Friedreich Ataxia (FA)


Friedreich ataxia (FA) is a neurological condition with autosomal recessive inheritance, characterized by the progressive failure of coordination of the extremities and trunk, spasticity, absence of lower extremity reflexes, dysarthria, and impaired proprioception, vision, and hearing. Although very rare, FA is the most common inherited form of progressive ataxia, occurring in approximately 1 in every 29,000 individuals of Caucasian ancestry.1,2

During the past 2 decades, clinical guidelines for the diagnosis and management of FA have been published by several organizations, including:

  • The EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood, published in 2014 by The European Federation of Neurological Societies (EFNS) and European Neurological Society (ENS) in 20143 (and since merged to form the European Academy of Neurology [EAN])4;
  • The Guidelines on the diagnosis and management of the progressive ataxias, published in 2019 by the Guideline Development Group, comprising more than 30 health professionals in the United Kingdom (UK) and representatives of the patient support organization Ataxia UK1; and 
  • Clinical management guidelines for Friedreich ataxia: best practice in rare diseases, published in 2022 by the Clinical Management Guidelines Writing Group, consisting of 70 expert clinicians using the Grading of Recommendations Assessment and Evaluation (GRADE) framework.2

The 2022 guidelines from the Clinical Management Guidelines Writing Group were based on the 2014 consensus clinical management guidelines written by several of the same authors.2,5 Similarly, the 2019 clinical management guidelines from the United Kingdom panel improved upon earlier versions published in 2007 and 2009, which did not assess the quality of the evidence supporting the recommendations.1

Diagnosis Guidelines for FA

A diagnosis of FA requires a thorough clinical examination, a comprehensive family medical history, and a workup that may include blood tests, neuroimaging, a lumbar puncture, nerve conduction studies, and genetic testing with next-generation sequencing (NGS).1,3 

In particular, age at onset and speed of symptom progression are important factors in the diagnosis of FA.1 Classic recessive ataxias such as FA sometimes manifest very late, even after the age of 50 years,3 although the onset most often is in children between the ages of 5 and 15.6 FA is the predominant recessive ataxia in Europe and the United States.3

If a recessive ataxia such as FA is suspected on the basis of the family medical history, an assessment of the noncerebellar features may help guide the workup and sort possible differential diagnoses. If cerebellar ataxia is accompanied by marked spasticity, it is essential to rule out both autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and spastic paraplegia. If severe saccades and chorea are present, ataxia with oculomotor apraxia type 2 (AOA2) and ataxia telangiectasia should be ruled out.3

Read more about FA differential diagnosis

Blood Tests for FA Diagnosis

The initial blood tests obtained by a primary care physician may include a complete blood cell count; measurement of the levels of creatinine, urea and electrolytes, C-reactive protein, liver enzymes, vitamin B12, folate, glucose, and ɣ-glutamyltransferase; and measurement of the erythrocyte sedimentation rate.1

Secondary care diagnostic testing may include measurement of the levels of copper/ceruloplasmin, lactate, creatine kinase, albumin, cholesterol, cholestanol, vitamin E, and ⍶-fetoprotein.1,3 Copper levels are often significantly reduced in individuals with FA.7 

Following this investigation, the primary care physician should immediately refer an adult with ataxia to a neurologist and a child with ataxia to a pediatric neurologist for more specialized diagnostic testing.1 Additionally, the neurologist should consult with a geneticist to arrange appropriate genetic testing.1

Read more about FA diagnosis

Neurologic Workup for FA Diagnosis

Neuroimaging, especially magnetic resonance imaging (MRI) of the brain and spinal cord, can detect atrophy of the cervical spinal cord with minimal cerebellar atrophy.8 

The 2014 EFNS/ENS guidelines recommended MRI of the brain as the first neurological diagnostic step in patients with chronic ataxia. MRI reveals structural or acquired causes of ataxia and can provide data suggestive of a heredodegenerative ataxia.3

