Freidreich’s ataxia

Author(s): Amit Sinha, MD, Joyce Oleszek, MD, Carrie Jones, MD

Originally published:09/20/2013

Last updated:09/20/2013

1. DISEASE/DISORDER:

Definition

Friedreich’s ataxia is an inherited degenerative disorder that causes ataxia, weakness and sensory loss.

Etiology

Friedreich’s ataxia (FA) is caused by an autosomal recessive mutated gene, FXN, that has been mapped to chromosome 9. Within the FXN gene, there is a GAA trinuceotide repeat. In individuals with FA, there is an increased number of repeats. Normally there are around 5 to 30 repeats, and in FA, there are anywhere from 70 to greater than 1000 repeats. This mutated gene affects the formation of a protein called frataxin.

Epidemiology including risk factors and primary prevention

FA is most common among white populations, with an estimated incidence of 1.5 per 100,000 in Europe and North America. It is much less common in African and Asian populations. FA is the most common autosomal recessive ataxia disorder, and it accounts for nearly 50% of all hereditary ataxia cases. The incidence is equal in males and females.

Patho-anatomy/physiology

The protein frataxin is located in the mitochondria, but its full function is unclear. It is thought to be involved in homeostasis, detoxification, and storage, as well as response to oxidative stress. An increased number of repeats leads to a decreased amount of frataxin, leading to a buildup of mitochondrial iron. This in turn leads to an increase in production of toxic free radicals, eventually causing cellular dysfunction and death. FA affects both the central and peripheral nervous system. In the central nervous system, the cerebellum (dentate nuclei) and spinal cord (posterior column, corticospinal and spinocerebellar tracts) are involved. In the peripheral nervous system, there is a primarily axonal neuropathy preferentially affecting large myelinated fibers.

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

The onset of symptoms in FA typically occurs before the completion of puberty, and symptoms worsen over time. The disease course tends to be more aggressive in patients with a younger age of onset. Neurologic complaints typically precede cardiovascular manifestations, and the severity of neurologic and cardiac symptoms is not related. Wheelchair use as the primary method of mobility typically occurs around 10 to 15 years after the onset of symptoms. Patients with FA have progressive neurologic symptoms, including weakness, sensory neuropathy, dysarthria, hearing loss, and optic atrophy, along with cardiomyopathy and skeletal deformities. Progression is typically slow, with death occurring around 35 years after symptom onset. There appears to be a direct relationship between the number of trinucleotide repeats and the severity of neurologic, cardiovascular, and skeletal manifestations of FA.

Specific secondary or associated conditions and complications

Patients with FA may have diabetes caused by a combination of insulin deficiency and peripheral insulin resistance. There does not appear to be a relationship between number of repeats and incidence of diabetes. The skeletal manifestations most commonly include scoliosis and pes cavus.

2. ESSENTIALS OF ASSESSMENT

History

  1. Age at onset and progression of symptoms.
  2. Ask about functional status (ability to ambulate, swallow, communicate and complete ADLs) as these will likely deteriorate over time.
  3. Given association of hypertrophic cardiomyopathy, inquire about progressive respiratory difficulties, orthopnea and peripheral edema.
  4. As 20% of cases are associated with diabetes mellitus, ask about unintentional weight loss, polyuria, and polydipsia.
  5. Family history.

Physical examination

Key abnormal physical findings include the following:

  1. Eyes: Abnormalities of eye movement, visual acuity
  2. Ears: Hearing loss
  3. Mouth/throat: Dysphagia
  4. Cardiovascular: Arrhythmias, abnormal heart sounds, murmurs, peripheral edema
  5. Spine: Scoliosis
  6. Musculoskeletal: Pes cavus, equinovarus foot deformity
  7. Genitourinary: Urinary hesitancy, urgency, retention and incontinence
  8. Neurologic:
    1. Mental State: Impaired attention, visuospatial reasoning and information processing
    2. Balance/coordination: Progressive ataxia (extremities, trunk and speech)
    3. Reflexes: Absent lower limb reflexes in the presence of upgoing plantar response
    4. Sensory: Loss of position and vibratory sense
    5. Motor: Distal weakness

Functional assessment

Friedreich Ataxia Rating Scale (FARS): Has three sections and several subsections1

Functional staging for ataxia

  1. Mobility score ranges from 0 (normal) to 6 (confined to wheelchair or bed with total dependency)
  2. Activities of daily living: score ranges from 0 (normal) to 4 (dependent)
  3. Neurological examination
    1. Bulbar
    2. Upper limb coordination
    3. Lower limb coordination
    4. Peripheral nervous system
    5. Upright stability

International Classification of Ataxia Scale (ICARS) – Has four sections and several subsections2

  1. Posture and gait disturbances
  2. Kinetic functions
  3. Speech disorders
  4. Oculomotor disorders

Laboratory studies

The following genetic tests can be ordered to confirm Friedreich’s ataxia:

  1. Testing for the number of GAA repeats in the FXN region of chromosome 9 using PCR, fragment analysis and Southern blot (this is the most commonly used method).
  2. An immunoassay-based test that measures the concentration of the frataxin protein in both whole blood and buccal cells.
  3. Identification of whole exon deletions within the FXN region via multiple ligation-dependent probe analysis.

