4,10 It is my recommendation that any patient presenting with symptoms of FA, regardless of age, receive genetic testing, including an FXN GAA repeat expansion test. Additionally, having a genetic counselor consult on their case can help patients make informed decisions by ensuring they understand genetic testing, its benefits and other considerations. Genetic counselors can also assist patients and families in determining if they are good candidates for genetic testing and understanding and addressing the implications of genetic testing results.

Treatment and Management

There was very little known about FA when I first began practicing, which meant there were no U.S. FDA-approved treatments for the disease. Through the establishment of UCLA’s first Ataxia Clinic in 1986, I was able to meet many people living with FA at different stages of disease progression. Earlier in my career, we focused on symptom management, including rehabilitation, medication for treatable symptoms and referrals for resources to improve a patient’s quality of life. With FA being a multifactorial and multisystem disorder, a multidisciplinary care team approach that includes a patient’s neurologist, cardiologist, endocrinologist, general internist and orthopedist is crucial.

As science has continued to advance, the FA treatment landscape has evolved, with symptom management no longer being the only option physicians can provide to their patients. 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 The approval of SKYCLARYS represented an important step forward in the treatment of FA.

SKYCLARYS is the first FDA-approved treatment for FA in adults and adolescents aged 16 years and older. In a clinical trial, treatment with SKYCLARYS (n=40) resulted in 2.41 lower modified Friedreich Ataxia Rating Scale (mFARS) scores, meaning less impairment, relative to patients on placebo (n=42) at Week 48 (-1.56 vs +0.85; P=0.0138).¹¹ Results from patient subgroups numerically favored SKYCLARYS over placebo in all four components of the mFARS assessment, 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.

The FA community is extremely well informed and involved in updates related to clinical research, and I received phone calls from many of my patients asking about SKYCLARYS when they learned of its approval by the FDA. In the two years since, I have discussed potential treatment with SKYCLARYS with all appropriate patients who are aged 16 years and older. In my experience working with patients taking SKYCLARYS, some of them have shared with me that they have observed some improvements in their limb coordination.

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

Future of FA

Looking ahead, physician awareness, including recognition of both typical and atypical symptoms, along with earlier and appropriate genetic testing, will continue to improve diagnosis and treatment outcomes of FA. Genetic testing can lead to a definitive diagnosis, but recognizing key traits of the disease early can help healthcare providers know what to look for and to order testing. The availability of treatments like SKYCLARYS will help spread awareness of FA among the physician community, which can lead to earlier diagnosis and treatment initiation.

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 SkyclarysPregnancySurveillance@ppd.com
• 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 25, 2025. Accessed June 23, 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. 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.
5. Perlman S. Hereditary Ataxia Overview. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Updated February 20, 2025. Accessed June 23, 2025. https://www.ncbi.nlm.nih.gov/books/NBK1138/
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; EFACTS (European Friedreich's Ataxia Consortium for Translational Studies). 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. Wallace SE, Bird TD. Molecular genetic testing for hereditary ataxia: what every neurologist should know. Neurol Clin Pract. 2018;8(1):27-32
10. Rummey C, Farmer JM, Lynch DR. Predictors of loss of ambulation in Friedreich’s ataxia. EClinicalMedicine. 2020;18:100213.
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 June 23, 2025. https://frdaguidelines.org/2-3/