Friedreich Ataxia (FA)

Friedreich ataxia (FA) is a progressive, degenerative, multisystem disease associated with mutations in the frataxin gene, FXN.¹ Symptoms of FA typically appear in patients between the ages of 10 and 15 years. Initial symptoms include gait instability and trunk and limb ataxia. Disease progression varies among patients; however, faster progression is linked to an earlier onset of the disease. Patients typically require the use of a wheelchair 11 to 15 years after the initial appearance of symptoms.²

Neurological Features

FA takes noticeable effect on several components of the nervous system, including factors of the large-fiber sensory systems, aspects of the corticospinal motor systems, and features of the cerebellar coordination systems.^1-3

WIthin the large-fiber sensory systems, the development of sensory neuropathy affects proprioception. The perception of position, vibration, temperature, pain, and light touch is compromised or lost in patients with FA.^1,3

In the corticospinal motor systems, degeneration of the pyramidal tracts results in lower-limb weakness, hypotonia, and spasticity. Contractures, spasms, and pain may develop. The Babinski sign is usually present.^1,2

Within the cerebellar coordination systems, ataxia is the result of a combination of spinocerebellar degeneration, peripheral sensory neuropathy, and cerebellar and vestibular pathology. Limb ataxia compromises the ability to perform daily activities. With disease progression, atrophy of the dentate nucleus in the cerebellum causes dysarthria, which is an early sign in more than 90% of patients. In advanced stages of FA, a patient’s speech is often unintelligible.^1,3

Other features of FA include impairment of neural conduction in the central auditory pathways, leading to hearing difficulties. Involvement of the optic nerve causes visual difficulties. Dysphagia may result in aspiration pneumonia.² When small sensory fibers are affected, neuropathic pain may develop. The autonomic fibers to the bladder may also be compromised, causing urinary urgency.¹

Read more about FA signs and symptoms

Cardiological Features

The main cause of death in FA is cardiac dysfunction; the average age of patients at death has been reported to be 36.5 years.² The level of cardiac dysfunction correlates with age at onset.^1,2 Cardiac dysfunction can be identified in patients with disease onset before the age of 18 years.¹

Patients with FA typically present with chronic myocarditis. Abnormalities of the cardiac wall, such as left ventricular hypertrophy, may be also observed.² An electrocardiogram can show T-wave inversion, flattening in lateral or inferior leads, and ST-segment changes.² In advanced stages of the disease, supraventricular tachyarrhythmias and heart failure may occur.^1,2 

Read more about FA complications

Musculoskeletal Features

Most patients with FA have scoliosis, which is typically observed at the time of presentation. The scoliosis may be mild and typically progress until adolescence, resembling the idiopathic form. Although the presentation is variable, unusual aspects, such as a left curve, are more likely in individuals with FA than in those with idiopathic scoliosis. Patients with an early onset of disease may require surgery.¹ Patients with a long GAA repeat length and an early onset of disease may have severe scoliosis, with ataxia presenting later in life.¹

Foot deformities, such as pes cavus and talipes equinovarus, may occur individually or in combination, affecting stability and mobility.^2,3 Talipes equinovarus appears in advanced disease, and patients may require walking aids or orthotic devices.³ In a case series, foot abnormalities were present in 55% to 90% of patients.³

Read more about FA comorbidities

Endocrinological Features

Diabetes mellitus and glucose intolerance can develop in FA. In patients with an early onset of disease, the pathogenic mechanism underlying the development of diabetes appears to be related to pancreatic β-cell insulin deficiency, whereas peripheral insulin resistance seems to play a role in older patients.¹ The presence of abdominal fat may correlate with β-cell dysfunction.²

Read more about FA prognosis

References 

1. Lynch DR, Schadt K, Kichula E, McCormack S, Lin KY. Friedreich ataxia: multidisciplinary clinical care. J Multidiscip Healthc. 2021;14:1645-1658. doi:10.2147/JMDH.S292945

2. Rodríguez LR, Lapeña T, Calap-Quintana P, Moltó MD, Gonzalez-Cabo P, Navarro Langa JA. Antioxidant therapies and oxidative stress in Friedreich’s ataxia: the right path or just a diversion? Antioxidants (Basel). 2020;9(8):664. doi:10.3390/antiox9080664

3. 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

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.