Friedreich Ataxia (FA)

Friedreich ataxia (FA) is a neurodegenerative condition of the central and peripheral nervous systems that is inherited through an autosomal recessive pattern. Although rare, FA is the most common of the hereditary ataxias, accounting for approximately half of all inherited cases of ataxia.¹

FA is characterized by the progressive loss of muscle coordination, strength, balance, speech, ambulation, and sensation, especially vibration and proprioception. Complications affect primarily the cardiovascular (hypertrophic cardiomyopathy, cardiac arrhythmias), musculoskeletal (scoliosis), and endocrine (diabetes mellitus) systems.¹

Friedreich Ataxia Subtypes

In approximately 75% of cases, the onset of FA begins before the age of 25 years. The remaining 25% of cases are classified as atypical FA and include the subtypes of late-onset FA (LOFA), very late-onset FA (VLOFA), and FA with retained reflexes (FARR). LOFA manifests in patients between the ages of 25 and 39 years, and VLOFA develops in individuals 40 years of age or older.^1-3 

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Clinical Features of Very Late-Onset FA

In addition to a delayed onset of ataxia, later onset forms of FA, such as VLOFA, are often characterized by slower progression,^3,4 milder symptoms,^2,3 a wider variety of signs and symptoms,³ and fewer complications.² 

The symptoms of VLOFA differ from those of typical FA, and later-onset forms of the disorder lack some of the features frequently seen in earlier-onset disease. Common features of typical FA that are often absent in patients with VLOFA include areflexia, dysarthria, diabetes, cardiac complications, scoliosis, sensory neuropathy, amyotrophy, and extensor plantar responses.⁵ 

Mortality and morbidity due to cardiac involvement are less likely in patients with VLOFA,³ who also may exhibit atypical features such as laryngeal dystonia^4,5, hyperreflexia⁵, and spasticity presenting as spastic tetraparesis without neuropathy or ataxia.^5,6

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Misdiagnosis of Very Late-Onset FA

Given the atypical clinical presentation of later-onset forms of FA, VLOFA may frequently be misdiagnosed.⁵ 

One case report described a 55-year-old patient who was admitted to the hospital with rapidly progressing ataxic VLOFA mimicking multiple system atrophy of the cerebellar type. One method to confirm a diagnosis of VLOFA is genetic testing. Genetic analysis in this patient revealed 8 GAA (guanine-adenine-adenine) trinucleotide repeats on one allele and 37 GAA repeats on the other allele, resulting in a diagnosis of VLOFA with likely compound heterozygous genotype.⁷

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Genetics of Very Late-Onset FA

Genetic testing may help identify atypical forms of FA such as VLOFA. Most cases (96%) are caused by a pathological expansion of the GAA trinucleotide within the noncoding region of intron 1 of the FXN gene³, also known as the X25 gene.^2,8 The atypical presentations of approximately 1% to 3% of the remaining cases are caused by point mutations or deletions that correlate with compound heterozygous expansions.^3,9

Normally, intron 1 of the FXN gene has fewer than 40 GAA trinucleotide expansions. In patients with a typical clinical presentation of FA, the number of GAA trinucleotide repeats is commonly between 600 and 1200.^3,10 

Researchers have discovered a correlation between age at onset and number of GAA repeats. Patients with later-onset forms, such as LOFA and VLOFA, often have shorter GAA expansions in at least one allele of the FXN (X25) gene; however, it is possible for individuals with later-onset forms of FA, such as VLOFA, to have larger GAA expansions.² 

Limited GAA trinucleotide expansions have been shown to correlate with VLOFA without cardiomyopathy. In 6 adult patients from 3 families who had VLOFA without cardiomyopathy, researchers identified  mitotic and gametic instability of the GAA repeat expansion.⁸

Individuals with VLOFA tend to have fewer than 300 GAA repeats in at least one expanded allele. Rarely, FXN alleles without perfect GAA repeats, which are interrupted by other nucleotides, may be associated with LOFA and VLOFA.¹⁰

Multigene panels including the FXN gene and other genes of interest may help identify atypical cases of FA. They may also assist in the differential diagnosis, distinguishing FA from other progressive neurologic conditions characterized by ataxia.¹⁰  

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References

1. Williams CT, De Jesus O. Friedreich ataxia. StatPearls [Internet]. Updated September 5, 2022. Accessed January 25, 2023. 
2. 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
3. Cook A, Giunti P. Friedreich’s ataxia: clinical features, pathogenesis and management. Br Med Bull. 2017;124(1):19-30. doi:10.1093/bmb/ldx034
4. Rota S, Marchina E, Todeschini A, et al. Very late-onset Friedreich ataxia with laryngeal dystonia. Case Rep Neurol. 2014;6(3):287-290. doi:10.1159/000370062
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. Lhatoo SD, Rao DG, Kane NM, Ormerod IE. Very late onset Friedreich’s presenting as spastic tetraparesis without ataxia or neuropathy. Neurology. 2001;56(12):1776-1777. doi:10.1212/WNL.56.12.1776
7. Vidhale TA, Gupta HR, Pj R, Gandhi C. Very late-onset Friedreich’s ataxia with rapid course mimicking as possible multiple system atrophy cerebellar type. BMJ Case Rep. 2021;14(7):e242073. doi:10.1136/bcr-2021-242073
8. Gellera C, Pareyson D, Castellotti B, et al. Very late onset Friedreich’s ataxia without cardiomyopathy is associated with limited GAA expansion in the X25 gene. Neurology. 1997;49(4):1153-1155. doi:10.1212/WNL.49.4.1153
9. Bidichandani SI, Ashizawa T, Patel PI. Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. Am J Hum Genet. 1997;60(5):1251-1256. 
10. Bidichandani SI, Delatycki MB. Friedreich ataxia. GeneReviews® [Internet]. Updated June 1, 2017. Accessed January 25, 2023. 

Reviewed by Kyle Habet, MD, on 1/31/2023.

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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.