Friedreich ataxia (FA) is caused by a genetic mutation of the frataxin (FXN) gene1
The frataxin protein resides in the mitochondrial matrix. Under normal circumstances, frataxin is thought to play several roles in mitochondrial iron metabolism, which includes2:
- Iron storage
- Regulation of heme synthesis
- Regulation of iron-sulfur cluster synthesis
A mutation in the frataxin gene in people with FA causes deficiency in the frataxin protein, which disrupts mitochondrial iron metabolism. This mitochondrial dysfunction leads to impaired adenosine triphosphate production and oxidative stress, which are thought to be the key drivers of FA pathogenesis.1
Friedreich ataxia mechanism of disease
How FA can be inherited3,4
FA is an autosomal recessive disease4
FA is most often caused by a variant within the frataxin gene called a GAA triplet-repeat expansion.4
96%
of cases are caused by GAA triplet-repeat expansions4
4%
of cases are caused by a GAA triplet-repeat expansion and a second FXN mutation4
A greater number of GAA triplet repeats typically means5:
- Earlier disease onset
- More severe symptoms
- More rapid progression
| Normal range6 | Threshold for diagnosis6 | Late onset (24+ years)7 | Intermediate onset (15 to 24 years)7 | Typical onset (8 to 14 years)7 | Early onset (0 to 7 years)7 |
|---|---|---|---|---|---|
| ≤33 repeats | 66 repeats | 136 to 360 repeats* | 376 to 630 repeats* | 600 to 820 repeats* | 700 to 896 repeats* |
Less severe with slower progressionMore severe with more rapid progression5,7
*Data reflects interquartile range of the shorter GAA expansion by onset group in the Friedreich Ataxia Clinical Outcomes Measures Study (n=1115).
A genetic test that includes a GAA triplet-repeat expansion analysis is the only way to confirm an FA diagnosis9
References
1. Delatycki MB, Bidichandani SI. Friedreich ataxia—pathogenesis and implications for therapies. Neurobiol Dis. 2019:132:104606. 2. Lane DJR, Merlot AM, Huang ML-H, et al. Cellular iron uptake, trafficking and metabolism: Key molecules and mechanisms and their roles in disease. Biochim Biophys Acta. 2015:1130-1144. 3. Jorde LB, Carey JC, Bamshad MJ. Autosomal dominant and recessive inheritance. In: Medical Genetics. 6th ed. Elsevier; 2016:60-78. 4. Galea CA, Huq A, Lockhart PJ, et al. Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia. Ann Neurol. 2016;79(3):485-495. 5. Bürk K. Friedreich ataxia: current status and future prospects. Cerebellum Ataxias. 2017;4(4). 6. Schulz JB, Boesch S, Bürk K, et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol. 2009;5(4):222-234. 7. Rummey C, Corben LA, Delatycki M, et al. Natural history of Friedreich ataxia: heterogeneity of neurologic progression and consequences for clinical trial design. Neurology. 2022;99(14):e1499-e1510. 8. Patel PI, Isaya G. Friedreich ataxia: from GAA triplet-repeat expansion to frataxin deficiency. Am J Hum Genet. 2001;69:15-24. 9. Wallace SE, Bird TD. Molecular genetic testing for hereditary ataxia: what every neurologist should know. Neurol Clin Pract. 2018;8(1):27-32.