Friedreich Ataxia (FA)

Friedreich ataxia (FA) is a genetic disease with an autosomal-recessive inheritance pattern. Symptoms usually start in childhood or early adolescence, mostly in persons between the ages of 8 and 15 years.^1,2 

Nikolaus Friedreich, a professor of medicine in Heidelberg, Germany, originally described FA, a progressive neurodegenerative condition, in 1863.³ The disease manifests as muscle weakness, difficulty walking, slurred speech, and loss of proprioception and sensation. The cerebellar region of the brain, peripheral nerves, and spinal cord are affected.^2,4 

Epidemiology of FA

FA is the most common of the inherited ataxias and occurs at the same rate in both sexes.⁵ The disease affects 1 in 50,000 Americans and mainly persons of western European ancestry. The worldwide prevalence is 1 in 40,000. FA is most often seen in South Asia, North Africa, the Middle East, and Europe.² 

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Etiology of FA

FA is caused by a loss-of-function mutation in the frataxin gene (FXN) on the centromeric region of chromosome 9q (9q13-21.1). Affected individuals have an abnormal number of  guanine-adenine-adenine (GAA) trinucleotide repeats on the FXN gene, which codes for the protein frataxin. Frataxin controls adenosine triphosphate (ATP) synthesis and iron homeostasis in mitochondria. The pathologic trinucleotide repeats in FA result in gene silencing and a decline in frataxin levels. Highly active cells that depend on ATP production, such as cardiomyocytes, neurons, and pancreatic beta cells, are therefore severely affected.^1,2 

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Clinical Presentation of FA

Progressive ataxia of the limbs during ambulation is the main symptom of FA. Ataxia is characterized by impaired muscle coordination resulting in poor control of fine movements of the limbs and unsteady gait. Slow loss of strength and sensation in the arms and legs, muscle stiffness or spasticity, and impairment of speech, hearing, and vision are other symptoms of FA. Intellect is usually spared. Foot deformities or lateral curvature of the spine (scoliosis) may also occur.^1,6 

Hypertrophic cardiomyopathy, in which the heart muscle is enlarged and weakened, develops in approximately half of patients with FA and can be fatal. Medical complications, such as diabetes mellitus, also occur in some patients. Because FA has no cure, the clinical symptoms worsen, and after initially using walking aids, people with FA eventually require a wheelchair for mobility.^1,6

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Classic Presentation of FA

FA is diagnosed in most patients before the age of 25, with symptoms typically beginning at or before puberty. The most frequent presenting symptoms are gait ataxia and generalized clumsiness.^1,7

Atypical Presentations of FA 

Late-Onset FA (LOFA) and Very Late-Onset FA (VLOFA)

Two subtypes of atypical FA are seen in approximately 15% of cases: LOFA and VLOFA. The age at onset of LOFA is between 26 and 39 years, whereas the age at onset for VLOFA is 40 years or older. Usually, a patient’s condition progresses more slowly in these subtypes compared to classic or typical FA.¹ 

FA with retained reflexes (FARR)

Approximately 12% of individuals with FA have FARR. Tendon reflexes can last for up to 10 years after they first appear in these cases.^1,7

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Diagnosis of FA

A diagnosis of FA requires a medical history and physical examination. Specific tests for FA diagnosis can include the following^2,4,8:

• Genetic testing is the backbone of an evaluation for FA. FA is the only disorder characterized by pathological GAA repeats, and a trinucleotide repeat expansion assay is available to detect these. Direct mutation testing is a method of prenatal testing.
• A complete medical history and physical examination should be conducted to look for signs of neurological problems, loss of proprioception, lack of reflexes, balance problems, and other symptoms.
• Blood tests should be performed to look for an increase in levels of glucose and vitamin E. 
• Modalities such as magnetic resonance imaging and computed tomography can obtain images of the brain and spinal cord and exclude various neurological diseases.
• Nerve conduction studies, in which electrical impulses are used to measure nerve activity, can reveal sensory axonal neuropathy. 
• Echocardiography is helpful to detect symmetrical, concentric ventricular hypertrophy. Some cases show asymmetrical septal hypertrophy. 

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Treatment of FA

A complete cure for this disease is not available. FA treatment is mainly supportive, consisting of the management of symptoms and complications, including diabetes mellitus and heart failure. The most effective approach is multidisciplinary, given that the illness affects various organ systems. The patient is advised to remain under continuous medical care to prevent complications.^1,2 

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Physical and Occupational Therapy

Physical therapy is recommended to slow disease progression and maintain function. Strengthening posture and promoting muscle use are the 2 main objectives of physical therapy. The focus of occupational therapy is on retaining independence through techniques such as transfers, mobility, “safe fall” measures, and mobility aids.² 

Medical Devices

Orthopedic footwear, avoidance of tight clothing, and the correct use of ambulatory aids like canes, wheelchairs, and orthoses have all been found to improve mobility, reduce muscular spasticity, and prevent the development of scoliosis and other deformities.²

Medication

The main goals of medication therapy are to control infection, treat heart failure, and manage pain.² 

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Genetic Counseling 

Genetic counseling is advised for patients and their families.¹  

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Surgery

When necessary, surgery may be considered for treating foot deformities and kyphoscoliosis. An automated implantable cardioverter-defibrillator can be placed when required. Heart transplant has been undertaken in patients with mild FA but severe cardiomyopathy.² 

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Prognosis of FA

FA has a dismal prognosis overall. Most patients are wheelchair-bound by 45 years of age. The mean duration of the disease is 15 to 20 years. The average age at death is 36.5 years (range, 12 to 87 years). Nearly two-thirds of patients die from a form of cardiac dysfunction, most frequently congestive heart failure or an arrhythmia.^2,9 

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References

1. Friedreich’s ataxia. National Organization for Rare Disorders. Updated February 15, 2018. Accessed January 12, 2023. 
2. Williams CT, De Jesus O. Friedreich ataxia. StatPearls [Internet]. Updated September 5, 2022. Accessed January 12, 2023.
3. Chawla J. Friedreich ataxia. Medscape. Updated May 4, 2021. Accessed January 12, 2023.
4. Friedreich’s ataxia. Johns Hopkins Medicine. Accessed January 12, 2023. 
5. Friedreich ataxia. Physiopedia. Accessed January 12, 2023.
6. Friedreich’s ataxia. MedlinePlus. Accessed January 12, 2023. 
7. Parkinson MH, Boesch S, Nachbauer W, Mariotti C, Giunti P. Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J Neurochem. 2013;126(Suppl 1):103-17. doi:10.1111/jnc.12317
8. Friedreich ataxia fact sheet. NIH. National Institute of Neurological Disorders and Stroke. Accessed January 12, 2023.
9. Chawla J. Friedreich ataxia follow- up. Medscape. Updated May 4, 2021. Accessed January 12, 2023.

Reviewed by Hasan Avcu, MD, on 1/28/2023.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.