Friedreich Ataxia (FA)

Friedreich ataxia (FA), a neurodegenerative condition with autosomal-recessive inheritance, is characterized by the progressive loss of motor coordination, muscular strength, proprioception and sensation, balance, ambulation, and speech.1

Most cases of FA are caused by mutations in the FXN gene that result in the excessive repetition and expansion of the guanine-adenine-adenine (GAA) trinucleotide, located on intron 1 of the gene.1 The FXN gene encodes the biosynthesis of frataxin protein, which is involved in mitochondrial iron homeostasis and storage, heme and iron-sulfur cluster (ISC) formation, and the mediation of oxidative stress.2

Progressive Neurodegeneration

The neurological symptoms of FA are those of a mixed sensory and cerebellar ataxia that disrupts proprioceptive pathways across the peripheral nervous system, spinal cord, and cerebellar nuclei. Gradual demyelination and degeneration of the long axons connecting Pacini and Ruffini corpuscles with sensory neurons in the dorsal root ganglia (DRG) and Clarke column impair vibration sensation, proprioception, and stretch sensation. As the disease progresses, the deterioration of neural structures within the pyramidal tracts results in motor deficits, such as muscle weakness and spasticity.3  

The hallmark feature of FA — cerebellar ataxia — is a consequence of neuronal loss within the lateral and ventral spinocerebellar tracts, Clarke column, dentate nucleus, dentatorubral tracts, and superior vermis.1 Neurological degeneration of the posterior column of the spinal cord corresponds to a loss of proprioception and sensory ataxia, and atrophy of the DRG impairs tendon reflexes.1 

Lack of proprioception, sensory deficits, and muscle spasticity contribute to balance problems and frequent falls in patients with FA. Patients may attempt to compensate by adopting a wide-based gait with constant shifting to maintain balance and may have a steppage gait. Attempts to maintain balance often result in uncontrolled movements. Progressive action and intention tremor and choreiform movements result in a loss of mobility and eventually of ambulation, so that the use of assistive mobility devices and wheelchairs becomes necessary.1

Common neurological features of FA include a reduction in the overall size of the DRG and the proliferation of residual nodules, derived from satellite or Schwann cells, around dying neurons that are being slowly absorbed.4 Progressive degeneration of the DRG leads to thinning of the dorsal roots, degeneration of the dorsal columns, trans-synaptic neuronal atrophy of nerve cells in the Clarke column and dorsal spinocerebellar fibers, atrophy of the gracile and cuneate nuclei, and peripheral sensory neuropathy.4

Although some studies indicate that only large and intermediate neurons are vulnerable to degeneration in FA,5 evidenced by a lack of large neurons seen on histologic staining,4 others suggest that neuronal hypoplasia and superimposed neuronal destruction and atrophy of the DRG provide a better explanation of the neurological deficits that develop as FA progresses.4 

Researchers have identified antibodies against 2 proteins — myelin basic protein and peripheral myelin protein P0 — involved in myelin sheath assembly. The presence of these antibodies results in deficiency of the proteins and the progressive demyelination of neuronal axons in patients with FA.4

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Dysphagia, Dysarthria, and Loss of Vision and Hearing

The frequent involvement of cranial nerves VII, X, and XII in FA results in facial muscle weakness, dysarthria, and dysphagia. Loss of vision corresponds to a loss of optic tract nerve fibers.1 

Problems with auditory processing are caused by neuropathy in cranial nerve VIII and the auditory brainstem, evidenced by the absence or distortion of electrophysiological responses during examination. In turn, impaired auditory processing limits the ability to understand speech and contributes to dysarthria and deficits in speech and language development, communication, socialization, and educational progress, particularly in children with FA.6

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Frataxin deficiency in FA has been shown to correlate with downregulation of the genes encoding the synthesis of contractile proteins, which in turn may contribute to the development of cardiomyopathy in many patients with FA.

A murine study showed that the rate of iron deposition in cardiomyocytes was higher in FA-positive mice than in FA-negative mice. Iron deposition and iron-mediated oxidative stress resulting in cardiac tissue damage and fibrosis contribute to cardiac dysfunction and complications that can be fatal.7 The gradual replacement of cardiac muscle fibers with macrophages and fibroblasts is evidence of cardiac inflammation and fibrosis.1 Changes within cardiomyocytes are followed by compensatory hypertrophic cardiomyopathy as the heart attempts to increase output.1

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As FA progresses, kyphoscoliosis frequently develops, due to spinal muscular imbalance resulting from neurologically induced motor weakness.1 Surgical intervention may be required, depending on the degree of curvature and its effects on organ function. Orthopedic shoes, avoidance of tight clothing, and correct usage of adjustable ambulatory devices like orthoses, canes, and wheelchairs, has shown benefit in decreasing muscle spasticity and preventing scoliosis.1

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  1. Williams CT, De Jesus O. Friedreich ataxia. StatPearls [Internet]. Updated September 5, 2022. Accessed January 13, 2023. 
  2. Babady NE, Carelle N, Wells RD, et al. Advancements in the pathophysiology of Friedreich ataxia and new prospects for treatments. Mol Genet Metab. 2007;92(0):23-35. doi:10.1016/j.ymgme.2007.05.009
  3. González-Cabo P, Palau F. Mitochondrial pathophysiology in Friedreich’s ataxia. J Neurochem. 2013;126(s1):53-64. doi:10.1111/jnc.12303
  4. Koeppen AH, Mazurkiewicz JE. Friedreich ataxia: neuropathology revised. J Neuropathol Exp Neurol. 2013;72(2):10.1097/NEN.0b013e31827e5762. doi:10.1097/NEN.0b013e31827e5762
  5. Inoue K, Hirano A, Hasson J. Friedreich’s ataxia selectively involves the large neurons of the dorsal root ganglia. Trans Am Neurol Assoc. 1979;104:75-76. doi:10.1093/jnen/nlw111
  6. Rance G, Corben L, Delatycki M. Auditory processing deficits in children with Friedreich ataxia. J Child Neurol. 2012;27(9):1197-1203. doi:10.1177/0883073812448963
  7. Miranda CJ, Santos MM, Ohshima K, et al. Frataxin knockin mouse. FEBS Lett. 2002;512(1-3):291-297. doi:10.1016/S0014-5793(02)02251-2

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