Friedreich Ataxia (FA)

Friedreich ataxia is an inherited, neurodegenerative disease affecting the central and peripheral nervous system as well as the cardiovascular, musculoskeletal, and endocrine systems.1 

Patients with Friedreich ataxia experience a progressive degeneration of neuromuscular function, including coordination of the limbs and trunk, balance, vibration sensation, two-point discrimination, and proprioception, as well as progressive muscle weakness and atrophy. Common disease-related complications include kyphoscoliosis, hypertrophic cardiomyopathy, cardiac arrhythmias, and diabetes mellitus.2

The primary cause of Friedreich ataxia is genetic variation in the frataxin (FXN) gene on chromosome 9, resulting in an abnormal number of guanine-adenine-adenine (GAA) trinucleotide repeats. This gene is responsible for producing a mitochondrial protein, frataxin, which is involved in iron homeostasis.2 

Friedreich Ataxia Subtypes

Around 75% of Friedreich ataxia (FA) cases occur in patients under 25 years of age; these cases are commonly referred to as typical, early-onset, or juvenile-onset FA.2 The remaining 25% of FA cases include atypical phenotypes, such as late-onset Friedreich ataxia (LOFA), very late-onset Friedreich ataxia (VLOFA), and FA with retained reflexes.2-7 

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Clinical Features of Late-Onset FA

Symptoms of LOFA manifest between the ages of 25 and 39 years. Misdiagnosis of LOFA often occurs due to its atypical clinical presentation.5 In particular, patients with LOFA demonstrate milder and more slowly progressing disease manifestations, longer mean disease durations, and less severe functional disability.6-9 Additionally, patients with LOFA often demonstrate longer disease duration before losing ambulation and requiring wheelchair use.9

Patients with later-onset forms of FA often do not exhibit the hallmark characteristics of FA, including areflexia, impaired extensor plantar reflexes, cardiac involvement, dysarthria, sensory neuropathy, diabetes, scoliosis, ganglionopathy, and amyotrophy.5,9 As age of onset increases further into adulthood, skeletal deformities and cardiomyopathy decrease in prevalence.6

Compared with typical FA, patients with LOFA more frequently present with lower limb spasticity and retained deep tendon reflexes but have fewer sphincter disturbances and echocardiographic abnormalities.7 In addition to spasticity, other atypical features such as laryngeal dystonia and hyperreflexia may manifest in patients with LOFA.5

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Pathophysiology of Late-Onset FA

Typical FA and LOFA demonstrate some similarity in neuropathological findings, including significant reductions in cross-sectional regions within the thoracic spinal cord and dorsal root ganglia, the dentate nucleus, and corticonuclear terminals.1 

In contrast, researchers discovered that ataxia in patients with LOFA involved delayed atrophy of the dentate nucleus; however, the reason for the delayed neurodegeneration of the dentate nucleus in LOFA is unknown.1 Superior cerebellar vermian atrophy also occurs more frequently in patients with LOFA than in those with typical FA.7

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Genetics of Late-Onset FA

Multiple studies have reported a correlation between LOFA and significantly shorter GAA trinucleotide repeat expansions in both FXN gene alleles. Milder symptoms, delayed disease onset, and slower rate of progression in LOFA have been found to correlate with smaller GAA trinucleotide expansions linked to the same genetic mutational locus as typical FA on chromosome 9. 1,6-9 

One study reported that smaller GAA expansions accounted for 62.9% of variations in the age of onset of FA, while large GAA expansions accounted for 15.6% of variations in age of onset.9

Speculation suggests that epigenetics involving the number of GAA triplet repeats influence the degree of gene silencing and heterochromatin formation. Shorter GAA repeats may offer earlier protection against more severe frataxin deficiency, resulting in a delayed onset of the neurodegenerative aspects of the disease.1

Individuals with LOFA tend to exhibit less than 500 GAA repeats in at least 1 expanded allele. In rare cases, these GAA repeat expansions are not perfect replicas and are interrupted by other nucleotides. These interrupted FXN alleles may be associated with LOFA and VLOFA.10

Multigene panels including the FXN gene may help identify atypical cases of FA and aid in differentiating FA from other progressive neurologic conditions causing ataxia.10  

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  1. Koeppen AH, Morral JA, McComb RD, Feustel PJ. The neuropathology of late-onset Friedreich’s ataxia. Cerebellum. 2011;10(1):96-103. doi:10.1007/s12311-010-0235-0
  2. Williams CT, De Jesus O. Friedreich ataxia. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated September 5, 2022. Accessed January 25, 2023.
  3. Teive HAG, Ashizawa T. Primary and secondary ataxias. Curr Opin Neurol. 2015;28(4):413-422. doi:10.1097/WCO.0000000000000227
  4. Harvey EA, Jones KS. Child neurology: Friedreich ataxia with upper motor neuron findings: a case study. Neurology. 2018;91(9):426-428. doi:10.1212/WNL.0000000000006086
  5. Fearon C, Lonergan R, Ferguson D, et al. Very-late-onset Friedreich’s ataxia: diagnosis in a kindred with late-onset cerebellar ataxia. Pract Neurol. 2020;20(1):55-58. doi:10.1136/practneurol-2019-002368
  6. Indelicato E, Nachbauer W, Eigentler A, et al; EFACTS (European Friedreich’s Ataxia Consortium for Translational Studies). Onset features and time to diagnosis in Friedreich’s ataxia. Orphanet J Rare Dis. 2020;15(1):198. doi:10.1186/s13023-020-01475-9
  7. Bhidayasiri R, Perlman SL, Pulst SM, Geschwind DH. Late-onset Friedreich ataxia: phenotypic analysis, magnetic resonance imaging findings, and review of the literature. Arch Neurol. 2005;62(12):1865-1869. doi:10.1001/archneur.62.12.1865
  8. De Michele G, Filla A, Cavalcanti F, et al. Late onset Friedreich’s disease: clinical features and mapping of mutation to the FRDA locus. J Neurol Neurosurg Psychiatry. 1994;57(8):977-979. doi:10.1136/jnnp.57.8.977
  9. Lecocq C, Charles P, Azulay JP, et al. Delayed-onset Friedreich’s ataxia revisited. Mov Disord. 2016;31(1):62-69. doi:10.1002/mds.26382
  10. Bidichandani SI, Delatycki MB. Friedreich ataxia. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2023. Updated June 1, 2017. Accessed January 25, 2023.

Reviewed by Harshi Dhingra, MD, on 1/31/2023.