Synonym: Friedreich ataxia

Friedreich's ataxia is the most common inherited ataxia in the UK. It is a degenerative disease that primarily affects the nervous system and the heart. There is progressive ataxia, dysarthria, decreased proprioception/vibration sense and muscle weakness. The inheritance is autosomal recessive.

Friedreich's ataxia was first described in 1863 by Nikolaus Friedreich, a German physician. The Friedreich's ataxia gene was discovered in 1996, leading to better recognition of the spectrum of disease.

Epidemiology¹

• The prevalence is about 1.8 per 100,000 in the UK.
• Friedreich's ataxia occurs in populations from Europe, the Middle East, North Africa and India. It is absent in populations from East Asia (China and Japan) and in American Indians.

Aetiology and genetics^2,3

• The gene disorder is a mutation of the frataxin gene on chromosome 9.
• Most patients (95%) have a GAA repeat expansion of the frataxin gene; the size of the expansion correlates with the severity of the disease.
• More rarely there is a point mutation in one gene.
• The mutation results in decreased synthesis of frataxin, a mitochondrial protein.
• The function of frataxin protein is unknown, but it seems to be involved in cellular iron homeostasis. Its dysfunction results in mitochondrial dysfunction and oxidative damage to cells.⁴
• The cellular damage primarily affects the nervous system and the heart (for unknown reasons). The sensory neurones involving proprioception are affected early and severely - so ataxia is an early feature of the disease.⁴

Clinical features^1,3

Onset:

• Usually presents before adolescence, with onset between ages 2-16 years.
• Late-onset presentation is possible, up to age 50 years with milder forms of Friedreich's ataxia.

Presenting symptoms:

• Unsteadiness of gait is the usual presenting symptom.
• Other presenting symptoms are general clumsiness or deterioration in athletic performance.
• Sometimes presents with scoliosis or pes cavus, which may precede neurological symptoms by several years.
• Rarely, presents with symptoms of cardiomyopathy.
• In one case report, presentation was without ataxia but with visual, motor and sensory loss.⁵

Neurological features:

• Ataxia mostly results from degeneration of the dorsal root ganglia neurons, resulting in afferent ataxia.
• Involvement of the cranial nerves may cause dysarthria, vision and hearing loss and dysphagia.
• Neurological signs are:
  • Progressive ataxia of the limbs and gait.
  • Extensor plantar responses.
  • Dysarthria (may begin >5 years after onset).
  • Areflexia.
  • Pyramidal weakness in the lower limbs.
  • Loss of joint position and vibration sense in the lower limbs.
  • Hearing loss and visual disturbance (optic atrophy or nystagmus) are common.

Other clinical features or complications:^1,2

• Orthopaedic - scoliosis and symmetrical pes cavus develop in most patients.
• Hypertrophic cardiomyopathy - left ventricular hypertrophy develops in about 75% of patients and conduction disturbances in 10%.¹ However, cardiac symptoms are relatively rare and occur late in the disease.³
• Optic atrophy occurs in 25-50% of patients.
• Diabetes mellitus develops in 10-20% of patients.
• Hearing loss (usually in the later stages of disease).
• Peripheral cyanosis, oedema and cold feet can be a problem, due to reduced muscle activity.³

Differential diagnosis¹

• Vitamin E deficiency can produce an identical picture - important to diagnose as it is treatable.³
• The differential diagnosis is wide because many diseases can cause early-onset, progressive ataxia with a chronic course.
• Clinical history and investigations should look for toxic, metabolic and immune diseases, paraneoplastic disorders, malformations, posterior fossa tumours, multiple sclerosis and leukodystrophies.
• Friedreich's ataxia cannot be confidently excluded on clinical grounds. However, Friedreich's ataxia is very unlikely in the presence of early prominent cerebellar atrophy, mental retardation, and preserved sensory nerve action potentials.
• Consider other causes of scoliosis or cardiomyopathy (if these are presenting symptoms).

A diagnostic algorithm for chronic, progressive ataxias in childhood is available.¹

Investigation and diagnosis³

Initial investigations:

• Nerve conduction studies show motor velocities >40 ms-1 in arms and absent sensory action potentials.
• Genetic analysis.
• ECG - there may be ventricular hypertrophy and T-wave inversion.
• Exclude vitamin E deficiency.

Further investigations:¹

• Blood tests: full blood count, U&E and glucose
• Echocardiography - may show ventricular hypertrophy, septal hypertrophy and hypertrophic cardiomyopathy.
• MRI scan of the brain and spinal cord - shows characteristic atrophic changes, particularly of the cervical spinal cord.
• Brainstem auditory evoked responses and visual evoked potentials - may be abnormal.
• Genetic counselling and tests - prenatal diagnosis is available. Carrier testing for relatives of affected patients and their partners is also possible.

Staging⁶

The World Federation of Neurology has issued an International Cooperative Ataxia Rating Scale (ICARS). This assesses:

• Posture and gait
• Kinetic function
• Speech disorders
• Oculomotor disorders

The Friedreich's Ataxia Rating Scale is another measure used.⁷

Management^1,3

A multidisciplinary approach is needed. This should include a neurologist, a geneticist, a genetic counsellor, physiotherapists, speech and language therapists, occupational therapists and social workers. Other specialities may be involved for specific problems, e.g. cardiology, orthopaedics and diabetes specialists.

