Friedreich’s Ataxia

Author(s): Joyce Oleszek, MD, Jordan Wyrwa, DO

Originally published:09/20/2013

Last updated:11/19/2019

1. 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.

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.

Epidemiology including risk factors and primary prevention

FA is most common among white populations, with an estimated prevalence of 1:20,000 and 1:725,000in Western populations.1 FA is much less common in African and Asian populations. FA is the most common inherited ataxia. The incidence is equal in males and females. In a study of 187 patients, the mean age at onset was reported as 15.5±8 years.2

Patho-anatomy/physiology

As noted above, FA is autosomal recessive disorder, caused by mutations of FXN on both copies of chromosome 9.

95% of cases are due to homozygous expansion of a guanine-adenine-adenine (GAA) trinucleotide repeat in intron 1 of FXN. This mutation leads to defective transcriptional initiation and impaired transcriptional elongation. These transcriptional defects ultimately lead to a decrease in the amount of frataxin expressed.1

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. Less functional frataxin leads to decreased activation of iron-sulfur-cluster (ISC) protein assembly (involved in the mitochondrial respiratory chain complex) and aconitase (catalyzes the conversion of citrate to isocitrate in the TCA cycle) and possibly decreased synthesis of heme-containing proteins. Decreased ISC protein assembly disrupts homeostasis of mitochondrial iron and of the respiratory chain complex, respectively leading to iron overload and H202 production in mitochondria. H202 oxidizes iron and produces toxic free radicals, eventually causing cellular dysfunction and death, either by autophagy or apoptosis.1

In FA patients, frataxin is decreased to 5-35% of normal levels. Asymptomatic heterozygotes are typically at 50% of normal levels.1

For unknown reasons, FA primarily affects the nervous system. In the central nervous system, the cerebellum (dentate nuclei and superior cerebellar peduncles) and the spinal cord (posterior columns, cuneate and gracile nuclei, dorsal nuclei of Clarke, corticospinal and spinocerebellar tracts) are involved. In the peripheral nervous system, large myelinated fibers of dorsal root ganglia are preferentially affected, resulting in primarily an axonal neuropathy.

FA additionally affects the heart, pancreas, spine, and feet. Cardiac involvement results in cardiomyopathy, most commonly causing diastolic dysfunction.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 the completion of puberty.2 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. Neurologic complaints typically precede non-neurologic manifestations. 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 typically occurs around 11 to 15 years after the onset of symptoms.4 Death is most commonly due to aspiration pneumonia, cardiac complications, diabetic coma, stroke, and trauma sequelae.1

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.

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). Skeletal manifestations most commonly include scoliosis and foot deformities (e.g. pes cavus). Patients with FA may have diabetes mellitus caused by a combination of insulin deficiency through loss of pancreatic islet β cells and peripheral insulin resistance.

2. ESSENTIALS OF ASSESSMENT

History

  1. Age at onset and progression of symptoms, starting with neurologic symptoms
  2. Functional status and barriers to age-appropriate independence with mobility, transfers, ADLs, and play/school/work
  3. Symptoms concerning for cardiac involvement – dyspnea, orthopnea, edema, etc.
  4. Symptoms concerning for diabetes mellitus -unintentional weight loss, polyuria, polydipsia, etc.
  5. Symptoms concerning for obstructive sleep apnea
  6. Fatigue
  7. Spasticity, pain, spasms with their associated exacerbating factors – infection, pain, constipation, diarrhea, dehydration, pressure sores
  8. Restless legs and symptoms associated with secondary causes
  9. Bowel and bladder function
  10. If age-appropriate, sexual function
  11. Family history

Physical examination

Key abnormal physical findings include the following:

