eMedicine Specialties > Orthopedic Surgery > Systemic Diseases

Friedreich Ataxia

Author: Stephen Kishner, MD, MHA, Professor of Clinical Medicine, Physical Medicine and Rehabilitation Residency Program Director, Louisiana State University School of Medicine in New Orleans
Contributor Information and Disclosures

Updated: Aug 21, 2009

Introduction

Background

Friedreich ataxia (FA) is the prototype of all forms of progressive ataxia, and accounts for approximately one half of all cases of hereditary ataxia. FA is an autosomal recessive spinocerebellar disorder that has a slow but relentlessly degenerative course.1

Pathophysiology

Friedreich ataxia (FA) is caused by mutations in the FXN gene, which provides instructions for making a protein called frataxin. Certain nerve and muscle cells cannot function properly with a shortage of frataxin, leading to the signs and symptoms of FA. Approximately 98% of mutant alleles have an expansion of a gossypol acetic acid (GAA) trinucleotide repeat in intron 1 of the gene, leading to reduced levels of frataxin.2,3,4,5,6,7,8

The current hypothesis is that frataxin is a mitochondrial protein important for normal production of cellular energy. A defect in its action may result in abnormal accumulation of iron in mitochondria, leading to excess production of free radicals, which then results in cellular damage and death.9 The neural pathways affected in FA are those associated with large neuronal cell bodies and extensive axon elongations, which are the long tracts of the dorsal columns, pyramidal system, and peripheral nerves.

Frequency

United States

Friedreich ataxia occurs in 1-2 per 100,000 of the US population.

International

Prevalence of Friedreich ataxia is 1-2 per 100,000 of the international population; prevalence appears to be slightly higher in Quebec, Canada.

Mortality/Morbidity

The rate of progression of Friedreich ataxia (FA) is variable, but more than 95% of individuals with FA cannot ambulate by the time they are aged 45 years, and on average, patients lose the ability to walk 15 years following onset of symptoms. Age at death is rather variable. Reported mean ages have been in the mid fourth decade of life, although survival into the sixth and seventh decades of life has been documented. Death tends to be earlier if heart disease and diabetes are associated.

Race

All races are affected.

Sex

Men and women are affected equally.

Age

Symptoms may begin in infancy or in the third decade; however, symptoms usually begin when an individual is aged 8-15 years.

Clinical

History

  • The essential criteria for diagnosis of Friedreich ataxia (FA) are progressive limb and gait ataxia developing before the patient is aged 25 years.
  • Ataxia of gait is the most frequent presenting symptom, but this occasionally is preceded by scoliosis or cardiac symptoms.
  • Difficulty in standing steadily and in running are early symptoms of FA. Children are slow in learning to walk, their gait is clumsy and awkward, and they are not as agile as other children.
  • Occasionally, it begins rather abruptly following a febrile illness, and one leg may become clumsy before the other.
  • A hemiplegic pattern (ie, the arm and leg on one side become ataxic before those on the other side) has been discussed, but it is exceptional; usually both legs are affected simultaneously.
  • The hands usually become clumsy months or years after the gait disorder, and dysarthric speech appears after the arms are involved (rarely is it an early symptom).
  • In some patients with FA, pes cavus and kyphoscoliosis precede the neurologic symptoms. In others, these follow by several years.
  • Mode of inheritance is autosomal recessive.
  • Diabetes mellitus occurs in 10% of patients with FA, and an additional 10-20% have impaired glucose tolerance. Most patients with diabetes require insulin therapy, but some achieve reasonable control with oral hypoglycemic drugs. Diabetes tends to cluster within families.
  • Heart disease is present in at least two thirds of patients with FA. Palpitations and angina sometimes occur.

Physical

  • Patients with very early onset of Friedreich ataxia (FA) tend to be rather short, but growth and development are normal in those who are ambulant throughout adolescence.
  • Optic atrophy occurs in approximately 25% of persons with FA.
  • Nystagmus is observed only in approximately 20% of individuals with FA; however, extraocular movements are nearly always abnormal, with broken-up pursuit, dysmetric saccades, square-wave jerks, and failure of fixation and suppression of the vestibuloocular reflex.
  • Significant sensorineural deafness occurs in 10% of persons with FA.
  • Heart disease is found in more than 75% of patients. Clinical evidence of ventricular hypertrophy, systolic ejection murmurs, and third or fourth heart sounds may be observed. Signs of heart failure occur late in the disease, often as a preterminal event. This usually is associated with arrhythmias such as atrial fibrillation. Peripheral cyanosis and edema in the lower limbs are very common.
  • Distal wasting, particularly in the upper limbs, is observed in approximately 50% of patients with FA.
  • Flexor spasms are common.
  • Weakness of the legs is severe in late disease. It rarely involves the arms before the patient is chair bound.
  • Deep tendon reflexes are absent. Plantar responses are extensor in 90% of patients.
  • Ataxia usually is present at the time of diagnosis.
  • Loss of vibration and position sense occurs in most persons with established FA. Two-point discrimination may be increased in individuals with early FA.
  • Sphincter dysfunction, particularly urgency of micturition and constipation, occurs but is not usually severe.
  • Scoliosis is frequent and may be severe and associated with increased cardiopulmonary morbidity.
  • Approximately 50% of patients have pes cavus and/or equinovarus deformity of the feet.

