Friedreich Ataxia (FA)

Friedreich ataxia (FA) is an autosomal recessive genetic disease caused by guanine-adenine-adenine (GAA) triplet repeat expansion in the frataxin (FXN) gene. The disorder is a progressive neurodegenerative illness resulting in degeneration of the spinal cord and peripheral nerves. The incidence of FA in the United States and Europe is around 1 in 40,000.¹ 

Although up to 25% of patients experience disease onset in adulthood, the condition usually begins in childhood or adolescence. Symptoms include dysarthria, sensory loss (especially proprioception and vibration), ataxia, difficulty walking, weakness, absent reflexes, high-arched feet, and hearing or visual issues. It is linked to diabetes, scoliosis, and heart disease, including cardiomyopathy and arrhythmias. FA has no impact on cognitive ability. Life expectancy may be reduced, particularly in people who have concomitant cardiac disease.¹ 

During diagnosis, it is important to rule out conditions that may present with similar features, as the signs and symptoms of FA can resemble those of other early-onset, progressive ataxias. However, the genetic profile and distinctive cardinal symptoms of FA can help differentiate it from other diseases.² 

Spinocerebellar Ataxia Types 1, 2, and 3 

Spinocerebellar ataxia (SCA) is a clinically and genetically diverse group of more than 40 progressive ataxia disorders, mostly with an autosomal dominant inheritance pattern. These diseases occur due to a translated cytosine-adenine-guanine (CAG) repeat expansion mutation.³

Early-onset ataxia, cerebellar atrophy, spasticity, facial and limb dystonias, epilepsy, hearing loss, ophthalmoplegia, oculomotor apraxia, sensorimotor polyneuropathy, and cognitive impairment are characteristics of SCA. Imaging reveals distinct typical characteristics of cerebellar atrophy, distinguishing it from FA.⁴

Read more about FA testing

Dentatorubral-Pallidoluysian Atrophy

Clinical manifestations of dentatorubral-pallidoluysian atrophy can resemble other familial degenerative or acquired ataxic diseases.⁵

Disease manifestations include myoclonus, choreoathetosis, epilepsy, ataxia, behavioral variations, and intellectual impairments. The intellectual, behavioral, and psychiatric symptoms differentiate the disease from FA.⁴

Chronic Inflammatory Demyelinating Polyneuropathy

A rare neurological condition known as chronic inflammatory demyelinating polyneuropathy causes inflammation of the peripheral nerves and nerve roots, as well as the breakdown of the lipid sheath that protects nerve fibers from damage.⁶ 

Sensorimotor peripheral neuropathy and symmetrical weakening of the distal and proximal muscles are symptoms of the illness. The presence of inflammation on lumbar puncture distinguishes it from FA.⁴ 

Read more about FA clinical features

Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth type 1 (CMT1) is a demyelinating peripheral neuropathy, and Charcot-Marie-Tooth type 2 (CMT2) is an axonal (nondemyelinating) peripheral neuropathy.⁷ 

CMT can present in childhood with areflexia, clumsiness, and minimal distal muscle weakness. In children with FA who do not display dysarthria or extensor plantar responses, it is difficult to rule out a diagnosis of CMT based only on clinical manifestations. CMT can be inherited in autosomal dominant, autosomal recessive, or X-linked forms.⁷ 

The Roussy-Levy variant of CMT is an autosomal dominant disease that causes ataxia and areflexia. The inheritance pattern and dysmyelination (as opposed to axonal neuropathy in FA) in this disease differentiates it from FA.⁴

CAPOS

CAPOS stands for cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. It is an autosomal dominant neurological febrile disease that manifests in early childhood with repeated episodes of acute ataxic encephalopathy.⁸ 

Genetic testing helps to differentiate it from FA. CAPOS disease shows a single mutation (E818K) of the ATP1A3 gene on chromosome 19q13.⁴ 

Read more about FA genetics

Episodic Ataxia

This rare type of hereditary ataxia is characterized by episodes of ataxia with minimal or no other symptoms when patients are not experiencing an episode.⁴ 

The episodes, which can last anywhere from minutes to hours, are typically brought on by specific triggers, such as sudden movement, stress, exercise, caffeine, or alcohol. As a person ages, episodic ataxia symptoms may go away, though occasionally the condition progressively worsens.⁹ The disease history helps to differentiate it from FA.⁴ 

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) occurs due to a mutation in the SACS gene.⁴ 

The disease is characterized by a triad of early spasticity, sensorimotor peripheral neuropathy, and cerebellar ataxia.¹⁰ It is differentiated from FA on brain magnetic resonance imaging (MRI), which shows the involvement of the pons in this disease. Compared to ARSACS, FA has a later onset, the presence of cardiomyopathy, the absence of hypermyelinated retinal fibers, and no white matter lesions on MRI.^4,10

