Friedreich Ataxia (FA)

Friedreich ataxia (FA), an inherited neuromuscular condition, is characterized by progressively worsening impairment of muscle coordination (ataxia); muscle weakness and spasticity; and impairments of proprioception, vibration sensation, vision, hearing, and speech. Common disease-related comorbidities include hypertrophic cardiomyopathy, diabetes mellitus, and scoliosis.¹

A diagnosis of FA requires not only a careful clinical examination, but extensive testing, including laboratory testing, imaging studies, neurological testing, cardiac testing, and genetic testing.

Laboratory Testing for FA

Frataxin Levels

Frataxin deficiency due to mutations in the FXN gene is the underlying cause of FA. Analysis of levels of frataxin protein in specimens of whole blood can detect rare variants of FA that may be missed on molecular trinucleotide repeat genetic testing.²

Iron, Zinc, and Copper

The evidence regarding blood testing for iron, zinc, and copper in patients with FA is conflicting. Some studies indicate that total iron and zinc levels do not differ significantly from normal,³ whereas others provide evidence that mean total free iron levels in the plasma of patients with FA (measured with the Nitro PAPS and Dibrom PAESA method) are significantly lower than those in healthy controls (6.2 ± 3.8 vs 15.2 ± 4.2).⁴ Both studies mention that levels of free copper are lower in patients with FA than in normal individuals.^3,4 

The researchers suggest that low levels of iron and copper are likely due to frataxin insufficiency, which leads to increased iron and copper deposition in the brain and cardiac cells.⁴

Read more about FA pathophysiology

Glucose Levels

Blood and urine tests assess for hyperglycemia and glycosuria to diagnose diabetes mellitus.⁵ Patients with FA are at increased risk for the development of disease-related diabetes, especially those who have cardiac complications or severe symptoms of FA and those who are older with a long duration of disease.⁶

Read more about FA complications

Cerebrospinal Fluid Analysis

Some sources report that the results of cerebrospinal fluid (CSF) testing do not provide any diagnostic evidence of FA,² whereas others describe potential biomarkers of FA in the CSF.⁷ In a recently published study that analyzed protein levels in CSF to identify potential biomarkers of FA, 7 differentially expressed proteins (DEPs) were over-represented and 6 were under-represented in CSF samples obtained via lumbar puncture from patients with FA in comparison with samples from healthy controls. The 7 over-represented proteins included SORCS3, PKM, FAM174A, PRCP, GPX3, NBL1, and SCG5; the 6 under-represented proteins included CNDP1, CD14, C3, C9, ISLF, and NRXN2.⁷

SORCS3 and SCG5 are found predominantly in the brain and correlate with neurodegeneration. The other 5 over-represented proteins are found in various tissues with metabolic, developmental, protease, and antioxidant roles.⁷

The under-represented proteins correlate with neuroinflammation as well as neurodegenerative disease. They are involved in the complement cascade, protein phosphorylation, insulin-like growth factor (IGF) regulation, extracellular matrix organization, and various signaling pathways.⁷

Imaging Studies for FA

Magnetic resonance imaging (MRI) of the brain and spinal cord reveals atrophic changes in the cervical spinal cord, cerebellum, and cerebrum.^8,9 Images of the cervical spinal cord may reveal a reduced anteroposterior diameter (thinning),⁸ reflecting the loss of myelinated nerve fibers and gliosis in the posterior and lateral columns.⁹

Diffusion-weighted imaging (DWI) may make it possible to quantify the extent of neurodegeneration in patients with FA, including microstructural involvement of the medulla, brainstem, thalamus, pallidus, caudate, putamen, dentate nucleus, corpus callosum, pyramidal tracts at posterior limb of internal capsule, cerebellar hemispheres, cerebellar vermis, optic radiations, and superior, middle, and inferior cerebellar peduncles.¹⁰

Transcranial sonography reveals hyperechogenicity of the dentate nucleus in approximately 85% of patients with FA, even those with a relatively short duration of disease, indicating that changes in the dentate nucleus occur early in the disease process. Additionally, the substantia nigra demonstrates hyperechogenicity on transcranial sonography, indicating regional changes in subcellular iron regulation in the brain.^8,11

Read more about FA prognosis

Cardiac Testing for FA

Given that disease-related hypertrophic cardiomyopathy develops in a substantial percentage of patients with FA, cardiac tests such as electromyography, echocardiography, electrocardiography, and cardiac MRI are recommended in all patients with a diagnosis of FA.^5,12,13 Cardiac complications are the leading cause of mortality in individuals with FA; two-thirds die of congestive heart failure or cardiac arrhythmias.¹⁴ 

Echocardiography, used to evaluate cardiac systolic and diastolic function and cardiac morphology,¹² often identifies symmetrical concentric ventricular hypertrophy in patients with FA, although asymmetric septal hypertrophy may be seen in some cases.^13,14

Electrocardiography reveals tachycardia or atrial fibrillation.¹⁴ Frequent findings in patients with FA include ventricular hypertrophy and T-wave inversion, especially in the inferior standard and lateral chest leads.¹³

