Friedreich Ataxia

Friedreich ataxia is the commonest inherited ataxia, an autosomal recessive disorder caused by a GAA trinucleotide repeat expansion in the FXN gene, which reduces frataxin. It causes progressive gait and limb ataxia, dysarthria, loss of vibration and position sense, cardiomyopathy and diabetes.

The prevalence is about 1 in 50,000 people in people of European descent, with a carrier frequency of about 1 in 100. It is rare in Asia and sub-Saharan Africa. Onset is typically between 5 and 15 years, and both sexes are affected equally.

Genetics. About 96% of patients are homozygous for a GAA expansion (typically 600 to 1200 repeats) in intron 1 of FXN, and 4% are compound heterozygous with a point mutation. Shorter repeats are associated with later onset and slower progression.

Course. Progressive over 10 to 15 years, with loss of walking by about 10 to 15 years from onset. Cardiomyopathy, arrhythmia and heart failure are the main causes of death, at a mean age of about 35 to 40 years.

Pathophysiology.

Reduced frataxin impairs mitochondrial iron sulphur cluster synthesis, causing iron accumulation, oxidative stress and energy failure.

Dorsal root ganglia, spinocerebellar tracts, corticospinal tracts, the dentate nucleus, heart and pancreatic beta cells are the most vulnerable.

• Progressive gait ataxia, clumsiness and frequent falls; limb ataxia and dysarthria.
• Loss of vibration and joint position sense, absent tendon reflexes and extensor plantar responses.
• Pes cavus, scoliosis, optic atrophy, hearing loss and nystagmus or square wave jerks.
• Hypertrophic cardiomyopathy with T wave inversion, arrhythmias (atrial fibrillation) and heart failure.
• Diabetes (about 10 to 30%), bladder urgency, depression and fatigue.

Red flags.

• Palpitations, syncope, chest pain or dyspnoea (arrhythmia or heart failure).
• Polyuria, polydipsia and weight loss (diabetes).
• Rapid decline or atypical features (consider other ataxias).

• Genetic testing for the GAA repeat expansion in FXN (repeat primed polymerase chain reaction or Southern blot), confirming the diagnosis.
• ECG and echocardiography at diagnosis; ambulatory ECG monitoring.
• Glucose and HbA1c yearly; vitamin E, B12 and lipids to exclude treatable look alikes (ataxia with vitamin E deficiency, abetalipoproteinaemia).
• Nerve conduction studies show a sensory axonal neuropathy; MRI shows cervical cord thinning.
• Scoliosis imaging, audiology and ophthalmology; genetic counselling for the family.

Differential diagnosis. Ataxia with vitamin E deficiency, spinocerebellar ataxias, ataxia telangiectasia, Charcot-Marie-Tooth disease, hereditary spastic paraplegia, multiple sclerosis, B12 deficiency and mitochondrial disease.

• Omaveloxolone, an approved disease modifying drug for patients aged 16 years and older: 150 mg orally once daily on an empty stomach, swallowed whole. Maximum 150 mg daily (100 mg daily with moderate CYP3A4 inhibitors; avoid strong CYP3A4 inhibitors). Reduce to 100 mg daily in mild hepatic impairment; avoid in moderate and severe hepatic impairment. Monitor alanine and aspartate aminotransferases, bilirubin, B-type natriuretic peptide, lipids and weight before starting, then monthly for 3 months and every 3 months for the first year. Avoid in pregnancy unless benefit outweighs risk; use effective contraception, since it may reduce hormonal contraceptive levels.
• Cardiac care: yearly ECG and echocardiography, with heart failure and arrhythmia treated by cardiology; anticoagulation for atrial fibrillation.
• Diabetes: screen yearly and treat with insulin or oral agents as needed.
• Physiotherapy, balance and strength training, aerobic exercise, gait aids and wheelchair provision.
• Orthopaedic care for scoliosis and foot deformity; speech and language therapy; swallowing assessment; hearing aids and low vision support.
• Treat bladder urgency, depression and fatigue; occupational therapy and psychological support.
• Genetic counselling; prenatal and preimplantation testing are available; siblings can be tested.

Monitoring. Yearly review of neurological scores, ECG, echocardiography, glucose, spine, hearing and vision; liver tests at the intervals given in Management while on omaveloxolone.

Referral and escalation. Neurology and ataxia clinic; cardiology; endocrinology; orthopaedics.

Special groups. Children: school adaptation and scoliosis surveillance. Women: pregnancy needs cardiac and neurological planning.