  1. Eyes: oculomotor abnormalities including square wave jerks (SWJ), visual acuity deficits
  2. Ears: Hearing loss
  3. Mouth/throat: poor secretion management, dysarthria
  4. Cardiovascular: Arrhythmias, abnormal heart sounds, murmurs, peripheral edema
  5. Musculoskeletal: Pes cavus, equinovarus foot deformity, scoliosis
  6. Genitourinary: Urinary hesitancy, urgency, retention, and incontinence
  7. Neurologic:
    1. Mental State: Impaired attention, visuospatial reasoning, and information processing
    2. Balance/coordination: Progressive ataxia (extremities, trunk)
    3. Reflexes: Areflexia, Babinski
    4. Sensory: Loss of proprioception and vibratory sense
    5. Motor: Distal weakness

Functional assessment

Three validated scales exist for the functional assessment of patients with FA.

Published in 2005 by Subramony et al., the Friedreich Ataxia Rating Scale (FARS) was developed specifically for FA, has a maximum score of 159 (0 is normal/unaffected), and is comprised of the following four sections:5

  1. Functional staging for ataxia – measuring overall mobility. Scores range from 0 (normal) to 6 (confined to wheelchair/bed with total dependency).
  2. Activities of daily living – scores range from 0 (normal) to 4 (dependent)
  3. Neurological examination – scores start at 0 (normal) and range from 2-5 depending on what is being examined
  4. Instrumental testing – applied as performance measures. Measured with “PATA” Rate, Nine-Hole Pegboard, and timed-walk of 50 feet

Published in 2005 by Schmitz-Hübsch et al., the Scale for the Assessment and Rating of Ataxia (SARA)6 only measures cerebellar symptoms, has a maximum score of 40 (most severe ataxia), and tests the following eight items:

  1. Gait
  2. Stance
  3. Sitting
  4. Speech disturbance
  5. Finger chase
  6. Nose-finger test
  7. Fast alternating hand movements
  8. Heel-shin slide

Published in 1997 by Trouillas et al., the International Cooperative Ataxia Rating Scale (ICARS)7 was designed for cerebellar disorders, has a maximum score of 100 (most severe disability), and is comprised of the following four sections:2

  1. Posture and gait disturbances – corresponds to vermis and anterior lobe of cerebellum
  2. Kinetic functions – corresponds to hemispheres of cerebellum
  3. Speech disorders
  4. Oculomotor disorders – corresponds to vermis and flocculus of cerebellum

Laboratory studies

The Clinical Management Guidelines for FA recommend the following  tests to confirm diagnosis:

  1. Quantifying the number of GAA repeats in FXN with Southern blot, PCR, or fragment analysis
  2. Immunoassay measurement of the concentration offrataxin in whole blood and buccal cells
  3. Multiple ligation-dependent probe analysis identification of whole exon deletions within FXN

Imaging

Echocardiogram:8

Echocardiogram at time of diagnosis and at least annual thereafter to monitor for cardiomyopathy (commonly hypertrophic, rarely dilated).

Electrocardiogram (ECG/EKG):8

    1. EKG at diagnosis and then at least annually, monitoring for arrhythmias (more common if cardiomyopathy is present)
    2. If patient experiences palpitations, then a Holter and/or Loop monitor is recommended

Spinal x-rays:

Corben et al. does not make recommendations on the timing of spinal imaging, but we recommend obtaining 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.

Supplemental assessment tools

Exercise testing: Peak oxygen consumption per unit time (peak VO2) is negatively related to number of GAA trinucleotide repeats and disease severity as measured by FARS and ICARS.

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.

Social role and social support system

  1. Fatigue is a prevalent symptom in FA that may be included in quality of life assessments
  2. Inquire about academic performance and if any assistance, modifications, or therapies are needed in school setting.
  3. Inquire about social and leisure activities. Encourage patients to participate in social activities with their peers and encourage parents/families to be supportive.
  4. Inquire about support systems (i.e., extended family, friends, social groups) for patients and their families.
  5. If age appropriate, discuss sexuality

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.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

In 2014, Corben et al. published an extensive clinical management guideline article. While this article gives official recommendations in the management of FA, the authors noted that a significant limitation of their work was the dearth of high-quality research to support their recommendations (62% of their recommendations are based on expert opinion or good practice).