Imaging

Cardiac echocardiogram:

  1. To detect presence of cardiomyopathy, which is a frequent cause of death.
  2. Usually develop hypertrophic cardiomyopathy, although dilated cardiomyopathy can occur.
  3. No consensus statement, but recommend obtaining baseline echocardiogram at time of diagnosis and every 12 months, to follow cardiac function.

Spinal x-rays:

  1. To detect presence and severity of scoliosis.
  2. No consensus statement, but recommend obtaining baseline spine x-rays at time of diagnosis and every 6 months, especially during rapid periods of growth, to monitor progression of scoliosis.
  3. Will likely not need serial spine films once growth has been completed.

Supplemental assessment tools

Electrocardiogram (ECG):

  1. Arrhythmias may occur but are rarer than expected, given the high prevalence of cardiac dysfunction.
  2. Atrial and ventricular arrhythmias are more common in dilated cardiomyopathy.
  3. No consensus statement, but recommend obtaining baseline ECG at time of diagnosis and every 12 months in conjuction with cardiac echocardiogram.

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

Early predictions of outcomes

Generally, early prediction is based on the greater the number of GAA repeats in the FXN region, the 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. Inquire about academic performance and if any assistance, modifications or therapies are needed in school setting.
  2. Inquire about social and leisure activities. Encourage patients to participate in social activities with their peers, and encourage parents/families to be supportive.
  3. Inquire about support systems (i.e., extended family, friends, social groups) for patients and their families.

Professional Issues

Individuals with a family history of Friedreich’s ataxia 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

Evidence-based guidelines for rehabilitation interventions in FA do not exist. The following case reports/series are available:

  1. Endurance exercise training in FA can increase peak VO2 and peak ventilation.3
  2. Inpatient rehabilitation may slow the functional decline in FA.4
  3. Whole body vibration increases blood flow velocity and surface muscle EMG activity in FA.5
  4. Cognitive rehabilitation therapy in addition to conventional neuromotor rehabilitation treatment may reduce cognitive decline in FA.6
  5. Intrathecal baclofen can be effective in treating painful, disabling lower extremity spasms in FA.7

Current cardiology guidelines should be followed for treatment of hypertrophic cardiomyopathy and heart failure.

  1. Symptomatic patients with left ventricular outflow tract obstruction
    • As symptoms are usually exertional, negative ionotropics (suppress contractility) and chronotropics (suppress heart rate) are mainstays.
      1. Beta-blockers
      2. Calcium channel blockers
      3. Disopyramide
  2. Symptomatic patients without obstruction
    • Symptoms may be related to diastolic dysfunction
      1. ACE inhibitors
      2. Beta-blockers
      3. Low-dose diuretics
  3. Asymptomatic
    • No data to support/refute prophylactic drug therapies
  4. Treatment of drug refractory patients
    • Invasive treatment options, such as septal myectomy, alcohol septal ablation and dual chamber pacemaker placement can be considered.
    • Although neurodegenerative disease is regarded by some as a contraindication, cardiac transplantation has been successfully carried out on patients with FA.
      1. It has been suggested that cardiac transplantation should not be contraindicated in neurodegenerative diseases, provided that the estimated survival in that particular patient exceeds average graft life.
  5. Cardioverter defibrillator implantation
    • Mechanism of sudden death in FA patients is not well understood.
    • Implantation of an ICD for recurrent syncope due to ventricular tachycardia in patient with FA has been described.8

At different disease stages

New onset/acute

  1. Consider equipment, such as canes and/or walkers, 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 wheelchair use for mobility as neurologic deficits progress and patient loses the ability to ambulate.
  2. Consider manual vs power wheelchair dependent on patient’s upper extremity coordination and strength.
  3. Monitor for lower extremity contractures; consider use of lower extremity orthotics (i.e., AFOs) to prevent contractures.
  4. 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
  5. Consider use of antioxidants (see “Cutting Edge Concepts and Practice”).
  6. Additional emotional and psychological support may be necessary by social work, psychology, MDA (Muscular Dystrophy Association), and FARA (Friedreich’s Ataxia Research Alliance).
  7. As disease progresses, hospice and palliative care services may be important and necessary.

