Friedreich Ataxia (FA)

Friedreich ataxia (FA) is an inherited neurodegenerative disease that mainly affects the nervous system, musculoskeletal system, and the heart.^1,2 FA is caused by genetic defects in the FXN gene, which is responsible for the production of frataxin, a protein involved in mitochondrial adenosine triphosphate (ATP) production and regulation of iron homeostasis. Frataxin can be found in higher concentration in the nervous system, in the heart, and in pancreatic beta cells.²

Signs and symptoms of FA vary from individual to individual, ranging from mild to severe. They typically involve problems with coordination, balance, and heart function, muscle weakness, and loss of proprioception.^2,3 Symptoms usually start when patients are between 5 to 15 years old, and the first neurological signs of FA appear frequently around puberty.^1,4 Non-neurological symptoms, such as scoliosis and pes cavus, can be present before the manifestation of neurological symptoms.¹

Neurological and neuromuscular symptoms

The typical presenting neurological symptom of FA is ataxia, which refers to a loss of coordination when walking. Patients also present with issues of balance and dysmetria.^2,3 Individuals with FA may have difficulty walking, standing, and performing other motor tasks.² They may experience muscle weakness in the legs and arms, which can make it difficult to perform daily activities. As the muscle weakness progresses, spasticity can also be observed.^2-5 As fine motor coordination becomes impaired, patients have difficulties with the precise movement of small muscles, such as of the hands, fingers, and toes.³ 

Some individuals with FA may also experience impaired proprioception, with a loss of sensation in the limbs.³ Perception of pain, light touch, and temperature may be also affected, and reduced or absent leg reflexes can be reported.⁵ A positive Babinski sign may point to damage of the corticospinal tract.³

Dysarthric speech, which progresses from slow to incomprehensible, follows cerebellar involvement. Dysphagia begins as the muscles involved in swallowing weaken.^2,3 Patients can report hearing loss following auditory neuropathy, and visual impairment due to the loss of optic tract fibers.^2,6

Read more about FA clinical features

Musculoskeletal symptoms

Scoliosis is another common presenting symptom of FA, and can be observed in up to two-thirds of FA patients.^4,7 Patients present other skeletal abnormalities, such as pes cavus and talipes equinovarus.⁷ These deformities can have a significant impact in the daily life of patients.⁵

Read more about FA surgical management

Cardiac symptoms

Friedreich ataxia is strongly associated with cardiomyopathy, as cardiac dysfunction occurs in nearly 75% of patients with FA. These abnormalities can have a wide range of severity, and many defects are only noticeable by testing. However, heart failure remains the leading cause of death in FA.^5,7

Patients with FA are prone to hypertrophic cardiomyopathy, which can lead to heart failure and abnormal heart rhythms. These conditions can be life-threatening.⁵ Cardiac symptoms experienced by FA patients derive from hypertrophic cardiomyopathy, myocardial fibrosis, and heart failure, and include chest pain, palpitations, shortness of breath, extreme fatigue, lightheadedness, and pooling of blood in the ankles.^4,5

Read more about FA diagnosis

Other signs and symptoms

FA patients may develop carbohydrate intolerance and diabetes mellitus due to frataxin deficiency in the pancreas and consequent decrease of insulin production.⁵ Diabetes is most often developed after many years following the first symptoms of the disease, and patients may require treatment with insulin.^6,7

Read more about FA comorbidities

References

 1. Schulz JB, Boesch S, Bürk K, et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol. 2009;5(4):222-34. doi:10.1038/nrneurol.2009.26

2. Williams CT, De Jesus O. Friedreich Ataxia. StatPearls [Internet]. Updated September 05, 2022. Accessed January 25, 2023

3. Friedreich ataxia symptoms. Genetic and Rare Diseases Information Center (GARD). Accessed January 25, 2023

4. Friedreich Ataxia Fact Sheet. National Institute of Neurological Disorders and Stroke. Accessed January 25, 2023

5. Friedreich’s Ataxia (FA) Signs and Symptoms. Muscular Dystrophy Association. Accessed January 25, 2023

6. 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

7. Cook A, Giunti P. Friedreich’s ataxia: clinical features, pathogenesis and management. Br Med Bull. 2017;124(1):19-30. doi:10.1093/bmb/ldx03

Reviewed by Harshi Dhingra, MD, on 1/29/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.