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Disease/Disorder

Definition

Friedreich’s ataxia (FA; also known as Friedreich Ataxia or FRDA) is a multisystem, autosomal recessive degenerative disorder and is the most common inherited ataxia.1-4

Etiology

FA occurs when a patient is homozygous for mutations of the FXN gene on chromosome 9. FXN encodes a mitochondrial matrix protein called frataxin, and the mutated FXN ultimately leads to decreased levels of functional frataxin.1-3 See pathophysiology below for details.

Epidemiology including risk factors and primary prevention

FA is the most common inherited ataxia. It is most common among white populations, with an estimated prevalence of 1:50,000 and 1:100,000 in the United States.  FA is much less common in Black and Asian populations. The incidence is equal in males and females. Typically, onset of FA occurs between the ages of 5 and 20 but it can present outside this range with some patients presenting as late as their 60s.1,2

Patho-anatomy/physiology

FA is autosomal recessive disorder that is caused by mutations of FXN on both copies of chromosome 9.  95% of cases are due to abnormal homozygous expansion of a guanine-adenine-adenine (GAA) trinucleotide repeat in intron 1 of FXN. While normal FXN alleles have fewer than 33 GAA repeats, patients with FA who are homozygous have abnormal GAA expansions of between 66–1500 repeats. This mutation leads to transcriptional defects, and ultimately to a decrease in the amount of frataxin expressed.1-3

The remaining 5% of cases are compound heterozygotes with the GAA trinucleotide repeat expansion on one allele and point mutations within FXN exons on the other allele. The point mutations lead to a non-functional protein.1

Both scenarios lead to decreased amounts of functional frataxin. Frataxin, a nuclear-encoded mitochondrial protein, plays a crucial role in mitochondrial iron metabolism and iron homeostasis, particularly in the maintenance of iron-sulfur clusters for enzymes involved in oxidative phosphorylation, the Krebs Cycle, and other cellular events. 

Frataxin is decreased to 5-35% of normal levels in patients with FA. Asymptomatic heterozygotes are typically at 50% of normal levels.1

For reasons not fully understood, FA primarily affects the nervous system. While frataxin deficiency is widespread across tissues in FA, cells most affected clinically include large sensory neurons of dorsal root ganglia (DRG), the dentate nucleus of the cerebellum, upper motor neurons giving rise to the corticospinal tract, cardiomyocytes, pancreatic islet cells and other selected cells of the brain and retina. Cardiac involvement results in cardiomyopathy, most commonly causing diastolic dysfunction.1,3

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Onset of FA is usually noted with unsteadiness of gait and typically occurs before completion of puberty. Progressive ataxia, often mixed with both cerebellar and sensory components, is typical. Disease progression is typically slow, with death occurring around 35 years after symptom onset. The disease course tends to be more aggressive in patients with onset prior to the age of 20 and those with cardiac involvement.1,3

Neurologic complaints typically precede non-neurologic manifestations  In addition to ataxia, other neurologic symptoms include weakness, sensory neuropathy, dysarthria, auditory deficits, bulbar dysfunction, neurocognitive deficits, affective disorders, restless legs, fatigue, spasticity, and optic atrophy.1,2 The severity of symptoms is independent from each other (i.e. a patient could have severe neurologic symptoms, but no cardiac problems), though the severity of most symptoms appears to be directly related to the number of GAA trinucleotide repeats. Wheelchair use as the primary method of mobility most often occurs around 11 to 15 years after the onset of symptoms.4 Causes of death include aspiration pneumonia, cardiac complications, diabetic coma, stroke, and trauma sequelae.1-4

Specific secondary or associated conditions and complications

Non-neurologic issues in FA include cardiac dysfunction, skeletal deformities, diabetes mellitus, and obstructive sleep apnea. Cardiac problems include cardiomyopathy (typically hypertrophic or dilated) and arrhythmia (more common if cardiomyopathy is present). Diastolic dysfunction may be exacerbated by volume overload (e.g., with excess intravenous fluid administration) or volume depletion (e.g., with diarrhea or vomiting).1

About 10% of patients with FA develop diabetes mellitus caused by a combination of insulin deficiency through loss of pancreatic islet β cells and peripheral insulin resistance.1,3

