Clinical Features of Friedreich Ataxia
Friedreich Ataxia (FA) is characterized by progressive cerebellar dysfunction, ataxia, scoliosis, diabetes mellitus, impaired speech, loss of vision and hearing, and most critically, cardiac disease which is the most frequent cause of death in affected individuals. 1
Genetic Basis and Epidemiology
- Autosomal recessive inheritance pattern
- Caused by triplet repeat expansion mutation (GAA) in the first intron of the gene encoding frataxin (FXN)
- Prevalence: approximately 1 in 50,000 individuals
- Carrier rate: 1 in 60 to 1 in 100 1
- Most patients (98%) have homozygous GAA expansions; 2% have compound heterozygosity with point mutations or deletions 2
- Normal GAA repeat size: ≤30 copies
- Affected individuals: typically >70 triplets on each copy of the gene
- Intermediate size (30-70): classified as premutation 1
Neurological Features
- Progressive gait and limb ataxia (unsteady, irregular stepping pattern)
- Wide-based stance
- Variable step length and timing
- Lateral veering or swaying
- Dysarthria (slurred speech)
- Absent lower limb reflexes (areflexia)
- Upgoing plantar responses (Babinski sign) 2
- Peripheral sensory neuropathy with loss of position and vibration sense 2
- Ocular dysmetria (impaired eye movements) 3
- Positive Romberg test (indicating proprioceptive deficits) 3
Cardiac Manifestations
- Most life-threatening manifestation of FA 1
- Left ventricular hypertrophy with fibrosis and scarring
- Arrhythmias
- Progressive heart failure
- Cardiac dysfunction is the most frequent cause of death 1
- Cardiomyopathy correlates with clinical neurologic age of onset and triplet repeat length rather than duration of disease 4
- Systolic function tends to be low-normal with acute decline at end of life 4
Other Systemic Features
- Scoliosis
- Diabetes mellitus (metabolic complication)
- Foot deformities (pes cavus)
- Vision and hearing impairment 1
- In rare cases, profound vision deficit with optic atrophy 5
Age of Onset and Disease Progression
- Typical onset: 5 to 15 years of age
- Late-onset cases (after 25 years) show slower progression and are associated with smaller GAA expansions
- Early-onset cases have more rapid progression with higher frequency of non-neurological features 6
- Disease severity correlates with the size of the smaller of the 2 expanded GAA repeats 1
- Most patients become wheelchair-bound within 15 years of diagnosis 4
Pathophysiology
- Frataxin deficiency leads to:
- Decreased iron-sulfur cluster biogenesis
- Mitochondrial iron accumulation
- Cytosolic iron depletion
- Enhanced cellular iron uptake
- Mitochondrial dysfunction
- Oxidative stress 7
- The spectrum of phenotypic features fits with a mitochondrial disorder, although frataxin is encoded by nuclear DNA 1
Atypical Presentations
- Late-onset FA (after age 25)
- Retained reflexes
- Spastic paraparesis without ataxia
- Profound vision deficit with optic atrophy 5
- Compound heterozygotes often have atypical features 6
Diagnostic Approach
- MRI brain without contrast is the gold standard imaging modality for evaluating suspected cerebellar lesions 3
- Genetic testing for GAA repeat expansion in the FXN gene is essential for definitive diagnosis
- Complete CNS examination including assessment of mental status, cranial nerves, motor system, sensory system, reflexes, and cerebellar function 3
FA should be considered in the differential diagnosis of progressive ataxia, particularly when associated with cardiac involvement, absent lower limb reflexes, and sensory neuropathy, even in cases with atypical presentations such as significant vision deficit with optic atrophy without ataxia 5.