A lumbar puncture is often performed to rule out conditions of inflammatory origin, including multiple sclerosis and anti-glutamic acid decarboxylase (anti-GAD)-related ataxia.3 No cerebrospinal fluid abnormalities are detected on lumbar puncture in patients with FA.7 

Nerve conduction studies and electromyography identify the presence of peripheral neuropathy and distinguish between axonal and demyelinating conditions.3

Referral to a neuro-ophthalmologist is recommended to rule out other conditions potentially contributing to ataxia, such as cataracts, retinitis pigmentosa, and cherry red spots.3

Read more about FA testing

Genetic Testing for FA Diagnosis

After a diagnosis has been established, targeted molecular genetic testing, aimed at identifying a mutation of the frataxin (FXN) gene, can confirm the diagnosis of FA.3 This mutation causes an abnormal repetition in a triplet sequence of DNA on the FXN gene, vastly limiting the amount of the protein frataxin produced by each cell.6 A specific trinucleotide repeat expansion assay is commercially accessible in the United States and can provide molecular confirmation of clinically suspected FA.7

Best practice recommendations to be followed before genetic testing include offering the patient genetic counseling to discuss the implications of the test results and obtaining the patient’s consent. If a test result indicates the presence of an FXN gene mutation, all future reproductive choices made by the patient and family members should be informed with further genetic counseling.1

Genetic counseling should also be offered to asymptomatic individuals, such as family members, who are at risk. Physical examinations and cardiac testing should be the first-line of assessment, and genetic testing can be considered on a case-by-case basis.1

Read more about FA genetics

Guidelines for the Monitoring and Management of FA 

Cardiac Management of FA

Given that cardiac complications are frequent in FA, all patients should undergo electrocardiography and echocardiography after a diagnosis of FA and annually thereafter. Additionally, individuals with FA who have palpitations should undergo 24-hour Holter monitoring or Loop monitoring to rule out arrhythmias. Referral to a cardiologist is recommended if a patient with FA has cardiac symptoms and abnormal cardiac test results.2

Read more about FA complications

Neurological Management of FA

Cognitive Impairment

It is recommended that cognitive dysfunction in a patient with FA not be treated with active neuromodulation, such as transcranial magnetic stimulation (TMS) or transcranial direct-current stimulation (tDCS).2

Auditory and Vestibular Impairment

Individuals with FA should undergo auditory and vestibular assessments annually or more often depending on symptoms.2

Vision Impairment

Individuals with FA whose vision is worse than 20/200 in each eye should be evaluated by a low vision specialist who can provide low-vision aids and help them register their visual disability.1,2 Treatment for nystagmus or oscillopsia, usually with baclofen or gabapentin, is recommended. An optometrist or neuro-ophthalmologist should use prisms to treat diplopia.1 

Dysphagia 

Patients who have FA with dysphagia should receive expert counseling on dysphagia management, with an emphasis on compensatory strategies to improve safety, and they should be educated about the specific mechanisms of dysphagia in the degenerative ataxias. On the basis of available evidence, the Clinical Management Guidelines Writing Group does not recommend either dietary modification/fluid thickening or no dietary modification to improve swallowing safety.2 

Behavioral therapy and neuromuscular electrical stimulation are not recommended for the treatment of dysphagia in FA.2

Dysarthria

Interventions should focus on improving the communication skills of listeners and caregivers rather than on treating dysarthria in FA because strong evidence of the efficacy of treatment is lacking. Such interventions include focusing attention during conversations, communicating in a quiet environment, and devising strategies to ameliorate communication breakdowns.2

Spasticity 

Patients with FA should undergo an assessment for spasticity, pain, spasms (including nocturnal spasms), and the onset of contractures or established contractures to guide treatment decision making. Acute factors that may aggravate spasticity and/or ataxia, such as pain, infection, diarrhea, constipation, dehydration, and pressure sores, must be addressed immediately.2

Patients with FA should be informed of the potential for increased muscle weakness and gait deterioration following anti-spasticity interventions. The first recommendation for the treatment of spasticity is physical therapy, including strengthening, stretching, serial casting, and standing machine stretches.2 

