Friedreich Ataxia (FA)


Friedreich ataxia (FA) is the most common autosomal recessive form of ataxia.1 The disease occurs due to an unstable guanine-adenine-adenine (GAA) trinucleotide repeat expansion (more than 120 repeats) in the first intron of the frataxin (FXN) gene on chromosome 9 in both alleles.2

Progressive gait and limb ataxia, the absence of lower limb reflexes, abnormal extensor plantar responses, dysarthria, a loss or reduction in vibration perception, and skeletal abnormalities are all manifestations of FA.2

General Prognosis of FA

The rate of disease progression varies between individuals. Usually, patients become wheelchair bound 10 to 20 years after the onset of initial symptoms. In the final phases of the illness, people may become entirely incapacitated. FA can reduce life expectancy. Nevertheless, some FA sufferers who have less severe symptoms live into their 60s or later. The most common cause of mortality is heart disease.3 Quality of life is severely impacted by this disease. Depending on the age of onset, the prevalence of complications, such as diabetes and cardiomyopathy, and other factors, the average lifespan is around 40 years.4 

Factors Affecting FA Prognosis

Overall, the prognosis of FA is poor. Factors that affect FA prognosis include the age at disease onset, severity of symptoms, treatment, and presence of comorbidities or complications.5

FA Prognosis Associated With Age of Onset 

The age of onset differs considerably among patients with FA. The majority of individuals (75% to 85%) receive an FA diagnosis before the age of 25 years. Early onset (prior to 5 years of age) is very uncommon. Atypical presentations, with disease onset occurring after age 25, occur in about 25% of patients.5 

Although life expectancy varies substantially depending on the severity of symptoms, most patients with FA live until 40 to 50 years of age. More than 95% of patients with FA become wheelchair bound by 45 years of age.5,6,7 

The age of onset and prognosis are linked to the number of trinucleotide repeats. The younger the age of onset, the more trinucleotide repeats the patient is likely to have.5 People with early-onset FA typically experience more severe symptoms, more rapid disease progression, and earlier death.5, 8-12 Earlier age at disease onset has an inverse correlation with the number of GAA repeats, with every 100 GAA repeats associated with an earlier disease onset of 2.3 years.9 

A lower number of repeats (less than 300) is linked to later disease development, less severe symptoms, and a better prognosis. Patients with late-onset FA and very late-onset FA typically have milder symptoms and a longer life expectancy.5  

Read more about FA epidemiology

Effects of Symptom Severity on FA Prognosis

Lower levels of frataxin are associated with longer GAA repeats. The length of the shorter of the two GAA repeat alleles is mostly responsible for frataxin levels. As a result, more GAA repeats on the shorter allele are linked to more severe cardiomyopathy, higher neurological severity, and earlier symptom onset, resulting in a worse disease prognosis.1

As the illness progresses, ataxia spreads to the arms and trunk. Titubation is observed during standing and sitting, and it can also affect the trunk. Patients have action and intention tremors as well as choreiform movements as the ataxia spreads to the arms. They may also experience tremors in their face and buccal area. Patients will eventually lose the ability to move, necessitating ambulatory devices like a walker, then a wheelchair, until they finally become bedridden.6 

Read more about FA signs and symptoms

Effects of Treatment on FA Prognosis

While FA cannot be cured, effective symptomatic treatments (such as those for diabetes and heart conditions, as well as orthopedic interventions) help people live longer by lessening the severity of complications and other risks associated with the disease.5

Read more about FA treatment

FA Prognosis Associated With Comorbidities and Complications 

Complications and related comorbidities, such as cardiac dysfunction, endocrine abnormalities, and gastrointestinal complications, can affect the prognosis of FA.

Cardiac Dysfunction

The most common cause of death in 59% of patients with FA is cardiac dysfunction.5 Cardiac disorders in FA include concentric left ventricular hypertrophy, which causes arrhythmias and heart failure, leading to death. Heart diseases can be asymptomatic or have symptoms such as dyspnea or palpitations. Early age of disease onset and long GAA repeat length are predictors of cardiac severity and worse left ventricular hypertrophy, left ventricular function, left ventricular mass, and mortality, with the majority of cardiac-related deaths occurring before the age of 40 years. The disease duration in patients with FA who die from cardiac causes is typically 10 years or less, and a disease duration of more than 20 years considerably lowers the probability of dying from cardiac causes.13 

Read more about FA risk factors

Endocrine Abnormalities

About 10% of patients with FA develop diabetes, and around 20% develop glucose intolerance.14 Evidence shows that an earlier age of FA onset and a higher number of GAA repeats in the FXN gene increase the risk of developing associated diabetes.15

Read more about FA comorbidities

Other Complications

Other complications that affect disease prognosis include ​​scoliosis, loss of ambulation, and difficulties in carbohydrate digestion.5 

Read more about FA complications

References

  1. Pousset F, Legrand L, Monin ML, et al. A 22-year follow-up study of long-term cardiac outcome and predictors of survival in Friedreich ataxia. JAMA Neurol. 2015;72(11):1334–1341. doi:10.1001/jamaneurol.2015.1855
  2. Bit-Avragim N, Perrot A, Schöls L, et al. The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia. J Mol Med (Berl). 2001;78(11):626-632. doi:10.1007/s001090000162 
  3. Friedreich ataxia fact sheet. National Institute of Neurological Disorders and Stroke (NINDS). Accessed January 20, 2023.
  4. Friedreich ataxia. Orphanet. Updated March 2014. Accessed January 20, 2023.
  5. Prognosis of Friedreich’s ataxia. Friedreich’s Ataxia News. Accessed January 20, 2023.
  6. Williams CT, De Jesus O. Friedreich ataxia. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated September 5, 2022. Accessed January 20, 2023.
  7. Chawla J. Friedreich ataxia follow-up. Medscape. Updated May 4, 2021. Accessed January 20, 2023.
  8. 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 20, 2023. 
  9. La Pean A, Jeffries N, Grow C, Ravina B, Di Prospero NA. Predictors of progression in patients with Friedreich ataxia. Mov Disord. 2008;23(14):2026-2032. doi:10.1002/mds.22248
  10. Reetz K, Dogan I, Costa AS, et al. Biological and clinical characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) cohort: a cross-sectional analysis of baseline data. Lancet Neurol. 2015;14(2):174-182. doi:10.1016/S1474-4422(14)70321-7
  11. Tai G, Yiu EM, Corben LA, Delatycki MB. A longitudinal study of the Friedreich Ataxia Impact Scale. J Neurol Sci. 2015;352(1-2):53-57. doi:10.1016/j.jns.2015.03.024
  12. Patel M, Isaacs CJ, Seyer L, et al. Progression of Friedreich ataxia: quantitative characterization over 5 years. Ann Clin Transl Neurol. 2016;3(9):684-694. doi:10.1002/acn3.332
  13. Hanson E, Sheldon M, Pacheco B, Alkubeysi M, Raizada V. Heart disease in Friedreich’s ataxia. World J Cardiol. 2019;11(1):1-12. doi:10.4330/wjc.v11.i1.1
  14. Diabetes in Friedreich’s ataxia. Friedreich’s Ataxia News. Accessed January 20, 2023.
  15. Cnop M, Mulder H, Igoillo-Esteve M. Diabetes in Friedreich ataxia. J Neurochem. 2013;126(Suppl 1):94-102. doi:10.1111/jnc.12216

Reviewed by Kyle Habet, MD, on 1/19/2023.

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