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. Parents of children with FA need to understand the inheritance pattern of FA so that they are aware of the risk of having other affected children. Patients and siblings of patients also need to understand the inheritance pattern of FA so that they can make educated reproductive choices. Also, educate patients and their families about palliative care services early on so that they can utilize all available resources.

Emerging/unique Interventions

Friedreich Ataxia Rating Scale (FARS) can be used to measure outcomes in terms of impairment and activity participation, but this scale is less useful in dependent patients.

4.CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

Multiple antioxidant drug trials (vitamin E, coenzyme Q10, idebenone) have been completed or are under way with the goal of reducing oxidative stress and improve ATP production.

  1. No consistent, statistically significant benefits

Novel class of histone deacetylase inhibitors (2-aminobenzamides) that may reverse silencing of FXN gene in FA

  1. Studies in mouse models for FA with this drug show increase FXN mRNA in the brain and improved neurologic symptoms.
  2. Full preclinical assessment of a lead clinical compound (RG2833) has been done.
    • Investigational New Drug application has been filed with U.S. FDA to initiate phase 1 clinical trial.11

Recombinant human erythropoietin increases frataxin expression in lymphocytes and fibroblasts of patients with FA without increasing FXN mRNA.12,13

  1. Open-label pilot trials of erythropoeitin increased frataxin expression in lymphocytes by 27% in 7 of 11 individuals with FA after 8 weeks of treatment and improved Ataxia Rating Scale scores after 6 months of treatment.14,15

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

Gaps in knowledge about FA:

  1. How severe the frataxin deficiency needs to be to cause disease?
  2. Whether FA causes production of reactive oxygen species?
  3. Why certain types of neurons are more affected than others?
  4. What are clear guidelines for cardiology evaluation and treatment?
  5. Whether there are clear short- and long-term benefits for therapeutic interventions–inpatient rehab, endurance training, cognitive rehab, etc.?

REFERENCES

1. 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.

2. 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.

3. Fillyaw MJ, Ades PA. Endurance exercise training in Friedreich ataxia. Arch Phys Med Rehabil. 1989;70:786-788.

4. Milne SC, Campagna EJ, Corben LA, et al. Retrospective study of the effects of inpatient rehabilitation on improving and maintaining functional independence in people with Friedreich ataxia. Arch Phys Med Rehabil. 2012;93:1860-1863.

5. Herrero AJ, Martin J, Martin T, et al. Whole-body vibration alters blood flow velocity and neuromuscular activity in Friedreich’s ataxia. Clin Ohysiol Funct Imaging. 2011;31:139-144.

6. Ciancarelli I, Cofini V, Carolei A. Evaluation of neuropsychological functions in patients with Friedreich ataxia before and after cognitive therapies. Funct Neurol. 2010;25(2):81-85.

7. Smail DB, Jacq C, Denys P, Bussel B. Intrathecal baclofen in the treatment of painful, disabling spasms in Friedreich’s ataxia. Mov Disord. 2005;20(6):758-759.

8. Asaad NE-MA, Al Suwaidi J. Recurrent ventricular tachycardia in patient with Friedreich’s ataxia in the absence of clinical myocardial disease. Pacing Clin Electrophysiol. 2010;33(1):109-112.

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.

11. Soragni E, Xu C, Plasterer HL, et al. Rationale for the development of 2-aminobenzamine histone deacetylase inhibitors as therapeutics for Friedreich ataxia. J Child Neurol. 2012;27(9):1164-1173.

12. Sturm B, Stupphann D, Kaun C, et al. Recombinant human erythropoietin: effects on frataxin expression in vitro. Eur J Clin Invest. 2005;35:711-717.

13. Acquaviva F, Castaldo I, Filla A, et al. Recombinant human erythropoietin increases frataxin protein expression without increasing mRNA expression. Cerebellum. 2008;7:360-365.

14. Boesch S, Sturm B, Hering S, et al. Friedreich’s ataxia: clinical pilot trial with recombinant human erythropoietin. Ann Neurol. 2007;62:521-524.

15. Boesch S, Sturm B, Hering S, et al. Neurological effects of recombinant human erythropoietin in Friedreich’s ataxia: a clinical pilot trial. Mov Disord. 2008;23:1940.

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.

Author Disclosures

Amit Sinha, MD
Nothing to Disclose

Joyce Oleszek, MD
Nothing to Disclose

Carrie Jones, MD
Nothing to Disclose

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