Based on their literature review, Corben et al. recommends the following treatment plan with regards to rehabilitation:

  1. Intensive inpatient rehabilitation is beneficial in improving function for people with FA
  2. People with FA may require a cardiologist opinion prior to undergoing aquatic physical therapy
  3. Rehabilitation may be provided in various home or community-based settings
  4. Rehabilitation should be provided by allied health staff with expertise in neurologic conditions
  5. People with FA may benefit from maintenance rehabilitation and regular review of function

Of note, metformin and thiazolidinediones should be avoided 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

  1. Consider mobility devices (canes, walkers, etc.) and/or orthotics to increase base of support to minimize risk of falls.
  2. Single case report of decreased falls when switching from a Rollator wheeled walker (standard braking system) to U-Step Walking Stabilizer (walker with reverse-braking system and tension-controlled wheels).9

Chronic/stable

  1. Consider a wheelchair prescription as neurologic deficits progress and gait deteriorates. Determine manual versus power based on patient’s upper extremity coordination and strength.
  2. Monitor for lower extremity hypertonicity and development of contractures; consider use of lower extremity orthotics (e.g. AFOs) to prevent contractures.
  3. If fixed foot deformities occur, discuss surgical correction to allow patient to potentially participate in stand-pivot transfers. A small case series reported all seven patients who were unable to stand to transfer independently before surgery. After undergoing surgical intervention, all seven were able to transfer independently after surgery. However, three of the seven patients had significant surgical complications.10
  4. Consider use of antioxidants (see “Cutting Edge Concepts and Practice”).
  5. Offer additional emotional and psychological support with social work, psychology, MDA (Muscular Dystrophy Association), and FARA (Friedreich’s Ataxia Research Alliance).
  6. As disease progresses, hospice and palliative care services are important and indicated given that no cure is currently available.

Coordination of care

A multi-disciplinary and integrated team approach is necessary to care for patients and families with FA. A core treatment team may include physiatry, neurology, therapy (speech, physical, and occupational), and social work. The physiatrist may coordinate care and make referrals to other disciplines, such as cardiology, orthopedic surgery, neuropsychology, and genetics, as appropriate.

Patient & family education

Patients and families need to understand the progressive nature of this disease and the associated complications. The patients, the patients’ siblings, and parents of patients with FA 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 so that they can ease the psychosocial burden of the disease as it progresses.

4.CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Multiple antioxidant drug trials (vitamin E with or without coenzyme Q10, Idebenone, α-tocopheryl quinone) have been completed or are under way with the goal of reducing oxidative stress and improving ATP production. Idebenone is a structural CoQ analogue with improved bioavailability. One of the few Grade A recommendations from Corben et al includes: “Idebenone is the most studied pharmacologic agent in FA. Studies to date indicate the use of Idebenone in individuals with FA does not result in significant changes to neurologic or cardiac status over an extended period of time.”8

Novel class of histone deacetylase inhibitors (2-aminobenzamides HDACi; nicotinamide or Vitamin B3) may reverse silencing of FXN in FA.

Additional potential therapies currently under investigation include:1,8,FARA Pipeline

  1. Energy metabolism enhancement
    1. L-carnitine with creatinine – failed to demonstrate benefits
    2. Thiamine – decreased symptoms
  2. Increasing frataxin
    1. Resveratrol – natural polyphenol, also antioxidative
    2. UCM
    3. TAT-frataxin fusion proteins
  3. Iron chelators
    1. Desferoxamine
    2. Deferiprone
  4. Immune modulators
    1. IFNγ-1b – increases frataxin
  5. Repeat-targeted nucleic acids
    1. Anti-GAA duplex RNAs or SS locked NAs