Friedreich's ataxia is a disease with multisystem involvement. Annual reviews should include assessment of neurology, cardiac function, musculoskeletal problems, a comprehensive systems review and blood tests (haematology and monitoring for diabetes).

Specific drug treatment

Most trials so far have focused on antioxidant therapy.

Idebenone:^1,8

• This is a a short chain quinine analogue which acts as a free-radical scavenger. It is a potent antioxidant and electron carrier. It is a synthetic analogue of co-enzyme Q10.
• It is well tolerated.
• A 2009 Cochrane review included only one study (the others did not fulfil the selection criteria); this found that idebenone (5 mg/kg for 12 months) improved left ventricular mass, but had no effect on the ataxia.⁸
• Recent reviews of idebenone used at different doses and in adult and paediatric patients suggest that idebenone might also benefit neurological function (in reducing progression). Further trials are now in progress.^9,10,11

Other potential treatments:

• These include deferiprone (an iron chelator), erythropoietin, pioglitazone and histone deacetylase (HDAC) inhibitors and peroxisome proliferator-activated receptors (PPAR)-gamma agonists.^8,12,13

Supportive treatment^1,3

May include:

• Physiotherapy and mobility aids.
• Speech and language therapy.
• Liaison with educational and social services.
• Treatment of cardiac failure and/or arrhythmias - using standard treatments.
• Orthopaedic surgery if there are troublesome symptoms from scoliosis, pes cavus or equinovarus deformity of feet.
• Foot deformities may also be helped by botulinum toxin or splints.
• Passive exercises and warming for peripheral cyanosis and cold feet.
• Diabetes (if present) will usually require insulin.
• Sphincter dysfunction symptoms, e.g. urgency, should be monitored. Urodynamic assessment and treatments such as oxybutinin may be helpful.
• Sexual dysfunction may require symptomatic treatment.
• Counselling or antidepressants for depression (selective serotonin reuptake inhibitors (SSRIs) are probably the most suitable antidepressant).
• Dysphagia may require dietary modification or (in later stages of disease) gastrostomy.
• Anaesthesia - propofol should probably be avoided.
• Pregnancy - potential complications are cardiac and respiratory impairment, pulmonary embolism and preterm labour. Unusual sensitivity to magnesium sulfate (for pre-eclampsia) has been reported.

Prognosis¹

• Average life expectancy is 40-50 years, but disease severity and progression vary; some patients live into their seventies.
• Loss of ability to walk typically occurs about 15 years after diagnosis.
• The most commonly reported causes of death are cardiac failure and arrhythmias.

Document references

1. Schulz JB, Boesch S, Burk K, et al; Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol. 2009 Apr;5(4):222-34. [abstract]
2. Brice A. Friedreich ataxia. Orphanet encyclopaedia. October 2004.
3. Ataxia UK. Friedreich's ataxia: a guide for the medical profession. Updated 2004.
4. Pandolfo M; Friedreich ataxia. Arch Neurol. 2008 Oct;65(10):1296-303. [abstract]
5. Diehl B, Lee MS, Reid JR, et al; Atypical, perhaps under-recognized? An unusual phenotype of Friedreich ataxia. Neurogenetics. 2010 Feb 17. [abstract]
6. Chawla J; Friedreich Ataxia. eMedicine. May 2010.
7. Lynch DR, Farmer JM, Tsou AY, et al; Measuring Friedreich ataxia: complementary features of examination and performance measures. Neurology. 2006 Jun 13;66(11):1711-6. [abstract]
8. Kearney M, Orrell RW, Fahey M, et al; Antioxidants and other pharmacological treatments for Friedreich ataxia. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007791. [abstract]
9. Tonon C, Lodi R; Idebenone in Friedreich's ataxia. Expert Opin Pharmacother. 2008 Sep;9(13):2327-37. [abstract]
10. Schulz JB, Di Prospero NA, Fischbeck K; Clinical experience with high-dose idebenone in Friedreich ataxia. J Neurol. 2009 Mar;256 Suppl 1:42-5. [abstract]
11. Meier T, Buyse G; Idebenone: an emerging therapy for Friedreich ataxia. J Neurol. 2009 Mar;256 Suppl 1:25-30. [abstract]
12. Tsou AY, Friedman LS, Wilson RB, et al; Pharmacotherapy for Friedreich ataxia. CNS Drugs. 2009;23(3):213-23. doi: 10.2165/00023210-200923030-00003. [abstract]
13. Marmolino D, Acquaviva F; Friedreich's Ataxia: from the (GAA)n repeat mediated silencing to new promising Cerebellum. 2009 Sep;8(3):245-59. Epub 2009 Jan 23. [abstract]

Internet and further reading

• Ataxia UK; A leading charity for people with ataxia
• Friedreich's Ataxia Research Alliance; Information for patients, families and healthcare professionals including summaries of current research.
• Box H, Bonney H, Greenfield J; The patient's journey: the progressive ataxias. BMJ. 2005 Oct 29;331(7523):1007-9.
• Ribai P, Pousset F, Tanguy ML, et al; Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up. Arch Neurol. 2007 Apr;64(4):558-64. [abstract]
• Drake D, Guillory D; Hereditary ataxia. Finding balance. Lancet. 2001 Dec;358 Suppl:S36.

Acknowledgements