Friedreich Ataxia (FA)


Friedreich ataxia (FA), the most common inherited form of ataxia in Europe, is a rare, progressive neurodegenerative disorder that primarily affects the nervous system and heart.1 Characteristics signs of FA are progressive gait and limb ataxia, lower limb areflexia, dysarthria, leg muscle weakness, and a positive Babinski sign (extensor plantar response). The disease also manifests with non-neurological signs, such as hypertrophic cardiomyopathy and diabetes mellitus.1

The symptoms of FA vary widely from person to person and can be similar to those of other neurological conditions (including Charcot-Marie-Tooth disease, ataxia with vitamin E deficiency [AVED], spinocerebellar ataxia with axonal neuropathy [SCAN1], and ataxia telangiectasia), so the path to diagnosis can be challenging.2,3 However, early diagnosis and treatment are crucial for managing the symptoms of FA and slowing its progression.

Physical and Neurological Examination 

A diagnosis of FA requires a careful clinical examination. The patient’s medical history should be reviewed, and a thorough physical and neurological examination should be performed.4 

A full neurological examination will assess balance, gait and standing capacity, muscle weakness and wasting, sphincter disturbances, swallowing difficulties, tendon reflexes, visual disturbances, and loss of joint sensation (proprioception).1,4

Read more about FA clinical features

Genetic Testing for FA Confirmation

Because FA is typically caused by a mutation of the frataxin (FXN) gene, molecular genetic testing is the most reliable method of confirming the diagnosis of FA. The FXN gene encodes the mitochondrial protein frataxin, and in cases of FXN mutations, there is a noted deficiency of the iron-sulfur protein aconitase and the iron-sulfur cluster-containing subunits of mitochondrial electron transport complexes I, II, and III.1 

The mutation most commonly observed in FA is an abnormally expanded GAA repeat in intron 1 of the FXN gene.5 Genetic testing with polymerase chain reaction or Southern blot techniques is usually used to detect these mutations and confirm diagnosis.1,5,6 Carrier testing should be performed in relatives and spouses of individuals with FA, as FA is an inherited autosomal recessive disorder.4 

Read more about FA genetics

Neurophysiology Testing for FA Diagnosis

Because the nervous system is involved in FA, the results of electrophysiological testing are typically abnormal. Motor nerve conduction tests can reveal sensory axonal neuropathy in which the sensory conduction velocities are affected (>40 m/s) and sensory nerve action potentials are reduced or absent.1,6 

Read more about FA signs and symptoms

Neuroimaging for FA Diagnosis

Magnetic resonance imaging (MRI) in a patient with FA shows thinning of the cervical spinal cord and, occasionally, signal abnormalities in the posterior and lateral columns.1 

MRI can be a useful tool in defining a differential diagnosis because an absence of cerebellar atrophy can indicate forms of ataxia other than FA. When cerebellar atrophy does occur in FA, it is in severe and advanced cases. Detection of fractional anisotropy and mean diffusivity on whole-brain quantitative analysis can indicate brainstem and cerebellar white matter degeneration.1

Read more about FA differential diagnosis

Cardiac Function Testing for FA Diagnosis

Patients with FA frequently have cardiac issues that may be severe and lead to disability and premature death, particularly in cases with an early onset.1 Electrocardiography and echocardiography should be performed at diagnosis (and annually thereafter), and a cardiologist should be consulted if the test results are abnormal or the patient has cardiac symptoms.7,8

The cardiac evaluation of a patient with FA includes Holter monitoring to detect supraventricular beats and occasional atrial fibrillation. Both electrocardiography and echocardiography can detect cardiac hypertrophy. Electrocardiography can reveal widespread T-wave inversion, ventricular hypertrophy, conduction disturbances, supraventricular ectopic beats, and atrial fibrillation. Echocardiography can reveal left ventricular hypertrophy with a normal ejection fraction, which is present in approximately 75% of cases.1

Read more about FA complications

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):222-234. doi:10.1038/nrneurol.2009.26

2. Friedreich’s ataxia. Signs & symptoms. National Organization for Rare Disorders. Accessed January 11, 2023.

3. Friedreich’s ataxia. Related disorders. National Organization for Rare Disorders. Accessed January 11, 2023.

4. Friedreich ataxia fact sheet. NIH. National Institute of Neurological Disorders and Stroke. Accessed January 11, 2023.

5. Friedreich’s ataxia. Causes. National Organization for Rare Disorders. Accessed January 11, 2023.

6. Friedreich ataxia. Orphanet. Accessed January 11, 2023.

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

8. 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(1):415. doi:10.1186/s13023-022-02568-3

Reviewed by Harshi Dhingra, MD, on 1/16/2023.