Causes

Friedreich ataxia (FA) is an autosomal recessive disorder caused by a mutation and abnormal expansion of a GAA repeat in intron 1 of the FXN gene, which is located on chromosome 9. It encodes a 210-amino-acid protein, called frataxin. The pathology in FA results from lack of frataxin or its function.

More on Friedreich Ataxia

Overview: Friedreich Ataxia
Differential Diagnoses & Workup: Friedreich Ataxia
Treatment & Medication: Friedreich Ataxia
Follow-up: Friedreich Ataxia
References
Further Reading
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References

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  2. Bidichandani SI, Patel PI, Ashizawa T. Friedreich Ataxia. Gene Clinics. 1998.

  3. Bradley JL, Blake JC, Chamberlain S, et al. Clinical, biochemical and molecular genetic correlations in Friedreich's ataxia. Hum Mol Genet. Jan 22 2000;9(2):275-82. [Medline].

  4. Wells RD. DNA triplexes and Friedreich ataxia. FASEB J. Jun 2008;22(6):1625-34. [Medline].

  5. Evidente VG, Gwinn-Hardy KA, Caviness JN, Gilman S. Hereditary ataxias. Mayo Clin Proc. May 2000;75(5):475-90. [Medline].

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  7. Martin JB. Molecular basis of the neurodegenerative disorders. N Engl J Med. Jun 24 1999;340(25):1970-80. [Medline].

  8. Friedreich ataxia: genetics. National Library of Medicine. Available at http://ghr.nlm.nih.gov/condition=friedreichataxia. Accessed May 12, 2009.

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  14. Study to Assess the Efficacy, Safety and Tolerability of Idebenone in the Treatment of Friedreich's Ataxia (IONIA). ClinicalTrials.gov. Available at http://clinicaltrials.gov/ct2/show/NCT00537680?term=idebenone&rank=1. Accessed May 12, 2009.

  15. Idebenone to Treat Friedreich's Ataxia. ClinicalTrials.gov. Available at http://clinicaltrials.gov/ct2/show/NCT00229632?term=idebenone&rank=5. Accessed May 12, 2009.

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  22. Rai M, Soragni E, Jenssen K, Burnett R, Herman D, Coppola G, et al. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS One. Apr 9 2008;3(4):e1958. [Medline].

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  24. Soragni E, Herman D, Dent SY, Gottesfeld JM, Wells RD, Napierala M. Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia. Nucleic Acids Res. Nov 2008;36(19):6056-65. [Medline].

  25. Correia AR, Pastore C, Adinolfi S, Pastore A, Gomes CM. Dynamics, stability and iron-binding activity of frataxin clinical mutants. FEBS J. Jul 2008;275(14):3680-90. [Medline].

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Keywords

Friedreich ataxia, Friedreich's ataxia, FA, progressive ataxia, hereditary spinal ataxia, heredotaxia

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Contributor Information and Disclosures

Author

Stephen Kishner, MD, MHA, Professor of Clinical Medicine, Physical Medicine and Rehabilitation Residency Program Director, Louisiana State University School of Medicine in New Orleans
Stephen Kishner, MD, MHA is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

Medical Editor

Jegan Krishnan, MBBS, FRACS, PhD, Professor, Chair, Department of Orthopedic Surgery, Flinders University of South Australia; Senior Clinical Director of Orthopedic Surgery, Repatriation General Hospital; Private Practice, Orthopaedics SA, Ashford Specialist Centre
Jegan Krishnan, MBBS, FRACS, PhD is a member of the following medical societies: Australian Medical Association, Australian Orthopaedic Association, and Royal Australasian College of Surgeons
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Paul E Di Cesare, MD, FACS, Chair and Professor, Department of Orthopedic Surgery, University of California Davis School of Medicine
Paul E Di Cesare, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, and Sigma Xi
Disclosure: stryker Consulting fee Consulting

CME Editor

Dinesh Patel, MD, FACS, Associate Clinical Professor of Orthopedic Surgery, Harvard Medical School; Chief of Arthroscopic Surgery, Department of Orthopedic Surgery, Massachusetts General Hospital
Dinesh Patel, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Association of Physicians of Indian Origin, American College of International Physicians, and American College of Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Harris Gellman, MD, Consulting Surgeon, Broward Hand Center; Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami School of Medicine
Harris Gellman, MD is a member of the following medical societies: American Academy of Medical Acupuncture, American Academy of Orthopaedic Surgeons, American Orthopaedic Association, American Society for Surgery of the Hand, and Arkansas Medical Society
Disclosure: Nothing to disclose.

 
 
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