Friedreich’s Ataxia

Friedreich’s Ataxia

Friedreich’s Ataxia (FA) is the most common inherited ataxia in the UK, affecting an estimated 1 in 50,000 people. It is a progressive, neurodegenerative, multi-system disorder that typically begins in childhood or adolescence.

 

Genetics and Pathophysiology

FA is an autosomal recessive condition caused by a GAA trinucleotide repeat expansion in the FXN gene on chromosome 9q13. Both parents must be carriers for a child to be affected. The expansion leads to reduced production of a protein called frataxin, which is crucial for mitochondrial function. The deficiency in frataxin causes nerve cells and other tissues, particularly those with high energy demands, to degenerate.

  • Genetic Diagnosis: A blood test to detect the GAA trinucleotide repeat expansion is the gold standard for a conclusive diagnosis. The length of the shorter GAA repeat is inversely correlated with the age of onset and disease severity.

 

Clinical Features

The disease is progressive, with symptoms typically presenting between ages 5 and 15 years. The initial symptom is usually gait ataxia.

  • Neurological:

    • Gait Ataxia: The most common initial symptom, characterised by a clumsy, unsteady walk.

    • Limb Ataxia: Poor coordination of voluntary movements in the arms and hands, leading to difficulty with fine motor tasks.

    • Dysarthria: Slurred, slow speech.

    • Loss of Reflexes: Absent lower limb reflexes (areflexia) is a key diagnostic sign.

    • Sensory Impairment: Progressive loss of proprioception (body position sense) and vibration sensation, particularly in the lower limbs.

    • Pyramidal Weakness: Weakness in the legs, which can lead to spasticity over time.

  • Musculoskeletal:

    • Scoliosis: Curvature of the spine, which is highly prevalent and may require surgical intervention in severe cases.

    • Foot Deformities: Such as pes cavus (high arches) or clubfoot.

  • Cardiac:

    • Hypertrophic Cardiomyopathy: A key feature, occurring in up to 80% of patients. It is the leading cause of death in FA.

    • Arrhythmias: Such as atrial flutter and heart block.

  • Other Associated Conditions:

    • Endocrine: Diabetes mellitus and glucose intolerance.

    • Ophthalmic: Optic atrophy leading to vision loss.

    • Auditory: Hearing loss or deafness.

    • Bladder: Urinary frequency or urgency.

    • Fatigue: A common and often debilitating symptom.

 

Management and Recent Developments

There is currently no cure for Friedreich’s Ataxia. Management is symptomatic, multidisciplinary, and aims to maximise quality of life and slow disease progression.

  • Multidisciplinary Care:

    • Neurology: Regular follow-up with a paediatric neurologist is essential for monitoring progression and managing symptoms.

    • Cardiology: All patients with FA require regular cardiac screening with an echocardiogram and ECG to detect cardiomyopathy and arrhythmias.

    • Physiotherapy: Crucial for maintaining mobility, strength, and balance, and for preventing contractures.

    • Orthopaedics: For the management of scoliosis and foot deformities.

    • Other: Speech and language therapy for dysarthria and dysphagia; audiology and ophthalmology for hearing and vision issues.

  • Recent Developments in Treatment:

    • Omaveloxolone (Skyclarys™): The UK’s Medicines and Healthcare products Regulatory Agency has approved Omaveloxolone for patients aged 16 and over. This is a major breakthrough as it is the first licensed treatment for FA. It works by activating the Nrf2 pathway, which helps cells respond to oxidative stress. It has been shown to slow neurological decline. The National Institute for Health and Care Excellence (NICE) approval is awaited for NHS availability. A global Phase 3 trial for children aged 2-15 is also underway.

    • Other Treatments: Clinical trials are ongoing for other potential therapies, including gene therapies to restore frataxin protein production and drugs like vatiquinone, which may delay the loss of walking ability in children.