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

  1. No treatments are currently proven to alter the natural history of FA.
  2. Why do some interventions increase frataxin but have no clinical benefits and vice-versa?
  3. Ongoing, high-quality research is needed to improve the strength of current clinical guidelines

REFERENCES

  1. Bürk K. Cerebellum Ataxias. 2017 Apr 7;4:4. doi: 10.1186/s40673-017-0062-x. eCollection 2017. Review. PMID: 28405347
  2. Durr, Alexandra, et al. “Clinical and Genetic Abnormalities in Patients with Friedreich’s Ataxia.” N Engl J Med, 1996; 335:1169-1175.
  3. Regner, Sean R, et al. “Analysis of Echocardiograms in a Large Heterogenous Cohort of Patients with Friedreich Ataxia.” Am J Cardiol, 2012;109:401-405.
  4. Harding IH, Corben LA, et al. Cerebral compensation during motor function in Friedreich ataxia: The IMAGE-FRDA study. Mov Disord. 2017 Aug;32(8):1221-1229. doi: 10.1002/mds.27023. Epub 2017 May 27. PMID: 28556242
  5. Subramony SH, May W, Lynch D, Gomez C, Fischbeck K, et al. Measuring Friedreich ataxia: Interrater reliability of a neurologic rating scale. Neurology. 2005;64:1261-1262.
  6. Schmitz-Hübsch T, du Montcel ST, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006 Jun 13;66(11):1717-20. Erratum in: Neurology. 2006 Jul 25;67(2):299. PMID: 16769946
  7. Trouillas P, Takayanagi T, Hallett M, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. J Neurol Sci. 1997;145(2):205-211.
  8. Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB; Clinical Management Guidelines Writing Group. Orphanet J Rare Dis. 2014 Nov 30;9:184. doi: 10.1186/s13023-014-0184-7. Review. PMID:2592862
  9. Harris-Love MO, Siegel KL, Paul SM, Benson K. Rehabilitation management of Friedreich ataxia: lower extremity force-control variability and gait performance. Neurorehabil Neural Repair. 2004;18:117-124.
  10. Delatycki MB, Holian A, Corben L, et al. Surgery for equinovarus deformity in Friedreich’s ataxia improves mobility and independence. Clin Orthop Relat Res. 2005;430:138-141.

Suggested Readings and Resources

  1. Bourke T, Keane D. Friedreich’s ataxia: a review from a cardiology perspective. Ir J Med Sci. 2011;180:799-805.
  2. Subramony SH, May W, Lynch D, Gomez C, et al. Measuring Friedreich ataxia: interrater reliability of a neurologic rating scale. Neurology. 2005;64(7):1261-1262.
  3. Lynch D, Deutsch E, Wilson R, Tennekoon G. Unanswered questions in Friedreich Ataxia. J Child Neurol. 2012;27(9):1223-1229.
  4. de Bot S, Willemsen M, Vermeer S, et al. Reviewing the genetic causes of spastic-ataxias. Neurology. 2012;79(14):1507-1514.
  5. Klockgether T. Update on degenerative ataxias. Curr Opin Neurol. 2011;24(4):339-345.
  6. Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012;366(7):636-346.
  7. Wilson RB. Therapeutic developments in Friedreich ataxia. J Child Neurol. 2012;27(9):1212-1216.
  8. Perlman SL. A review of Friedreich ataxia clinical trial results. J Child Neurol. 2012;27(9):1217-1222.
  9. Drinkard BE, Keyser RE, Paul SM, et al. Exercise capacity and idebenone intervention in children and adolescents with Friedreich ataxia. Arch Phys Med Rehabil. 2010;91(7):1004-1050.
  10. FARA website

Original Version of the Topic

Amit Sinha, MD, Joyce Oleszek, MD, Carrie Jones, MD. Friedreich’s ataxia. Original Publication Date: 09/20/2013

Author Disclosures

Joyce Oleszek, MD
Nothing to Disclose

Jordan Wyrwa, DO
Nothing to Disclose

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