Skeletal manifestations most commonly include scoliosis and foot deformities (e.g., pes cavus). Ninety percent of individuals with early onset of FA symptoms develop intermediate to severe scoliosis, while those who present later (>14 years old) are more likely to develop mild scoliosis or no scoliosis at all. The main predictors of progression of scoliosis are symptom onset before the age of 10 years and presence of scoliosis before the age of 15 years. Bracing appears to provide some slowing of progression, but curvature angles greater than approximately 45 degrees normally require surgery (spinal fusion). Pes cavus, occurring in 55–75% of individuals, contributes to decreased functionality of the foot.1

Essentials of Assessment

History  

Age at onset and progression of symptoms should be determined. Initial neurological symptoms often include unsteady walking or frequent tripping due to impairment of balance and coordination.  With disease progression, impaired sensation and strength in the limbs or slurred speech may be reported.  A comprehensive review of systems determines impact of the disease on different body systems.  Involvement of visual or auditory pathways may result in impaired vision and/or hearing.  Symptoms of cardiac involvement may include dyspnea, orthopnea, edema, palpitations, fatigue and decreased exercise tolerance.  Diabetes mellitus may manifest with unintentional weight loss, polyuria, and polydipsia. Bladder and bowel function should be assessed; urine dysfunction is usually reported as a sense of urgency rather than true incontinence.  Fatigue, sleep impairment, and pain may be multifactorial.

Assessment of functional status and barriers to age-appropriate independence with mobility, activities of daily living and participation in play, school, or work. 

Family history is important, although may not always be positive or skip generations due to the autosomal recessive inheritance of the disease.

Physical examination

Findings on cardiovascular exam may include irregular pulse due to arrhythmias, and abnormal heart sounds, murmurs and peripheral edema due to cardiac dysfunction. Pes cavus, equinovarus foot deformity or scoliosis may be present on musculoskeletal exam. Oculomotor abnormalities, visual acuity deficits, hearing loss, and/or dysarthria may be detected on HEENT exam. 

Neurological findings typically include ataxia, often with mixed cerebellar and sensory features.  Muscle stretch reflexes may be decreased or absent along with distal weakness and impaired proprioception and vibratory sense in the limbs. Many features of FA are similar to other early onset, progressive ataxias. Absence of lower limb reflexes may differentiate FA from some of these ataxias. Other features such as cardiomyopathy, optic atrophy and severe scoliosis may also suggest the diagnosis of FA in patients with ataxia.1-4

Clinical diagnostic criteria for FA can be used to make a probable diagnosis and initiate specialist referral and/or genetic testing for a definitive diagnosis. For example, the following criteria were developed in 1976 by the Quebec Cooperative study of Friedreich’s Ataxia (QCSFA): Onset before the end of puberty but not over 20 years old, gait ataxia, progression of ataxia within the last two years with no remission, dysarthria, muscle weakness, and lower extremity deep tendon areflexia. Babinski sign, pes cavus, scoliosis, and cardiomyopathy are often present but are not necessarily required for diagnosis.

Functional assessment

The Friedreich Ataxia Rating Scale (FARS) was developed specifically for FA and is comprised of four sections: functional staging for ataxia, activities of daily living, neurological examination, and instrumental testing. The Goal Attainment Scale is an individualized outcome measure to assess the extent the patient meets their goals. The following measures assess and track status of specific aspects of functioning often affected by FA.5 

  • The International Cooperative Ataxia Rating Scale (ICARS) assesses the level of impairment from ataxia and cerebellar involvement related to genetic conditions in four sections (posture and gait disturbances, kinetic functions, speech disorders, and oculomotor disorders). The Scale for the Assessment and Rating of Ataxia (SARA) is similar to the ICARS for assessing ataxia but shorter to administer. Items tested include gait, stance, sitting, speech disturbance, finger chase, finger-nose test, fast alternating hand movements, and heel-shin slide.
  • The 6 Minute Walk Test assesses aerobic capacity and gait.  Timed Up and Go (TUG) assesses fall risk, balance and gait.
  • Berg Balance Scale is primarily useful in early stages when individual is not yet using a wheelchair. Timed Up and Go (TUG) assesses fall risk, balance and gait.  Pediatric Balance Scale is used to assess balance in everyday tasks with a specific focus on adolescents.

