Friedreich Ataxia (FA)


Friedreich ataxia (FA), while rare, is one of the most common autosomal recessive ataxias, accounting for around 50% of all cases of inherited ataxias.1 

Approximately 90% of individuals with FA present with mutations in the frataxin (FXN) gene, predominantly GAA repeat mutation expansions in intron 1. A child must inherit 2 mutated FXN genes — 1 from each carrier parent — for FA to manifest.2

Prevalence of FA

Friedreich ataxia occurs at a global prevalence of 1 individual per every 22,000 to 50,000 people.1-3 The carrier frequency for abnormal FA genes ranges from 1 in 60 to 1 in 100.1,3

The prevalence of FA in the United States is estimated at 1 individual per every 40,000 to 50,000 people.4-6 

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Geographical Factors of FA

Friedreich ataxia is the most commonly inherited ataxic disorder throughout Europe, South Asia (the Indian subcontinent), Northern Africa, and the Middle East.2-4 

Race/Ethnicity Factors of FA

Friedreich ataxia is more likely to affect individuals of European ancestry, as FA is believed to have originated 10,000 years ago from a single European ancestor.1 Frataxin gene expansions have not been detected in Southeast Asian individuals, subSaharan African individuals, or Native American individuals. Mexico maintains a significantly decreased average prevalence.1,3

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Sex Factors of FA

Both male and female individuals inherit FA equally.5,6 

While men and women inherit FA with the same probability, sex differences may play a protective role in disease progression, particularly related to the development of cardiac symptoms, which is a major cause of mortality and morbidity among patients with FA. Women with FA demonstrate larger left ventricular ejection fractions than men on echocardiographic studies, potentially decreasing the likelihood that women will compensate for the cardiac insufficiency seen in FA with ventricular hypertrophy.7

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Age Factors of FA

As FA is an inherited autosomal recessive disorder, all individuals with FA have 2 mutated copies of the FXN gene at birth; however, symptom onset occurs at varying ages. 

Friedreich ataxia manifests predominantly between early childhood and early adulthood prior to the age of 25 years, usually before age 20.1-3 The onset of FA symptoms ranges anywhere from 2 years of age to as late as the eighth decade of life.3 

The patient’s age at symptom onset classifies the disease type as typical FA (75% of cases) or atypical FA (25% of cases).3,4 Atypical FA includes late-onset FA (LOFA), very late-onset FA (VLOFA), and FA with retained reflexes in the tendons.3 The mean age of typical FA onset ranges from 5 to 15 years,1,3,4 whereas LOFA occurs between the ages of 26 and 39 years and VLOFA occurs after the age of 40 years.2 

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Impact of Age on FA Disease Progression

The progressive nature of FA combined with the frequently early age of onset results in significant morbidity and mortality among this patient population. Neurological progression tends to be more rapid among those with earlier disease onset. FA is typically associated with progressive muscle weakness, spasticity (especially of the lower extremities), absent lower extremity reflexes, dysarthria, scoliosis, bladder dysfunction, and lack of proprioception and vibration sense.3 

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Approximately 95% of patients with FA become wheelchair dependent by 45 years of age. Most patients with FA experience loss of ambulation 10 to 15 years following initial diagnosis.1,3

A study by Tsou and colleagues published in 2011 reported that the age at mortality among individuals with FA averaged around 36.5 years. Cardiac complications (38 out of 61 patients with FA) were the most common cause of death, followed by noncardiac complications (17 of 61), such as pneumonia, and unknown causes (6 of 61).8 

The most commonly reported complication of FA is hypertrophy cardiomyopathy, occurring in around two-thirds of patients.3

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References

  1. Chawla J. Friedreich ataxia: epidemiology. Medscape. Updated May 4, 2021. Accessed January 10, 2023.
  2. Friedreich’s ataxia. National Organization for Rare Disease (NORD). Accessed January 10, 2023.
  3. Bidichandani SI, Delatycki MB. Friedreich ataxia. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993. December 18, 1998. Updated June 1, 2017. Accessed January 10, 2023.
  4. Friedreich ataxia. MedlinePlus. Updated July 2, 2021. Accessed January 10, 2023.
  5. Friedreich ataxia fact sheet. National Institute of Neurological Disorders and Stroke. Accessed January 10, 2023.
  6. Williams CT, De Jesus O. Friedreich ataxia. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated September 5, 2022. Accessed January 10, 2023. 
  7. Ghorbani M, Pousset F, Tucker A, et al; Clinical Partners of the EFACTS Consortium. Analysis of Friedreich’s ataxia patient clinical data reveals importance of accurate GAA repeat determination in disease prognosis and gender differences in cardiac measures. Inform Med Unlocked. 2019;17:100266. doi:10.1016/j.imu.2019.100266
  8. Tsou AY, Paulsen EK, Lagedrost SJ, et al. Mortality in Friedreich ataxia. J Neurol Sci. 2011;307(1-2):46-49. doi:10.1016/j.jns.2011.05.023

Reviewed by Harshi Dhingra, MD, on 1/16/2023.

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