Read more about FA etiology

Abetalipoproteinemia (Bassen-Kornzweig Syndrome)

Bassen-Kornzweig syndrome is an autosomal recessive disease caused by a mutation in the microsomal triglyceride transfer protein (MTTP) gene. Because of the gene abnormality, the body has difficulty effectively digesting fat and other essential vitamins.^4,11 

Disease manifestations include low cholesterol and triglyceride levels, the absence of serum beta lipoprotein, peripheral neuropathy, retinal degeneration, and ataxia. Abnormal lipid levels and improvements in neurological symptoms following the administration of fat-soluble vitamins help to differentiate this disease from FA.^4,11 

Drug-Induced Ataxia

Temporary or persistent ataxia that may have cerebellar or sensory causes can be driven by drugs and toxins.¹² 

A wide-based and unsteady gait, poor dexterity, aberrant eye movements (nystagmus), scanning dysarthria, or a combination of these symptoms may indicate cerebellar ataxia.¹² Patient history and normalization of disease symptoms when the offending drug or toxin is removed aids in the differentiation of this disease from FA.⁴ 

Ataxia With Vitamin E Deficiency

Ataxia with vitamin E deficiency (AVED) occurs due to biallelic pathogenic variants in TTPA, which encodes the alpha-tocopherol transfer protein.⁴ 

Patients with AVED meet the diagnostic criteria for FA, but they often experience manifestations like titubation and hyperkinesia more frequently than in FA. Patients with AVED also cardiomyopathy less frequently than patients with FA. The differentiation between these two diseases is very significant as AVED is effectively treated with continuous and lifelong vitamin E supplementation. AVED can be differentiated from FA by the low levels of vitamin E and improvements in neurological abnormalities following vitamin E supplementation seen in this disease.^4,7

Read more about FA treatment

Ataxia-Telangiectasia

Ataxia-telangiectasia is an autosomal recessive disorder that occurs due to a mutation in the ATM gene.⁴ 

The disease features include progressive cerebellar ataxia, a deficient immune system, abnormal eye movements, oculocutaneous telangiectasias, and other neurological problems. The disease is differentiated from FA as patients with this disease exhibit increased alpha-fetoprotein levels.⁴ 

Refsum Disease

Refsum disease is an autosomal recessive disease caused by a mutation in the PHYH gene. 

The disease is characterized by increased phytanic acid levels, sensorineural hearing loss, sensorimotor polyneuropathy, retinitis pigmentosa, ichthyosis, and cerebellar ataxia. The elevation in phytanic acid levels and disease improvements upon dietary restriction help to differentiate this disease from FA.⁴ Refsum disease is also usually associated with progressive sensorineural hearing loss.¹³ 

Read more about FA prognosis

References

1. Adams J, Barbano RL. Friedreich ataxia. VisualDx. Updated April 11, 2022. Accessed January 27, 2023.
2. Friedreich’s ataxia. Physiopedia. Accessed January 27, 2023.
3. Jacobi H, Hauser TK, Giunti P, et al. Spinocerebellar ataxia types 1, 2, 3 and 6: the clinical spectrum of ataxia and morphometric brainstem and cerebellar findings. Cerebellum. 2012;11(1):155-166. doi:10.1007/s12311-011-0292-z 
4. Williams CT, De Jesus O. Friedreich ataxia. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated September 5, 2022. Accessed January 27, 2023.
5. Rocha Cabrero F, De Jesus O. Dentatorubral pallidoluysian atrophy. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated September 21, 2022. Accessed January 27, 2023.
6. Chronic inflammatory demyelinating polyneuropathy. National Organization for Rare Disorders (NORD). Updated January 4, 2021. Accessed January 27, 2023.
7. Bidichandani SI, Delatycki MB. Friedreich ataxia. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews^® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2023. December 18, 1998. Updated June 1, 2017. Accessed January 27, 2023. 
8. Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss; CAPOS. Online Mendelian Inheritance in Man (OMIM). July 9, 1996. Updated February 1, 2021. Accessed January 27, 2023. 
9. Types: ataxia. National Health Service (NHS). Accessed January 27, 2023.
10. Vermeer S, van de Warrenburg BP, Kamsteeg EJ, Brais B, Synofzik M. ARSACS. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews^® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2023. December 9, 2003. Updated January 2, 2020. Accessed January 27, 2023.
11. Bassen-Kornzweig syndrome. MedlinePlus. Accessed January 27, 2023.
12. Vermilion J, Osborne C, Barbano RL. Drug-induced ataxia. VisualDx. Updated October 28, 2021. Accessed January 27, 2023.
13. Waterham HR, Wanders RJA, Leroy BP. Adult Refsum disease. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews^® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2023. March 20, 2006. Updated September 30, 2021. Accessed January 27, 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.