Laboratory studies

Genetic testing

Genetic testing is the gold standard for diagnosing FA. Although the unique features of FA can differentiate it from other causes of early onset, progressive ataxia, molecular testing methods should be performed to make an accurate diagnosis. The diagnosis is confirmed by testing for expansions or mutations in the FXN (frataxin) gene.1-3

Nerve Conduction Tests

Nerve conduction testing may help differentiate FA from certain variants of Charcot-Marie Tooth disease that may also present with sensory ataxia and absent muscle stretch reflexes.1,2

Imaging

Echocardiogram

Echocardiogram is prudent at time of diagnosis and periodically thereafter to monitor for cardiomyopathy (commonly hypertrophic, rarely dilated).

Electrocardiogram

EKG is indicated at diagnosis and then periodically, monitoring for arrhythmias (more common if cardiomyopathy is present), Holter and/or Loop monitor maybe recommended if the patient experiences palpitations.

Spinal x-rays

While recommendations on the timing of spinal imaging are not standardized, it is reasonable to obtain spine x-rays at time of diagnosis and follow-up x-rays every 6 months until skeletal maturity is achieved, especially during rapid periods of growth, to monitor for progression of scoliosis.1,3,6

Early predictions of outcomes

The number of GAA repeats in FXN is directly related to prognosis with regards to earlier onset of disease, more rapid progression of neurologic decline, higher chance of developing scoliosis that requires surgical fixation, and greater extent of left ventricular hypertrophy.1

Social role and social support system

Fatigue is a prevalent symptom in FA and may be included in quality of life assessments. Academic performance and need for assistance, modifications, or therapies in the school setting, the available support system, measures to facilitate participation in social and leisure activities, and addressing sexuality in an age-appropriate manner, are all important aspects of a comprehensive and wholistic approach to care.

Resources for emotional and psychological support may include social work, psychology, MDA (Muscular Dystrophy Association), and FARA (Friedreich’s Ataxia Research Alliance).

Professional issues

Individuals with a family history of FA who intend to have children should consider genetic screening and counseling to determine their risk of having affected children.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Management of FA follows an interdisciplinary symptom-management approach.6-10 Although additional research is needed to determine the optimal rehabilitation prescription for best results in this specific patient population, the management of cerebellar ataxias in general can be applied to individuals with FA. Interventions may include proprioceptive neuro-facilitation, balance retraining, and Frenkel exercises. In addition, aerobic exercise may help to decrease weakness and fatigue.

Of note, metformin and thiazolidinediones should be used with caution in the treatment of diabetes mellitus in patients with FA due to the concern for these agents impairing complex I of the mitochondrial respiratory chain complex and the latter class being associated with congestive cardiomyopathy.

At different disease stages

New onset/acute

Physical therapy may improve or maintain balance, flexibility, strength, and accuracy of limb movements in patients with FA.  An appropriate exercise program and use of mobility devices (canes, walkers) and/or orthotics to increase base of support may help prolong ambulation and reduce risk of falls.1,3,8

Chronic/stable

Wheelchair prescription is often indicated as neurologic deficits progress and gait deteriorates, with determination of manual versus power based on patient’s upper extremity coordination and strength.

Physical therapy, splinting, and botulinum toxin injection may prevent or delay foot deformities. When conservative measures are not effective and fixed foot deformities occur, surgical correction may allow patient to potentially participate in stand-pivot transfers.11

Speech language therapy may improve speech generation, provide alternative modes of communication, and address swallowing.

Bracing may provide some slowing of scoliosis progression, but spinal surgery is typically indicated for curvature angles greater than 45 degrees.1,3,7

Antioxidant therapy: While current treatment of FA continues to be largely symptomatic and supportive, a significant recent advance has been FDA approval of omaveloxolone, an agent with antioxidant properties that reduces the downstream impact of frataxin deficiency.  It was approved in 2023 as a therapy for individuals with FA who are 16 years or older, following clinical trials that demonstrated slower progression of FA over 2-3 years compared to controls.12,13 (See sections below on Cutting Edge Therapies and Gaps in Knowledge)

As disease progresses, hospice and palliative care services are indicated given that no complete cure is currently available.

