Friedreich ataxia

Friedreich ataxia (FRDA), also known as Friedreich's ataxia, is the most common inherited ataxia, caused by pathogenic variants in the FXN gene on chromosome 9q21.11, which encodes the mitochondrial protein frataxin. The vast majority of affected individuals are homozygous for a GAA trinucleotide repeat expansion in intron 1 of the FXN gene, while a small percentage are compound heterozygous for the expansion and a point mutation or deletion. Reduced frataxin levels lead to mitochondrial iron accumulation, impaired iron-sulfur cluster synthesis, oxidative stress, and progressive cellular damage, particularly in the nervous system and heart. Friedreich ataxia is a multisystem disorder that primarily affects the nervous system, heart, and endocrine system. The hallmark feature is progressive gait and limb ataxia, typically beginning before age 25 (most commonly between ages 5 and 15). Key neurological features include dysarthria, loss of deep tendon reflexes (areflexia), sensory neuropathy affecting proprioception and vibration sense, and progressive muscle weakness. Pyramidal tract signs such as extensor plantar responses are common. Hypertrophic cardiomyopathy is present in the majority of patients and is the leading cause of death. Scoliosis, pes cavus (high-arched feet), and diabetes mellitus (affecting approximately 10–30% of patients) are frequent associated features. Most individuals require a wheelchair within 10–15 years of symptom onset. There is currently no cure for Friedreich ataxia, but management is multidisciplinary. In 2023, omaveloxolone (Skyclarys) became the first FDA-approved treatment specifically for FRDA, acting as an Nrf2 activator to reduce oxidative stress. Cardiac surveillance and management of cardiomyopathy and arrhythmias are essential. Physical therapy, occupational therapy, speech therapy, orthopedic interventions for scoliosis and foot deformities, and monitoring for diabetes are important components of care. Several investigational therapies targeting frataxin restoration, gene therapy, and other pathways are under active clinical investigation.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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