Friedreich's Ataxia (FRDA)

Friedreich's ataxia is the most common inherited progressive ataxia in the UK.¹ It was first described in 1863 by Nikolaus Friedreich, a german physician. It is characterised by problems with balance, coordination and commonly slurring of speech. The inheritance is autosomal recessive.

The prevalence is 1/50,000 in Caucasian populations. It is rare in sub-Saharan Africans and does not exist in the Far East.²

The gene disorder is a mutation in a gene locus on chromosome 9.² This results in decreased synthesis of a protein called frataxin, essential for mitochondrial function including oxidative phosphorylation and iron homeostasis. Mitochondrial iron accumulation is thought to occur. This has been implicated in mitochondrial abnormalities, oxidant damage and cell death.^3,4,5 There is progressive degeneration of the dorsal root ganglia, spinocerebellar tracts, corticospinal tracts and Purkinje cells of the cerebellum. Loss of cells in the nuclei of cranial nerves VIII, X, and XII causes facial weakness and speech and swallowing problems.

Myocardial muscle fibres undergo degeneration, become hypertrophied and lose their striations.³ Spinal muscle imbalance can lead to scoliosis.

• Usually presents before adolescence.
• Average age of onset is 15 years but symptoms can start as early as 2 years.¹
• Late-onset presentation is possible with some cases presenting after the age of 30 or even 40 years. This tends to have a lower occurrence of skeletal deformities and slower disease progression.^2,6

Symptoms

• Gait problems (usually the presenting symptom, slow and clumsy walking, difficulty standing and running)
• Difficulty writing
• Difficulty performing activities of daily living
• Slurred speech
• Swallowing problems
• Hearing problems
• Visual disturbance

Signs²

• Incoordination of limb movements (both lower limbs are usually affected equally and first with arms later)
• Ataxic gait - both sensory ataxia (loss of joint position sense results in a steppage gait where there is uneven and irregular striking of the floor by the bottom of the feet) and cerebellar ataxia (wide based gait). There is difficulty turning.
• Dysarthria - speech is slurred and slow
• Nystagmus
• Reduced or absent tendon reflexes
• Positive Babinski sign (extensor plantar responses)
• Impairment of joint position sense
• Impairment of vibration sense
• Sensory neuropathy
• Action and intention tremors can develop as the disease progresses
• Progressive motor weakness of the lower limbs occurs, leading to inability to walk. Arm weakness occurs in advanced disease. Ataxic head movements (titubation) can occur in advanced disease.
• Dysphagia
• Reduced visual acuity
• Deafness
• Cognitive dysfunction
• Emotional lability
• Chorea occurs rarely

• Diabetes mellitus develops in 10%³
• Hypertrophic cardiomyopathy develops in > 50%³
• Optic atrophy occurs in 25%³
• Deafness occurs in < 10%
• Scoliosis in 85%
• Pes cavus in 50%
• Hammer toe

• Other forms of inherited ataxias
• Spinocerebellar ataxia
• Hereditary motor and sensory neuropathies

• Genetic studies: There are assays available that can show if the gene mutation is present. Carrier testing for relatives of affected patients and their partners is available.
• MRI of the brain and spinal cord: This shows characteristic atrophic changes, particularly of the cervical spinal cord.
• Echocardiography: This may show ventricular hypertrophy, septal hypertrophy and hypertrophic cardiomyopathy.
• ECG changes: There may be evidence of ventricular hypertrophy and t wave inversion.
• Nerve conduction studies: Sensory nerve conduction velocities are abnormal while motor nerve conduction is normal or mildly reduced.⁷
• Brainstem auditory evoked responses and visual evoked potentials: These may be abnormal.
• Prenatal diagnosis: DNA markers can be used to allow prenatal diagnosis.

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

A total ataxia score marked out of 100 is given. The Friedreich Ataxia Rating Scale is another measure used.⁸

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. Referral to a cardiologist is necessary if there is cardiomyopathy. An orthopaedic surgeon should be consulted to manage scoliosis or pes cavus.¹ Specific treatment of cardiac failure, arrhythmias and diabetes mellitus is needed.

Specific drug treatment

There is no proven specific drug treatment. Various drugs have been trialled experimentally including 5-hydroxytryptophan and recombinant human erythropoietin⁹ but most trials so far have focussed on antioxidant therapy.

Coenzyme Q, an antioxidant, and its analogue, idebenone, have been shown to reduce cardiac hypertrophy¹⁰ but their effects on cardiac and neurological function are unclear.^11,12 In one study, treatment with idebenone decreased cardiac hypertrophy but cardiac and neurological function did not improve.¹³ In another study, treatment with combined coenzyme Q and vitamin E showed a slowing of progression of certain clinical features and a significant improvement in cardiac function.¹⁴

Gene therapy

Recently, research has been carried out using viral vector delivery of frataxin cDNA in Friedreich's ataxia fibroblast cell lines. The results showed increased mitochondrial iron and sensitivity to oxidant stress with evidence of expression of the frataxin protein and partial reversal of phenotype.¹⁵

• Prognosis is generally poor.
• Kyphoscoliosis, if severe, can lead to significant respiratory problems and death.
• Cardiomyopathy can lead to cardiac arrhythmias, cardiac failure and death.
• Inability to walk typically occurs by 15 years after diagnosis. > 95% are wheelchair bound by age 45 years.
• Some people have survived into their 50s and 60s but usually patients die at 25-30 years old.³