Coordination of care

A multi-disciplinary and integrated team approach is necessary to care for patients and families with FA.9 A core treatment team may include physiatry, neurology, therapy (speech, physical, and occupational), and social work. Ideally a single provider, which could be the physiatrist, can coordinate care and make referrals to other disciplines and tertiary care specialists, such as cardiology, orthopedic surgery, neuropsychology, and genetics, as appropriate. A coordinated and smooth transition from pediatric to adult care is important.

Patient & family education

Patients and families need to understand the progressive nature of this disease and the associated complications. Patients with FA, and their siblings and parents, need to understand the inheritance pattern of FA so that they can make educated reproductive choices. Educating patients and families about palliative care services early on is important to ease the psychosocial burden of the disease as it progresses.1,3,9

Cutting Edge/Emerging and Unique Concepts and Practice

New developments and investigations in treatment of FA focus either on reversal of frataxin deficiency (through gene therapy, protein replacement, epigenetic therapy, reversal of FXN silencing) or on mitigating the pathogenic downstream events.14-16 Greater advances to clinical translation have been made in mitigating downstream events compared to those focused on reversing frataxin deficiency.  The lack of antioxidant reserve associated with impaired activation of the transcription factor NRF2 appears to play an important role in the downstream events, so NRF2 activation offers a target for downstream pharmacological intervention in FA. Several agents such as omaveloxolone and dimethyl fumarate can increase levels of NRF2 by preventing its degradation.  Omaveloxolone showed promising results in clinical trials, including slowed rate of FA progression with relatively few adverse events, and received FDA approval in 2023 for use in individuals with FA who are 16 years or older.12,13

Gaps in the Evidence-Based Knowledge

Further work is needed to translate ongoing promising trials to optimal clinical response. While omaveloxolone has received FDA approval as noted above, there are still unresolved questions about the length and durability of benefit. The protective role of antioxidants, iron chelators, and mitochondrial cofactors used in potential combination strategies needs further study. Gaps in current understanding on when frataxin be restored, where must it be restored, and the minimum amount of restoration needed for efficacy need to be resolved to advance approaches that focus on reversing frataxin deficiency in FA.14-16

