Key Facts

Friedreich ataxia (FA) is the commonest inherited ataxia in Europeans. The combination of progressive ataxia, absent reflexes, upgoing plantars, and cardiomyopathy is highly characteristic. Cardiac disease is the primary determinant of prognosis.

Epidemiology

Prevalence ~2-4 per 100,000 (European populations). Carrier frequency ~1 in 100. Onset typically before age 25 (mean ~10-15 years). Equal sex distribution.

Aetiology

Autosomal recessive. Homozygous GAA trinucleotide repeat expansion in intron 1 of FXN gene (chromosome 9q21). ~96% are homozygous for expansion; ~4% are compound heterozygotes (expansion + point mutation). Longer GAA repeats → earlier onset and more severe phenotype.

Pathophysiology

Frataxin is a mitochondrial protein essential for iron-sulphur cluster assembly. Deficiency → mitochondrial iron accumulation → oxidative stress → mitochondrial dysfunction and cell death. Most affected tissues: dorsal root ganglia (large sensory neurones → sensory neuropathy/areflexia), spinocerebellar tracts (ataxia), corticospinal tracts (upgoing plantars), posterior columns (proprioception loss), cardiac myocytes (hypertrophic cardiomyopathy), pancreatic β-cells (diabetes).

Neurological

• Progressive gait ataxia: broad-based, unsteady; earliest feature
• Limb ataxia: dysmetria, intention tremor, dysdiadochokinesis
• Dysarthria: scanning/cerebellar speech (progressive)
• Areflexia: absent deep tendon reflexes (peripheral sensory neuropathy — large fibre)
• Upgoing plantars (Babinski sign): corticospinal tract degeneration — UNIQUE combination with areflexia
• Sensory loss: vibration and proprioception (posterior columns); Romberg positive
• Square-wave jerks and fixation instability (ocular)
• Dysphagia: late

Cardiac (~75%)

• Hypertrophic cardiomyopathy: concentric LVH; may progress to dilated cardiomyopathy
• Arrhythmias: AF, heart block
• Heart failure: leading cause of death

Musculoskeletal

• Scoliosis (~80%): progressive; may require surgical correction
• Pes cavus (high-arched feet) and hammer toes

Metabolic

• Diabetes mellitus (~30%): insulin-dependent; pancreatic β-cell dysfunction
• Impaired glucose tolerance in additional ~20%

Red Flags

• Young-onset progressive ataxia + areflexia + upgoing plantars → strongly suggests FA
• Associated cardiomyopathy → echocardiographic screening mandatory
• Scoliosis in ataxic child → consider FA

Genetic Testing (Diagnostic)

• FXN gene GAA repeat analysis: homozygous expansion ≥66 repeats confirms diagnosis (~96%)
• If one allele expanded: sequence FXN for point mutations (compound heterozygote ~4%)

Cardiac

• ECG: T-wave inversion, LVH; arrhythmias
• Echocardiography: concentric LVH; serial monitoring essential (annually)
• Cardiac MRI: iron deposition, fibrosis assessment

Neurophysiology

• NCS: sensory axonal neuropathy (absent sensory nerve action potentials); motor conduction usually preserved

Bloods

• HbA1c/glucose: diabetes screening (annually)
• Frataxin levels: research/emerging clinical use

Imaging

• MRI brain: cerebellar atrophy (mild initially); cervical spinal cord atrophy
• MRI spine: cord atrophy

Musculoskeletal

• Scoliosis: spinal X-ray; Cobb angle monitoring

No Curative Treatment

• Omaveloxolone (Skyclarys): Nrf2 activator; reduces oxidative stress; modest improvement in neurological function (mFARS score) in FRD-001/MOXIe trial; approved in USA/EU; NICE evaluation pending

Cardiac Management (Critical)

• Regular echocardiography (at least annually)
• Heart failure treatment: ACE inhibitors (ramipril 1.25-10mg OD), beta-blockers (bisoprolol 1.25-10mg OD)
• Arrhythmia management: rate/rhythm control for AF
• Cardiac transplantation: rare but described

Diabetes

• Insulin therapy often required (β-cell dysfunction)
• Annual HbA1c screening

Musculoskeletal

• Scoliosis: bracing; surgical correction (spinal fusion) if Cobb angle >40-50°
• Pes cavus: orthotics, surgical correction if necessary

Rehabilitation (Essential)

• Physiotherapy: balance, gait, stretching, strengthening; assistive devices; wheelchair prescription
• OT: home adaptations, ADL aids
• SALT: dysarthria, dysphagia management

Genetic Counselling

• Autosomal recessive: 25% risk for siblings; carrier testing for family members

Referral Criteria

• Specialist ataxia centre/neurology
• Cardiology: annual cardiac review
• Orthopaedic: scoliosis management
• Genetics: family counselling

Progressive. Wheelchair-dependent ~10-15 years after symptom onset. Mean age of death ~35-40 years (range 25-70). Cardiomyopathy is the leading cause of death (~60%). Longer GAA repeats → earlier onset and faster progression. Late-onset FA (>25 years): slower progression, may remain ambulant longer. Diabetes develops in ~30%. Quality of life significantly affected by loss of mobility, dysarthria, and cardiac disease.

Friedreich Ataxia — Key Feature Combination

Hereditary Ataxias Comparison