Friedreich’s ataxia pathophysiology

Last updated March 31, 2025, by Lindsey Shapiro, PhD
Medically reviewed by David Lynch, MD, PhD

Friedreich’s ataxia (FA) is caused by mutations in the FXN gene that lead to a deficiency in the mitochondrial protein frataxin. Clinical manifestations of the disease arise as a consequence of cellular degeneration secondary to mitochondrial dysfunction resulting from frataxin loss.

Role of frataxin

Frataxin is a small protein found in mitochondria. It plays a role in regulating iron homeostasis by chaperoning iron and managing its metabolism, storage, and distribution. Frataxin is also involved in the formation of iron-sulfur (Fe-S) clusters, which are critical for the function of enzymes involved in mitochondrial respiration and ATP production.

FA-causing mutations typically lead to transcriptional silencing of FXN. Most patients produce a functionally normal frataxin protein, but at levels that are around 5%-30% of normal. A minority of patients produce a version of frataxin that is dysfunctional or unstable.

The mechanisms by which frataxin deficiency drives the clinical manifestations of FA are likely multifactorial and thought to involve mitochondrial dysfunction.

A lack of frataxin leads to an inhibition of mitochondrial oxidative phosphorylation, which in turn causes reduced ATP production and a failure to meet cellular energy demands, ultimately causing cellular degeneration.

Affected cells

Frataxin is found in all tissues, but the most affected cells in FA are those that have a high dependence on mitochondrial ATP production. Pathological involvement likely begins during embryonic development and continues throughout life.

The severity and progression of disease is usually related to the amount of frataxin produced, with lower frataxin levels generally being linked to earlier disease onset and faster progression.

Neurons

Frataxin loss affects several neuronal systems. It is believed that the proprioceptive system is affected early, namely the dorsal root ganglia (DRG).

The loss and dysfunction of DRG neurons and of their large myelinated axons in the dorsal roots lead to sensory neuropathy.

With time, the dentate nucleus of the cerebellum and, to some extent, the corticospinal tracts degenerate. Motor control is then affected, resulting in impaired balance and gait.

It is believed that these — the dentate nucleus of the cerebellum and the corticospinal tract — are the major sites of active disease progression in FA.

Later in disease, corticospinal dysfunction leads to spasticity and weakness.

Degeneration of retinal ganglion cells and auditory nerve cells can also occur in FA, driving vision and hearing loss.

Cardiomyocytes

Cardiomyocytes are also highly reliant on mitochondrial oxidative phosphorylation for contractions. In FA, muscle fibers in cardiac tissue are replaced by macrophages and fibroblasts, driving fibrosis and inflammation. There are also signs of iron accumulation in the heart.

Pathological changes in cardiomyocytes ultimately lead to hypertrophic cardiomyopathy, a leading cause of death in FA.

Pancreatic beta cells

Mitochondrial defects also drive progressive destruction of the islets of Langerhans, leading to a loss of pancreatic beta cells in FA.

A subsequent insulin deficiency and insulin resistance can lead to diabetes or glucose intolerance for many FA patients.

Diseases with overlapping pathophysiology

Mitochondrial dysfunction has been implicated in the pathogenesis of other neurodegenerative diseases or forms of ataxia. That includes conditions that may be considered in the differential diagnosis of FA, such as spinocerebellar ataxia or ataxia with vitamin E deficiency.

However, no conditions other than FA have been definitively linked to frataxin deficiency. Genetic testing for FXN mutations is crucial for homing in on an FA diagnosis.

Therapeutic strategies based on pathophysiology

Disease management for FA relies largely on interventions to manage symptoms and comorbidities. The only approved disease-modifying therapy for the disease is Skyclarys (omaveloxolone), an activator of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and an inhibitor of nuclear factor kappa B (NF-kB), a pro-inflammatory transcription factor.

Experimental treatments are being developed that seek to address the disease’s underlying pathophysiology. Some are aimed at increasing FXN activity or frataxin levels, while others work downstream to mitigate the cellular consequences of frataxin loss. That includes strategies to improve mitochondrial function and reduce oxidative stress.