What is Friedreich's ataxia?

What is Friedreich's Ataxia

Friedreich's ataxia is an autosomal recessive neurodegenerative disorder caused by GAA trinucleotide repeat expansion in the FXN gene, resulting in reduced frataxin protein levels and leading to progressive ataxia, cardiomyopathy, and multisystem involvement. 1, 2

Genetic Basis and Pathophysiology

• The disease results from expanded GAA triplet repeats in the first intron of the frataxin gene (FXN), causing reduction of messenger RNA and frataxin protein levels in affected tissues 2, 3
• The size of the GAA repeat expansion directly correlates with disease severity and age of onset 1
• Reduced frataxin leads to mitochondrial dysfunction, iron accumulation, and oxidative stress in multiple organ systems 2

Clinical Presentation

Neurological manifestations:

• Progressive ataxia with gait instability and limb incoordination, typically beginning in the second decade of life 3
• Sensory loss and peripheral neuropathy due to dorsal root ganglia degeneration 3
• Dysarthria (speech difficulties) 4, 3
• Muscle weakness progressing to loss of ambulation within 10-15 years of onset 3

Cardiac involvement:

• Hypertrophic cardiomyopathy is the most life-threatening manifestation and the most frequent cause of death 1, 2
• Cardiac disease may be asymptomatic initially, requiring regular screening 1
• Patients are at risk for sudden cardiac death even with only mildly decreased left ventricular function 1

Other systemic features:

• Skeletal abnormalities including scoliosis and foot deformities 2, 3
• Diabetes mellitus develops in approximately 10% of patients 3
• Glucose metabolism disturbances 2

Neuropathological Characteristics

• Spinal cord and dorsal root ganglia atrophy with loss of peripheral sensory nerve fibers and degeneration of posterior columns 2, 3
• Dentate nucleus atrophy without global cerebellar volume reduction 2
• Progressive cerebellar hemispheric and vermian volume loss may develop over time 5
• Early imaging may be normal or subtly abnormal, with abnormalities becoming more apparent on follow-up due to the progressive nature of the disease 5

Epidemiology

• Friedreich's ataxia is the most common autosomal recessive ataxia worldwide and the most common early-onset inherited ataxia in populations of European, Arab, and Indian descent 2, 6
• The disease affects approximately 1 in 50,000 Caucasians 3

Diagnosis

• DNA analysis demonstrating GAA repeat expansion is the hallmark for diagnosis 2
• Genetic testing is important for confirming diagnosis and identifying at-risk family members 1
• MRI may show spinal cord atrophy and dentate nucleus changes, though imaging in early stages can be normal 5, 2

Disease Course and Prognosis

• Initial symptoms typically appear around the beginning of the second decade of life 3
• Most patients lose the ability to walk, stand, or sit without support within 10-15 years of disease onset 3
• Variation in neurophysiological abnormalities correlates with GAA repeat expansion size and accounts for individual variation in disease progression 3
• Cardiac disease represents the primary mortality risk 1

Current Treatment Landscape

• Omaveloxolone, a nuclear factor erythroid 2-related factor 2 activator, was recently approved as the first disease-specific therapy for Friedreich's ataxia 6
• No treatment currently stops disease progression, though multiple therapeutic approaches are under investigation to improve mitochondrial functioning and increase frataxin expression 2
• Management requires multidisciplinary care including cardiac monitoring, respiratory support, nutritional management, and physical therapy 1