Friedreich’s ataxia

Friedreich’s ataxia is the most common type of inherited ataxia, and symptoms may start any time between childhood and late adolescence.¹ It is a multi-system disease for which there are no approved disease-modifying therapies, and it often shortens the lifespan of patients.^2–4

Friedreich’s ataxia also has a significant impact on caregivers and healthcare systems.^5–8

Early and accurate diagnosis of Friedreich’s ataxia is essential for patients to receive timely intervention and supportive care tailored to their needs.² Affected patients and their families should receive genetic counselling.² Should disease-modifying therapies for Friedreich’s ataxia become available, early diagnosis will be even more important.

Friedreich’s ataxia is caused by bi-allelic mutations in the FXN gene which encodes the mitochondrial protein frataxin,¹ significantly reducing its expression and resulting in oxidative stress and neuronal degeneration.^2,9,10 Friedreich’s ataxia has an autosomal recessive inheritance pattern.^2,3 Mutations occur in the gene that encodes frataxin, a protein which is involved in regulating mitochondrial function.¹ Affected patients have trinucleotide repeat expansions in both copies of the FXN gene, resulting in a significant reduction in frataxin protein levels.^11,12

Trinucleotide repeat expansions cannot be identified by conventional sequencing in a genetic testing panel, and a specific genetic test must be performed in order to make a diagnosis.¹⁴

Decreased frataxin levels are associated with mitochondrial iron accumulation and increased oxidative stress, which can lead to cell death through ferroptosis.^2,9,10 Consequently, reduced frataxin levels are responsible for impaired neurological function in the cerebellum, the pancreas, the heart, and the skeletal musculature.^9,11,15,16

Ferroptosis is a type of programmed cell death driven by oxidative stress and iron overload in the mitochondria. It is associated with glutathione depletion and production of lipid peroxides, and has been linked to a number of neurodegenerative and epileptic diseases.^10,17,18 Ferroptosis plays a major role in contributing to neuronal degeneration in Friedrich’s ataxia.^17,18

Ferroptosis is a multi-stage pathway driven by several enzymes and cofactors. 15-lipoxygenase (15-LO) is an enzyme whose activity is key in driving the ferroptosis pathway. In Friedreich’s ataxia, a lack of frataxin results in oxidative stress and downstream activation of 15-LO, leading to ferroptosis.^{2,9,10,17,19–22}

Friedreich’s ataxia is primarily a disease of white, western-European populations and affects approximately 1:20,000 live births in Western Europe, where the disease originated.²³

Friedreich’s ataxia is a progressive and systemic neuromuscular disease typically characterized by worsening ataxia and scoliosis, resulting in loss of ambulation.^2,3 Cardiomyopathy and diabetes mellitus are common and serious manifestations of the disease.^2,3 Speech is impacted, and many patients experience loss of vision and hearing.^2,3

Clinical diagnosis of Friedreich’s ataxia may be difficult as the clinical phenotype is similar to Charcot-Marie-Tooth disorder, ataxia with a vitamin E deficiency, ataxia with coenzyme Q10 deficiency, and others.^12,24

Genetic testing plays a critical role in accurate diagnosis.²⁵ Genetic tests include:²⁵

• Triplet-repeat primed polymerase chain reaction (TP-PCR), which uses a set of 3 primers to amplify the region containing the repeat  
• Long-range PCR, which is used to amplify regions of DNA containing GAA repeats  
• Real time quantitative PCR 
• Southern blotting 
• Lateral flow immunoassay 

The gold standard of genetic testing for Friedreich’s ataxia is southern blot analysis.²⁶  

Patients with a genetically confirmed diagnosis of Friedreich’s ataxia should undergo a comprehensive clinical and neurological assessment, including:²⁷ 

• Electrocardiography (ECG), echocardiography and other cardiological evaluations  
• Neurological evaluation  
• Ophthalmological examination 
• Electronystagmography  
• Selected hematological tests, including red and white cell blood counts and concentrations of hemoglobin, glucose and electrolytes 
• Magnetic resonance imaging (MRI)

Friedreich’s ataxia has a variable disease course, with symptoms of early onset Friedreich’s ataxia typically starting by 10–15 years of age.¹ Less than a fifth of patients have adult-onset disease and tend to have a less severe disease course.^1,29

Most patients start requiring a wheelchair ~11 years following disease onset in early adulthood.¹²

Friedreich’s ataxia often shortens the lifespan of patients, with a mean mortality age of 37 years, though this is highly variable.⁴

Cardiomyopathy is a universal feature and is the leading cause of death in Friedreich’s ataxia.⁴

There are no approved therapies which can impact the course of the disease.² As such, current treatment for Friedreich’s ataxia involves supportive care focused on alleviating symptoms.^2,3,30

The management of Friedreich’s ataxia involves many healthcare professionals, and coordination among them is crucial to maximizing therapeutic benefit.