Friedreich ataxia

Friedreich ataxia (FRDA) is the most common inherited ataxia. It is characterised by progressive loss of muscle co-ordination and strength, spasticity and increasing sensory dysfunction, particularly in the lower extremities.

Clinical features may include the below.

• Neurological features:
  • progressive gait and limb ataxia;
  • sensory dysfunction, particularly decreased or loss of proprioception and vibration sense in the lower extremities;
  • pyramidal weakness of the legs;
  • absent lower limb reflexes (areflexia) – though note that reflexes may be retained for some time after disease onset;
  • extensor plantar responses;
  • dysarthria and/or dysphagia; and
  • spasticity leading to contractures.
• Musculoskeletal features:
  • muscle weakness;
  • scoliosis; and
  • foot deformities (pes cavus and talipes equinovarus).
• Cardiac symptoms:
  • hypertrophic nonobstructive cardiomyopathy.
• Endocrine symptoms:
  • glucose intolerance and diabetes mellitus.
• Visual symptoms:
  • fixation instability (square wave jerks);
  • nystagmus; and
  • visual loss (this may occur later in the disease course).
• Hearing symptoms:
  • hearing difficulties or deafness due to auditory neuropathy.
• Urinary symptoms:
  • bladder hyperactivity.

Symptoms usually begin in childhood or adolescence, with disease onset typically occurring before the age of 25. Some individuals present later in adulthood, however, and late-onset (over 25) and very late-onset (over 40) FRDA have both been reported.

The first symptoms are usually gait ataxia or general clumsiness, followed by pyramidal signs, upper limb ataxia and dysarthria.

The rate of progression of symptoms may vary, but the average time from onset of symptoms to wheelchair dependence is 10 to 20 years.

Investigations that can aid diagnosis and management include:

• electromyogram (EMG) and nerve conduction studies (motor nerve conduction velocity over 40m/s and absent or reduced sensory nerve action potential may be evident;
• MRI or CT (imaging may show spinal and cerebellar atrophy);
• electrocardiograms (ECG) or echocardiogram;
• glucose and HbA1c testing; and
• genomic testing, which will provide a conclusive diagnosis.

FRDA is caused by pathogenic variants in the FXN gene, which encodes the frataxin protein. Although the function of frataxin is not fully understood, it is believed to be critical for assembly of iron and sulphur used by many other proteins, including those with roles in energy production. Deficiency in the frataxin protein leads to progressive central and peripheral nervous system damage.

In patients with FRDA, pathogenic variants in both copies of the FXN gene (biallelic variants) are identified. The most common variant in FXN is a triplet repeat expansion of GAA in intron 1, which is found on both alleles in 96% of affected individuals. A normal triple repeat allele size is 6 to 34 repeats, whereas individuals with FRDA may have 67 to 1,700 repeats.

Less commonly, individuals with FRDA can be compound heterozygotes for an intragenic pathogenic variant (point variants or deletions) on one allele and a pathogenic triplet repeat expansion on the other allele.

The GAA repeat size on the shorter allele has been shown in studies to have an inverse correlation with age of onset and duration until wheelchair use, and a positive correlation with cardiomyopathy prevalence. Those who present with late- or very late-onset FRDA may have a shorter GAA repeat size and a milder phenotype than those with typical FRDA. In isolation, allele size is not sufficiently sensitive to predict prognosis for individual patients.

The carrier frequency is around 1:85 in the White population, and is rare in Asian and African populations.

FRDA is an autosomal recessive condition, which means that the parents of most affected individuals are healthy carriers. There is a one-in-four (25%) chance that each additional child the parents have will also be affected. An affected individual can only transmit an expanded allele, which means that all of their children will at least be carriers. The likelihood of their children being affected by the condition depends on the status of their partner, and testing for the expansion in at-risk partners is available, as well as prenatal testing if required.

As with many degenerative neurological conditions, there is currently no cure for FRDA. Management of individuals with FRDA is complex and should be delivered via a multidisciplinary team. Surveillance and symptomatic management, which may help improve an individual’s quality of life, can include:

• physiotherapy, walking aids and wheelchairs to help maintain mobility;
• occupational therapy;
• speech and language therapy for symptoms of dysarthria (dietary modification or percutaneous endoscopic gastrostomy tubes are sometimes needed for dysphagia);
• orthopaedic assessment for scoliosis and foot malformations;
• pharmacologic agents such as baclofen and botulinum toxin for treatment of spasticity and antispasmodics for bladder dysfunction;
• cardiac surveillance (ECG and echocardiograms) and management as required, such as anticoagulants, antiarrhythmics and pacemaker insertion;
• monitoring of blood glucose and HbA1c and management of diabetes mellitus;
• psychological support;
• hearing assessments every two to three years and the provision of hearing devices as required; and
• sleep studies to investigate sleep apnoea and continuous positive airway pressure (CPAP) treatment if required.

Life expectancy can vary depending on age of onset and presence of cardiomyopathy or diabetes. Individuals with FRDA tend to have a shorter life expectancy than the general population, with a mean length of 40 years.

For clinicians

• GeneReviews: Friedreich ataxia
• NHS England: National Genomic Test Directory

References:

• Corben LA, Lynch D, Pandolfo M and others. ‘Consensus clinical management guidelines for Friedreich ataxia’. Orphanet Journal of Rare Diseases 2014: volume 9, page 184. DOI: 10.1186/s13023-014-0184-7

For patients

• Ataxia UK
• Friedreich’s Ataxia Research Alliance
• Muscular Dystrophy Association
• The Brain Charity: Ataxia