Friedreich Ataxia (FA)

Friedreich ataxia (FA), although rare, is the most commonly inherited ataxia causing progressive degeneration of the central and peripheral nervous system.¹

Typically, the neurodegenerative condition occurs before the age of 25 years. Patients with typical early-onset FA present with ataxic gait, absence of lower extremity reflexes, extensor plantar response, and sensory neuropathy impacting vibration and proprioception.²

Friedreich Ataxia Subtypes

Around 75% of patients with FA are diagnosed with the typical or classical form of the condition before 25 years of age. The remaining 25% experience atypical presentations of FA that do not meet the usual diagnostic criteria for typical FA. These FA subtypes often have a later age of disease onset. Atypical subtypes of FA include late-onset FA (LOFA) that develops between the ages of 25 and 39 years, very late-onset FA (VLOFA) that manifests after age 40, and FA with retained reflexes (FARR).³

Read more about FA types

Genetics of Friedreich Ataxia 

Friedreich ataxia is caused by mutations in the FXN gene, which encode a mitochondrial protein, frataxin.⁴ Normal alleles of the FXN gene contain guanine-adenine-adenine (GAA) trinucleotide sequences that repeat between 5 and 33 times.^2,3

Most patients with a typical FA presentation have full-penetrance, homozygous expansion of the GAA trinucleotide, commonly repeating between 600 and 1200 times.^2,3 

Approximately 15% of patients with homozygous GAA repeat expansion experience a later onset of the condition, either with LOFA or VLOFA. These later-onset subtypes of FA have been found to correlate with a smaller number of GAA repeats, typically less than 500 in LOFA and less than 300 in VLOFA.² 

Friedreich ataxia with retained reflexes occurs in around 11% to 12% of patients with FA who are homozygous for the GAA repeat expansion.^3,5 Similar to LOFA and VLOFA, patients with FARR demonstrate smaller GAA triplet repeat expansions, averaging 408 repeats compared with 718 GAA repeats in typical FA.^2,5

Genotype strongly influences the neurological and systemic manifestations of FA as well as disease severity and rate of progression.²

Read more about FA genetics

Clinical Features of FARR

Mean age of disease onset for patients with FARR is 26.6 years, which is much later than the presentation of typical FA, which has a mean age onset of 14.2 years.^2,5 Length of the GAA repeat expansion accounts for around half of the variation in age of FA onset.^3,6 In addition to milder symptom presentation, patients with FARR may also experience a slower rate of disease progression that often correlates with shortened length of allele expansion, particularly in cases with fewer than 600 GAA repeats.³

Patients with FARR retain reflexes, particularly in the lower extremities, while patients with typical FA exhibit areflexia.⁵ Patients with FARR may retain tendon reflexes for more than 10 years following disease onset.³ Additionally, some individuals diagnosed with FARR may exhibit hyperreflexia that may also be accompanied by clonus.³

In addition to exaggerated myotatic reflexes, patients with FARR may demonstrate positive bilateral extensor plantar responses (Babinski sign) as well as severe swaying with tandem walking, indicating a positive Romberg’s sign.²

Upon neurophysiological examination, patients with FARR are found to have milder peripheral neuropathy and milder impairments affecting somatosensory function. Impaired proprioception and vibration sense are either milder or normal in patients with FARR compared with those who have typical FA.^2,5 

Nerve conduction velocity studies performed in patients with FARR may reveal absent sensory nerve action potentials with normal distal latency, conduction velocity, and amplitude of compound muscle action potential. Magnetic resonance imaging scans of the brain and cervical spinal cord may demonstrate significant thinning of the cervical spinal cord but a normal-sized cerebellum.²

Read more about FA clinical features

Complications of FARR

Patients with FARR demonstrate significantly less incidence of skeletal abnormalities, pes cavus, and hypertrophic cardiomyopathy than patients with early-onset FA.^2,5 Diabetes may also not occur as frequently in FARR, although a family history of diabetes and ataxia may be significant for patients with FARR.²

Read more about FA complications

References

1. Friedreich ataxia fact sheet. National Institute of Neurological Disorders and Stroke (NINDS). Accessed January 26, 2023.
2. Verma R, Gupta M. Friedreich’s ataxia with retained reflexes: a phenotype and genotype correlation. BMJ Case Rep. 2012;2012:bcr2012007496. doi:10.1136/bcr-2012-007496
3. 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 26, 2023. 
4. FXN gene mutation. ClinLab Navigator. Accessed January 26, 2023. 
5. Coppola G, De Michele G, Cavalcanti F, et al. Why do some Friedreich’s ataxia patients retain tendon reflexes? A clinical, neurophysiological and molecular study. J Neurol. 1999;246(5):353-357. doi:10.1007/s004150050362
6. 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 Hasan Avcu, MD, on 1/28/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.