Friedreich Ataxia (FA)

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Friedreich ataxia (FA) is a progressive, inherited, neurodegenerative movement disorder characterized by problems with balance and coordination, muscle weakness, spasticity, difficulty walking, scoliosis, dysarthria, and hearing and vision impairment. These symptoms are caused by degenerative changes in the sensory nerve fibers as they enter the spinal cord in the dorsal root ganglia.1,2 

Friedreich ataxia is an autosomal recessive genetic disorder, resulting from each parent passing down a mutated copy of the FXN gene that encodes the protein, frataxin. Frataxin plays a role in normal mitochondrial function.1 

The FXN gene has a segment of DNA located in intron 1 known as a trinucleotide repeat containing 1 guanine and 2 adenines (GAA). Normally, this GAA segment repeats 5 to 33 times within the FXN gene, whereas in patients with FA, it repeats between 66 and 1000 times.1

Genetic Risk Factor

Since FA is an autosomal recessive, inherited neurological condition, the strongest risk factor for developing FA is a family history of the disease, particularly among immediate family members, such as siblings. If both parents are carriers of a mutated FXN gene, each of their children has a 25% chance of inheriting FA.2

Read more about FA genetics

Risk Factors of Sex 

The risk of inheriting FA is equal between male and female individuals.2 Female individuals, however, may have a better prognosis than male individuals, as female sex may contribute to protective aspects in terms of cardiac complications during progression of the disease. Women demonstrate larger left ventricular ejection fractions than men, potentially resulting in a decreased likelihood of developing hypertrophic cardiomyopathy of the ventricles.3 Hypertrophic cardiomyopathy is one of the most predominant complications of FA, occurring in approximately two-thirds of patients.4 

Read more about FA complications

Risk Factors of Race/Ethnicity

European ancestry is a risk factor, as the disease is believed to have originated in Europe over 10,000 years ago from a single progenitor.5 

Friedreich ataxia occurs more prevalently throughout Europe, the United States, Northern Africa, the Middle East, and South Asia (the Indian subcontinent), but it is virtually nonexistent in subSaharan Africa, Southeast Asia, and among Native Americans.4

Read more about FA epidemiology

Risk Factors for Disease Progression

The rate of neurological progression in patients with FA is variable.4 The 2 major risk factors predictive of hypertrophic cardiomyopathy, scoliosis, and FA disease progression include age at disease onset/diagnosis and the trinucleotide (GAA) repeat expansion length, which results in increased oxidative stress and the loss of frataxin.6 

Earlier age at disease onset/diagnosis is typically predictive of more rapid disease progression.4,6-9 Earlier age at disease onset is also inversely correlated with the number of GAA repeats, as every 100 GAA repeats is associated with an earlier disease onset of 2.3 years.7 Longer GAA repeat lengths correlate with faster neurological disease progression.9 

One study reported that shorter GAA allele length was correlated more with the variability in age at diagnosis (46%) and less with the actual age at disease onset (27%).6

Read more about FA prognosis

Approximately one-third of patients with FA develop disease-related diabetes mellitus.2 One study reported that age, FA disease severity, and FA-related cardiac complications correlated positively with the risk of developing FA-related diabetes. In general, patients with FA demonstrated well-controlled diabetes, usually managed with insulin and metformin and less commonly with newer glucose-lowering medications.10 

Read more about FA comorbidities

References

  1. Friedreich ataxia. MedlinePlus. Updated July 2, 2021. Accessed January 10, 2023.
  2. Friedreich’s ataxia. National Organization for Rare Disease (NORD). Accessed January 10, 2023.
  3. 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
  4. 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. 
  5. Chawla J. Friedreich ataxia: epidemiology. Medscape. Updated May 4, 2021. Accessed January 10, 2023.
  6. 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
  7. 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
  8. 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
  9. 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
  10. Tamaroff J, DeDio A, Wade K, et al. Friedreich’s ataxia related diabetes: epidemiology and management practices. Diabetes Res Clin Pract. 2022;186:109828. doi:10.1016/j.diabres.2022.109828

Reviewed by Kyle Habet, MD, on 1/10/2023.