Read more about FA comorbidities

Neurological Testing for FA

The results of nerve conduction velocity studies are often normal, or the conduction velocities are mildly reduced; however, sensory nerve action potentials (SNAPs) are absent in more than 90% of patients with FA, and reduced-amplitude SNAPs are seen in the remaining cases.¹³

Noninvasive confocal microscopy of the skin measures the density of Meissner corpuscles and epidermal nerve fibers and determines quantitative thresholds for sensory testing, which provide useful information about the structural and physiological markers of sensory involvement and disease progression in FA.^13,15

Brainstem auditory testing often shows an absence of waves III and IV with preservation of wave I, suggesting involvement of the central auditory pathways.^13,14

Visual evoked potential abnormalities are seen in approximately two-thirds of patients with FA, particularly absent or delayed latency and reduced amplitude of the p100 wave.^13,14

Somatosensory evoked potentials exhibit a delayed central conduction time, abnormal central motor conduction, and dispersion of potentials at the sensory cortex.¹³

In terms of clinical testing, the sensitivity of spatial position sense (SPS) is greater than that of joint position sense (JPS) and vibration sense (VS), allowing deficits to be detected earlier. The SPS findings correlate with the severity of ataxia. These findings indicate that ataxia and proprioceptive impairment occur earlier in FA and tend to be more severe than is suggested by routine clinical testing.^13,16

Read more about FA clinical features

Genetic Testing for FA

Genetic testing analyzes the FXN gene sequence to assess for mutations that cause FA, the most common of which is the guanine-adenine-adenine (GAA) trinucleotide repeat expansion.^5,14 DNA for testing is obtained through blood samples.⁵ Prenatal direct mutation testing can also be performed to confirm the presence of FA in a developing fetus that is at risk.^5,14 Genetic testing is a reliable method of confirming a definitive diagnosis of FA.⁵

Read more about FA genetics

References

1. Friedreich ataxia. MedlinePlus. Accessed January 14, 2023.
2. Friedreich ataxia, frataxin, quantitative, blood. Mayo Clinic Laboratories. Accessed January 14, 2023.
3. Chawla J. Friedreich ataxia workup: laboratory studies. Medscape. Updated May 4, 2021. Accessed January 14, 2023.
4. Pathak D, Srivastava AK, Gulati S, Rajeswari MR. Assessment of cell-free levels of iron and copper in patients with Friedreich’s ataxia. Biometals. 2019;32(2):307-315. doi:10.1007/s10534-019-00186-4
5. Diagnosis of Friedreich’s ataxia. Friedreich’s Ataxia News. Accessed January 14, 2023.
6. Tamaroff J, DeDio A, Wade K, et al. Friedreich’s ataxia related diabetes: epidemiology and management practices. Diabetes Res Clin Pract. 2022;186:109828. doi:10.1016/j.diabres.2022.109828
7. Imbault V, Dionisi C, Naeije G, Communi D, Pandolfo M. Cerebrospinal fluid proteomics in Friedreich ataxia reveals markers of neurodegeneration and neuroinflammation. Front Neurosci. 2022;16. doi:10.3389/frins.2022.885313
8. Chawla J. Friedreich ataxia workup: imaging studies. Medscape. Updated May 4, 2021. Accessed January 14, 2023.
9. Bell D. Friedreich ataxia. Radiopaedia. Updated July 1, 2019. Accessed January 14, 2023. 
10. Rizzo G, Tonon C, Valentino ML, et al. Brain diffusion-weighted imaging in Friedreich’s ataxia. Move Disord. 2011;26(4):705-712. doi:10.1002/mds.23518
11. Synofzik M, Godau J, Lindig T, Schöls L, Berg D. Transcranial sonography reveals cerebellar, nigral, and forebrain abnormalities in Friedreich’s ataxia. Neurodegener Dis. 2011;8(6):470-475. doi:10.1159/000327751
12. Kvistholm Jensen M, Bundgaard H. Cardiomyopathy in Friedreich ataxia. Circulation. 2012;125(13):1591-1593. doi:10.1161/CIRCULATIONAHA.112.095364
13. Chawla J. Friedreich ataxia workup: other tests. Medscape. Updated May 4, 2021. Accessed January 14, 2023.
14. Williams CT, De Jesus O. Friedreich ataxia. StatPearls [Internet]. Updated September 5, 2022. Accessed January 14, 2023. 
15. Creigh PD, Mountain J, Sowden JE, et al. Measuring peripheral nerve involvement in Friedreich’s ataxia. Ann Clin Transl Neurol. 2019;6(9):1718-1727. doi:10.1002/acn3.50865
16. Borchers S, Synofzik M, Kiely E, Himmelbach M. Routine clinical testing underestimates proprioceptive deficits in Friedreich’s ataxia. Cerebellum. 2013;12(6):916-922. doi:10.1007/s12311-013-0508-5

Reviewed by Debjyoti Talukdar, MD, on 1/27/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.