References

  1. Keita M, McIntyre K, Rodden LN, Schadt K, Lynch DR. Friedreich ataxia: clinical features and new developments. Neurodegener Dis Manag. 2022 Oct;12(5):267-283. doi: 10.2217/nmt-2022-0011. Epub 2022 Jun 29. PMID: 35766110; PMCID: PMC9517959.
  2. Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M. The inherited cerebellar ataxias: an update. J Neurol. 2023 Jan;270(1):208-222. doi: 10.1007/s00415-022-11383-6. Epub 2022 Sep 24. PMID: 36152050; PMCID: PMC9510384.
  3. Cook A, Giunti P. Friedreich’s ataxia: clinical features, pathogenesis and management. Br Med Bull. 2017 Dec 1;124(1):19-30. doi: 10.1093/bmb/ldx034. PMID: 29053830; PMCID: PMC5862303.
  4. Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med. 1996 Oct 17;335(16):1169-75. doi: 10.1056/NEJM199610173351601. PMID: 8815938.
  5. Milne SC, Roberts M, Ross HL, Robinson A, Grove K, Modderman G, Williams S, Chua J, Grootendorst AC, Massey L, Szmulewicz DJ, Delatycki MB, Corben LA. Interrater Reliability of the Scale for the Assessment and Rating of Ataxia, Berg Balance Scale, and Functional Independence Measure Motor Domain in Individuals With Hereditary Cerebellar Ataxia. Arch Phys Med Rehabil. 2023 Oct;104(10):1646-1651. doi: 10.1016/j.apmr.2023.05.003. Epub 2023 Jun 1. PMID: 37268274.
  6. Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB; Clinical Management Guidelines Writing Group. Consensus clinical management guidelines for Friedreich ataxia. Orphanet J Rare Dis. 2014 Nov 30;9:184. doi: 10.1186/s13023-014-0184-7. PMID: 25928624; PMCID: PMC4280001.
  7. Corben LA, Collins V, Milne S, Farmer J, Musheno A, Lynch D, Subramony S, Pandolfo M, Schulz JB, Lin K, Delatycki MB; Clinical Management Guidelines Writing Group. Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. Orphanet J Rare Dis. 2022 Nov 12;17(1):415. doi: 10.1186/s13023-022-02568-3. PMID: 36371255; PMCID: PMC9652828.
  8. Milne SC, Corben LA, Roberts M, Murphy A, Tai G, Georgiou-Karistianis N, Yiu EM, Delatycki MB. Can rehabilitation improve the health and well-being in Friedreich’s ataxia: a randomized controlled trial? Clin Rehabil. 2018 May;32(5):630-643. doi: 10.1177/0269215517736903. Epub 2017 Oct 26. PMID: 29072092.
  9. Lynch DR, Schadt K, Kichula E, McCormack S, Lin KY. Friedreich Ataxia: Multidisciplinary Clinical Care. J Multidiscip Healthc. 2021 Jun 28;14:1645-1658. doi: 10.2147/JMDH.S292945. PMID: 34234452; PMCID: PMC8253929.
  10. Rummey C, Flynn JM, Corben LA, Delatycki MB, Wilmot G, Subramony SH, Bushara K, Duquette A, Gomez CM, Hoyle JC, Roxburgh R, Seeberger L, Yoon G, Mathews KD, Zesiewicz T, Perlman S, Lynch DR. Scoliosis in Friedreich’s ataxia: longitudinal characterization in a large heterogeneous cohort. Ann Clin Transl Neurol. 2021 Jun;8(6):1239-1250. doi: 10.1002/acn3.51352. Epub 2021 May 5. PMID: 33949801; PMCID: PMC8164850.
  11. Delatycki MB, Holian A, Corben L, Rawicki HB, Blackburn C, Hoare B, Toy M, Churchyard A. Surgery for equinovarus deformity in Friedreich’s ataxia improves mobility and independence. Clin Orthop Relat Res. 2005 Jan;(430):138-41. doi: 10.1097/01.blo.0000150339.74041.0e. PMID: 15662315.
  12. Pilotto F, Chellapandi DM, Puccio H. Omaveloxolone: a groundbreaking milestone as the first FDA-approved drug for Friedreich ataxia. Trends Mol Med. 2024 Feb;30(2):117-125. doi: 10.1016/j.molmed.2023.12.002. Epub 2024 Jan 24. PMID: 38272714.
  13. Mullard A. FDA approves first Friedreich’s ataxia drug. Nat Rev Drug Discov. 2023 Apr;22(4):258. doi: 10.1038/d41573-023-00041-9. PMID: 36890218.
  14. Pallardó FV, Pagano G, Rodríguez LR, Gonzalez-Cabo P, Lyakhovich A, Trifuoggi M. Friedreich Ataxia: current state-of-the-art, and future prospects for mitochondrial-focused therapies. Transl Res. 2021 Mar;229:135-141. doi: 10.1016/j.trsl.2020.08.009. Epub 2020 Aug 22. PMID: 32841735.
  15. Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J. Emerging therapies in Friedreich’s Ataxia. Expert Rev Neurother. 2020 Dec;20(12):1215-1228. doi: 10.1080/14737175.2020.1821654. Epub 2020 Sep 21. PMID: 32909841; PMCID: PMC8018609.
  16. Gunther K, Lynch DR. Pharmacotherapeutic strategies for Friedreich Ataxia: a review of the available data. Expert Opin Pharmacother. 2024 Apr;25(5):529-539. doi: 10.1080/14656566.2024.2343782. Epub 2024 Apr 18. PMID: 38622054.

Original Version of the Topic

Amit Sinha, MD, Joyce Oleszek, MD, Carrie Jones, MD. Friedreich’s ataxia. 9/20/2013

Previous Revision(s) of the Topic

Joyce Oleszek, MD, Jordan Wyrwa, DO. Friedreich’s Ataxia. 11/19/2019

Author Disclosures

Sunil Sabharwal, MD
Demos Medical Publishing, Receipt of royalties, Editor/Author
American Board of PM&R, Non-remunerative Positions of Influence, Board Director

Andrew Tsitsilianos, MD
Nothing to Disclose

Fareea Khaliq, MD
Nothing to Disclose