Friedreich Ataxia (FA)

Friedreich ataxia (FA) is an autosomal recessive, progressively neurodegenerative condition caused by biallelic pathogenic variations in the FXN gene. Approximately 96% of individuals with FA test positive for biallelic repeat expansions in the guanine-adenine-adenine (GAA) trinucleotide on intron 1 of the FXN gene.1

Typical Friedreich Ataxia

A majority (75%) of patients with typical FA experience disease onset before 25 years of age. Mean age of symptom onset ranges from 10 to 15 years of age, but FA may manifest as early as 2 years of age.1

The disorder is characterized by a slow degeneration of muscular coordination and strength along with sensory deficits, such as proprioceptive and vibratory sense. Typical neurological manifestations include absent lower extremity deep tendon reflexes and balance impairments accentuated during the Romberg test as well as with the eyes closed or in a darkened environment. Other common clinical features include scoliosis, hypertrophic cardiomyopathy, and diabetes.1

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Atypical Friedreich Ataxia

The remaining 25% of patients demonstrate an atypical presentation with a delayed age of disease onset or retained tendon reflexes. Use of a multigene panel may help identify individuals with atypical FA presentations.1 Atypical presentations include several subtypes, including late-onset FA (LOFA), very late-onset FA (VLOFA), FA with retained reflexes (FARR), and several more rare presentations. 

Late-Onset FA

Late-onset FA occurs in patients between 26 and 39 years of age.1,2 Sequence variations in the GAA repeat expansion along with shorter GAA trinucleotide repeat size appear to correlate  with atypical phenotypic expressions of FA, particularly in late-onset subtypes.2

Similar to patients with typical FA, patients with LOFA also demonstrate gait and limb ataxias, dysarthria, loss of vibration sense, and fixational/gaze instability. Patients with LOFA present more often with lower extremity spasticity and retained reflexes compared with those who have typical FA. Additionally, cerebellar vermian atrophy is not uncommon in patients with LOFA.2

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Very Late-Onset FA

Very late-onset FA occurs in patients older than 40 years of age.1,3 The oldest recorded age of onset of FA occurred in an individual who was 80 years old and homozygous for the GAA trinucleotide expansion.1,4

Two studies analyzed associations between genotype and phenotypic presentation of FA.5,6 One study, including 44 patients with LOFA and 30 with VLOFA, reported milder manifestations of dysarthria, absent tendon and extensor plantar reflexes, muscle weakness, cerebellar atrophy, scoliosis, cardiomyopathy, amyotrophy, ganglionopathy, and functional disability compared with patients with typical FA. The researchers noted that these patients with LOFA and VLOFA often had smaller numbers of GAA trinucleotide repeats on the FXN allele.5 The second study published one year later confirmed similar findings with a correlation between GAA repeat size and age of FA onset.6 

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FA with Retained Reflexes

FA with retained reflexes occurs in approximately 12% of individuals who test homozygous for the GAA trinucleotide expansion. Often, those with FARR demonstrate a later onset of the disease with decreased incidence of musculoskeletal or cardiac complications related to FA.1

Some patients with intact reflexes demonstrate brisk tendon reflexes accompanied by clonus. In this FA subtype, patients may retain their tendon reflexes for more than 10 years after disease onset.1

Rare Atypical FA Subtypes

There are rare cases of patients with biallelic, full-penetrance GAA expansions who present with spastic paraparesis causing gait disturbance but no gait or limb ataxia. These individuals often demonstrate hyperreflexia with a later age of disease onset, usually around 6 years after onset of typical FA.1 

Another rare presentation of FA involves chorea and pure sensory ataxia, while a third rare presentation of FA causes seemingly isolated cardiomyopathy with ataxia occurring significantly after disease onset.1

Disease-Onset and Clinical Presentation Variability

Variations in genetic background, such as Arcadian ethnicity, the p.Cys282Tyr variation in the HFE gene7, somatic heterogeneity of the GAA repeat expansion, and other currently unknown factors, may contribute to variable phenotypic disease manifestations, age of onset, and thus, the type of disease presentation. GAA repeat expansion size accounts for approximately 50% of variations in age of FA onset.1,8 

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  1. Bidichandani SI, Delatycki MB. Friedreich ataxia. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews®. University of Washington, Seattle; 1993. Accessed January 18, 2023. 
  2. 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
  3. Bidichandani SI, Garcia CA, Patel PI, Dimachkie MM. Very late-onset Friedreich ataxia despite large GAA triplet repeat expansions. Arch Neurol. 2000;57(2):246-251. doi:10.1001/archneur.57.2.246
  4. Alvarez V, Arnold P, Kuntzer T. Very late-onset Friedreich ataxia: later than life expectancy? J Neurol. 2013;260(5):1408-1409. doi:10.1007/s00415-013-6874-6
  5. 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
  6. Martinez ARM, Moro A, Abrahao A, et al. Nonneurological involvement in late-onset Friedreich Ataxia (LOFA): exploring the phenotypes. Cerebellum. 2017;16(1):253-256. doi:10.1007/s12311-015-0755-8
  7. Delatycki MB, Tai G, Corben L, et al. HFE p.C282Y heterozygosity is associated with earlier disease onset in Friedreich ataxia. Mov Disord. 2014;29(7):940-943. doi:10.1002/mds.25795
  8. Filla A, De Michele G, Cavalcanti F, et al. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet. 1996;59(3):554-560.

Reviewed by Debjyoti Talukdar, MD, on 1/31/2023.