These interventions can also be used to assess the efficacy of pharmacological treatments for FA, including localized treatment with botulinum toxin for focal spasticity, or as a basis for recommending systemic pharmacotherapy with agents including baclofen, tizanidine, gabapentin, dantrolene sodium, benzodiazepines, and others.1,2 Neuromodulation is not recommended.2 Surgery should be considered only when physical therapy and pharmacological treatments have been ineffective.1

Dystonia

Botulinum toxin injections are recommended for focal dystonia. Oral medications followed by surgery are recommended for generalized dystonia.1 Physical therapy and oral medications are recommended for dystonic tremor. Surgery is recommended if physical therapy and oral medications are ineffective.1 

Tremors

Pharmacological treatments, such as propranolol, primidone, propranolol/primidone, topiramate, clonazepam, and gabapentin, are recommended (they are listed in order of preference) to treat tremor. Functional neurosurgery should be considered if tremor is debilitating and does not respond to pharmacological treatments.1

Read more about FA prognosis

Musculoskeletal Management of FA

Scoliosis

Routine assessment for the development of scoliosis, particularly in children with FA, is recommended to enable prompt treatment. Referrals to a physical therapist and spinal surgeon are recommended if scoliosis is detected. Bracing for mild scoliosis and surgical intervention for severe scoliosis should be considered. Routine follow-up with the surgeon after spinal surgery is recommended.1

Ambulation 

Physical therapy to improve balance, strength, and mobility and to reduce falls is recommended so that ambulant mobility can be maintained for as long as possible. Patients should be instructed in the use of gait aids, and during and after the transition to full-time wheelchair use, it is essential that they maintain the capacity to transfer safely and independently for as long as possible.2

Upper Extremity Rehabilitation 

Intensive upper limb rehabilitation is recommended conditionally and may facilitate the transition to wheelchair use by preserving the strength needed for transfer.2

Read more about FA treatment

Urogenital Management of FA

Frequent evaluation to detect urinary tract infections and prostate enlargement, as well as to ensure patient adherence to pelvic floor exercises, is recommended. Overactive bladder should be treated with antimuscarinic medications (tolterodine, oxybutynin, propiverine, and solifenacin).1 

Patients should receive practical advice on reducing caffeine, alcohol, and carbonated beverage consumption; education on timed voiding and bladder retraining; and counseling regarding adherence to customized recommendations for fluid intake.1

Sexual dysfunction should be identified and treated because of the potential complication of erectile dysfunction (ED) in men with FA. Phosphodiesterase-5 inhibitors are recommended for the treatment of ED.1

Read more about FA comorbidities

References

  1. de Silva R, Greenfield J, Cook A, et al. Guidelines on the diagnosis and management of the progressive ataxias. Orphanet J Rare Dis. 2019;14:51. doi:10.1186/s13023-019-1013-9
  2. Corben LA, Collins V, Milne S, et al. Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. Orphanet J Rare Dis. 2022;17:415. doi:10.1186/s13023-022-02568-3
  3. van de Warrenburg BPC, van Gaalen J, Boesch S, et al. EFNS/ENS consensus on the diagnosis and management of chronic ataxias in adulthood. Eur J Neurol. 2014;21(4):552-562. doi:10.1111/ene.12341
  4. Grisold W. ENS + EFNS = EAN. World Neurology Online. Accessed January 7, 2023.
  5. Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB; Clinical Management Guidelines Writing Group. Consensus clinical management guidelines for Friedreich ataxia. Orphanet J Rare Dis. 2014;9:184. doi:10.1186/s13023-014-0184-7
  6. Friedreich ataxia fact sheet. National Institute of Neurological Disorders and Stroke. Accessed January 7, 2023.
  7. Chawla J. Friedreich ataxia workup: laboratory studies. Medscape. Updated May 4, 2021. Accessed January 7, 2023.
  8. Chawla J. Friedreich ataxia workup: imaging studies. Medscape. Updated May 4, 2021. Accessed January 7, 2023.

Reviewed by Harshi Dhingra, MD, on 1/15/2023.