Overview

  • FA is an inherited, life-shortening, debilitating, and degenerative neuromuscular disorder. Nursing and rehabilitative interventions are the mainstays of therapy1
  • FA is diagnosed in about one in 50,000 people worldwide, making it the most common in a group of related disorders called hereditary ataxias, affecting approximately 6,000 patients in the US1-3
  • FA is an autosomal recessive, single gene disorder that is caused by mutations in the FXN gene, which provides instruction for making the protein frataxin, that helps assemble clusters of iron and sulfur critical for energy production in the mitochondria4
  • Reata is conducting a pivotal registration study of omaveloxolone for the treatment of FA

Diagnosis and Prognosis

FA is usually diagnosed by genetic testing. Approximately 75% of people with FA are diagnosed between six and 20 years of age. Typically, the most common symptom is loss of balance and coordination, which usually occurs between five to 15 years of age.5

People with FA experience progressive loss of coordination, muscle weakness, and fatigue, which commonly leads to wheelchair reliance.1,6 Because FA is a multisystem disease, individuals may also experience visual impairment, hearing loss, skeletal abnormalities, diabetes, and cardiomyopathy.6,7 Childhood-onset FA is more common than later-onset FA, and is usually marked by rapid disease progression, which can occur as early as five years of age.6-8

Most individuals with FA experience disease onset between approximately 13 to 15 years of age, and often require use of a wheelchair within 10 to 15 years.6-8 The mean age of death is 35 years, and more than half of these deaths are caused by cardiac complications.6

Pathophysiology

FA is characterized by a decrease in frataxin expression, which is caused by the transcriptional silencing of the FXN gene. A deficiency of frataxin in cells leads to mitochondrial iron overload and poor cellular iron regulation, increased sensitivity to oxidative stress, and mitochondrial dysfunction that impairs ATP production.1,4,7 Impaired ATP production likely accounts for the decreased coordination, progressive muscle weakness, exercise intolerance, and fatigue observed in patients with FA, as well as other disease manifestations.

impaired-mitochondrial-2

References
  1. Aranca TV, Jones TM, Shaw JD, et al. Emerging therapies in Friedreich’s ataxia. Neurodegener Dis Manag. 2016;6(1):49-65.
  2. Vankan P. Prevalence gradients of Friedreich's ataxia and R1b haplotype in Europe co-localize, suggesting a common Palaeolithic origin in the Franco-Cantabrian ice age refuge. J Neurochem. 2013;126(suppl 1):11-20.
  3. Polek B, Roach MJ, Andrews WT, Ehling M, Salek S. Burden of Friedreich’s ataxia to the patients and healthcare systems in the United States and Canada. Front Pharmacol. 2013;4:66.
  4. Li K, Besse EK, Ha D, Kovtunovych G, Rouault TA. Iron-dependent regulation of frataxin expression: Implications for treatment of Friedreich ataxia. Hum Mol Genet. 2008;17(15):2265-2273.
  5. Friedreich’s Ataxia Research Alliance. The voice of the patient: Friedreich’s ataxia. http://www.curefa.org/pdf/news/FA-Voice-of-the-Patient.pdf. Published August 20, 2017. Accessed November 8, 2018.
  6. Parkinson MH, Boesch S, Nachbauer W, Mariotti C, Giunti P. Clinical features of Friedreich’s ataxia: Classical and atypical phenotypes. J Neurochem. 2013;126(suppl 1):103-117.
  7. Santos R, Lefevre S, Sliwa D, Seguin A, Camadro JM, Lesuisse E. Friedreich ataxia: Molecular mechanisms, redox considerations, and therapeutic opportunities. Antioxid Redox Signal. 2010;13(5):651-690.
  8. Klockgether T, Lüdtke R, Kramer B, et al. The natural history of degenerative ataxia: A retrospective study in 466 patients. Brain. 1998;121(Pt 4):589-600.
  9. Paupe V, Dassa EP, Goncalves S, et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS One. 2009;4(1):e4253.
  10. Dürr A. Friedreich’s ataxia: Treatment within reach. Lancet Neurol. 2002;1(6):370-374.
View References