Friedreich Ataxia (FA)

Friedreich ataxia (FA) is the most common type of inherited ataxia. The frataxin (FXN) gene on chromosome 9 has homozygous guanine-adenine-adenine (GAA) expansions on the first intron in the majority of cases.¹ 

Friedreich ataxia is inherited in an autosomal recessive pattern, and symptoms usually start in childhood.² The disease can affect the central and peripheral nervous system, heart, skeleton, and endocrine pancreas.³ FA usually causes neurodegeneration and presents as a combination of speech impairment, muscle weakness, loss of sensation and proprioception, and problems in ambulation. Hypertrophic cardiomyopathy is the leading cause of death in patients with FA.² 

Histological findings in FA are primarily seen in the central nervous system (CNS), peripheral nervous system, and the heart, as described below.

Histological Features of the Central Nervous System

Gross Examination of the CNS

Regardless of the onset of FA, the spinal cord is thinner than normal, or hypoplastic.⁴ The dorsal root ganglia (DRG) in FA are gray in color and smaller than usual. They may be challenging to identify during dissection. The diameter of the spinal cord is smaller overall, with the thoracic region showing the most thinning. The transverse diameter of the thoracic spinal cord is frequently smaller than 10 mm.³ A loss of fibers in the anterolateral fields that correspond to the spinocerebellar and corticospinal tracts of the spinal cord may also be evident on gross examination.^2,3 Atrophy of the dorsal nerve and its efferent fibers contrast sharply against the completely normal cerebellar cortex and white matter.³ 

Histological Examination of the CNS

The transverse section of the thoracic spinal cord in patients with FA shows an overall reduction in size and the characteristic symmetrical loss of myelinated fibers in the dorsal columns and the dorsal spinocerebellar and lateral corticospinal spinal cord tracts.⁴ 

Friedreich ataxia mainly affects the DRG, which are atrophied. Their nuclei become smaller in size and show destruction.^2,5

The DRG in FA are highlighted due to the smaller neurons and subcapsular hypercellularity. The histological section of a DRG ganglion also shows marked irregularity in the outlines of many neurons, which occurs due to the proliferation of satellite cells. This results in complete absorption of the neurons into residual nodules. The normal DRG exhibit a single-cell layer of satellite cells surrounding normal neurons as seen by the S100α immunostain. Very small neurons in FA, on the other hand, exhibit a severely uneven, multilayered rim of these cells, as well as the replacement of neurons by nodules.⁶ 

Degeneration and death of fibers in the dorsal columns and corticospinal tracts are also central nervous system lesions in FA. Additionally, there is a lack of Betz cells in the motor cortex.^2,6 

 Other histological findings that have been documented in FA include²: 

• Patchy reduction in Purkinje cells in the superior vermis of the cerebellum
• Degeneration and loss of Clarke column cells in the thoracic spinal cord
• Progressive atrophy of large neurons in the dentate nucleus
• Loss of neurons in the inferior olivary, pontine, and medullary nuclei
• Compact fibrillary gliosis with no inflammation within dorsal columns and corticospinal tracts
• Loss of neurons in the optic tracts

Read more about FA pathophysiology

Histological Features of the Peripheral Nervous System

In the majority of patients with FA, a severe form of sensory peripheral neuropathy is noted in the legs. Biopsies obtained from sural nerves have revealed histological alterations in sensory peripheral nerves in cases of FA.⁶ The primary histological alterations are a scarcity of myelinated fibers and a lack of large fibers.³ 

The nerve and root lesions exhibit similarities because the parent cell bodies of peripheral sensory nerves and dorsal spinal roots are located in the DRG. The findings include the persistence of thin axons, a loss of myelin sheaths, and significantly decreased numbers of S100α-positive Schwann cells.⁶ Electron microscopy confirms the absence of myelin and closely packed clusters of unmyelinated fibers in the affected sural nerves.³ 

Read more about FA testing

Histological Features of the Heart 

Cardiomyopathy in patients with FA is significant and commonly results in fatalities. Histological examinations performed during autopsies of patients with FA have revealed degeneration of cardiac muscle fibers, interstitial myocardial fibrosis, and left ventricular hypertrophy.⁷ 

Biopsies of the transverse section of the interventricular septum show highly variable fiber sizes, splitting of fibers, abnormal sarcoplasmic nuclei, and an excessive endomysium. A small number of cardiomyocytes have clusters of small reactive inclusions highlighted by iron staining that are oriented parallel to myofibrils. Ultrastructural examination after the enhancement of ferritin by bismuth subnitrate reveals these inclusions to be electron-dense mitochondrial inclusions.³ 

Histological sections from the heart muscle can also show necrosis of myocardial fibers with a marked inflammatory response in more severe forms of cardiomyopathies.³ 

Read more about FA life expectancy

References

1. Bürk K. Friedreich ataxia: current status and future prospects. Cerebellum Ataxias. 2017;4:4. doi:10.1186/s40673-017-0062-x
2. Williams CT, De Jesus O. Friedreich ataxia. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated September 5, 2022. Accessed January 30, 2023.
3. Koeppen AH. Friedreich’s ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci. 2011;303(1-2):1-12. doi:10.1016/j.jns.2011.01.010
4. Koeppen AH, Becker AB, Qian J, Feustel PJ. Friedreich ataxia: hypoplasia of spinal cord and dorsal root ganglia. J Neuropathol Exp Neurol. 2017;76(2):101-108. doi:10.1093/jnen/nlw111
5. Rodríguez LR, Lapeña T, Calap-Quintana P, Moltó MD, Gonzalez-Cabo P, Navarro Langa JA. Antioxidant therapies and oxidative stress in Friedreich’s ataxia: the right path or just a diversion? Antioxidants (Basel). 2020;9(8):664. doi:10.3390/antiox9080664 
6. Koeppen AH, Mazurkiewicz JE. Friedreich ataxia: neuropathology revised. J Neuropathol Exp Neurol. 2013;72(2):78-90. doi:10.1097/NEN.0b013e31827e5762
7. Meyer C, Schmid G, Görlitz S, et al. Cardiomyopathy in Friedreich’s ataxia-assessment by cardiac MRI. Mov Disord. 2007;22(11):1615-1622. doi:10.1002/mds.21590

Reviewed by Kyle Habet, MD, on 1/30/2023.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.