|Synonyms||Spinocerebellar ataxia, Friedreich, FDRA, FA|
|Symptoms||lack of coordination, balance issues, gait abnormality|
|Complications||cardiomyopathy, scoliosis, diabetes|
|Usual onset||5-15 years|
Friedreich's ataxia, or FDRA, is an autosomal recessive inherited disease that causes progressive damage to the nervous system. It is the most common inherited ataxia, affecting approximately 1 in 29,000 individuals. FDRA manifests in initial symptoms of poor coordination such as gait disturbance; it can also lead to scoliosis, heart disease and diabetes, but does not affect cognitive function. The disease is progressive, and in most cases a wheelchair is required for mobility.
The particular genetic mutation (expansion of an intronic GAA triplet repeat in the FXN gene) leads to reduced expression of the mitochondrial protein frataxin. Over time this deficiency causes the aforementioned damage, as well as frequent fatigue due to effects on cellular metabolism.
The ataxia of Friedreich's ataxia results from the degeneration of nervous tissue in the spinal cord, in particular sensory neurons essential (through connections with the cerebellum) for directing muscle movement of the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath (the insulating covering on some nerve cells that helps conduct nerve impulses).
- 1 Signs and symptoms
- 2 Genetics
- 3 Pathology
- 4 Diagnosis
- 5 Treatment
- 6 Prognosis
- 7 Clinical research
- 8 Treatment strategies proven to be inefficient
- 9 Epidemiology
- 10 History
- 11 References
- 12 External links
Signs and symptoms
Symptoms typically begin sometime between the ages of 5 to 15 years, but in Late Onset FA may occur in the 20s or 30s. Symptoms include any combination, but not necessarily all, of the following:
- Muscle weakness in the arms and legs
- Loss of coordination
- Vision impairment
- Hearing impairment
- Slurred speech
- Curvature of the spine (scoliosis)
- High plantar arches (pes cavus deformity of the foot)
- Diabetes (about 20% of people with Friedreich's ataxia develop carbohydrate intolerance and 10% develop diabetes mellitus)
- Heart disorders (e.g., atrial fibrillation, and resultant tachycardia (fast heart rate) and hypertrophic cardiomyopathy)
It presents before 22 years of age with progressive staggering or stumbling gait and frequent falling. Lower extremities are more severely involved. The symptoms are slowly progressing. Long-term observation shows that many patients reach a plateau in symptoms in the patient's early adulthood. On average, after 10–15 years with the disease, patients lose the ability to stand or walk without assistance. However, disease progression is variable, and some patients may still be ambulatory decades after onset, while others require the use of a wheelchair within a few years.
The following physical signs may be detected on physical examination:
- Cerebellar: nystagmus, fast saccadic eye movements, truncal ataxia, dysarthria, dysmetria.
- Lower motor neuron lesion: absent deep tendon reflexes.
- Pyramidal: extensor plantar responses, and distal weakness are commonly found.
- Dorsal column: Loss of vibratory and proprioceptive sensation occurs.
- Cardiac involvement occurs in 91% of patients, including cardiomegaly (up to dilated cardiomyopathy), symmetrical hypertrophy, heart murmurs, and conduction defects.
Friedreich's ataxia is an autosomal recessive disorder that occurs when the FXN gene on chromosome 9 contains amplified intronic GAA repeats (an example of Trinucleotide repeat expansion). The FXN gene encodes the protein frataxin. GAA repeat expansion causes frataxin levels to be reduced and long tracts of GAA repeats induce chromosome breaks in (in vivo yeast studies). Frataxin is an iron-binding protein responsible for forming iron–sulphur clusters. One result of frataxin deficiency is mitochondrial iron overload which can cause damage to many proteins. The exact role of frataxin in normal physiology remains unclear.
The mutant gene contains expanded GAA triplet repeats in the first intron; in a few pedigrees, point mutations have been detected. Because the defect is located in an intron (which is removed from the mRNA transcript between transcription and translation), this mutation does not result in the production of abnormal frataxin proteins. Instead, the mutation causes gene silencing (i.e., the mutation decreases the transcription of the gene) through induction of a heterochromatin structure in a manner similar to position-effect variegation.
The primary site of pathology is in the spinal cord and peripheral nerves. Sclerosis and degeneration of dorsal root ganglion, spinocerebellar tracts, lateral corticospinal tracts, and posterior columns. The motor neurons of the spinal cord are spared. In peripheral nerves there is a loss of large myelinated fibres.
Progressive destruction of dorsal root ganglia accounts for thinning of dorsal roots, degeneration of dorsal columns, transsynaptic atrophy of nerve cells in Clarke's column and dorsal spinocerebellar fibers, atrophy of gracile and cuneate nuclei and neuropathy of sensory nerves. The lesion of the dentate nucleus consists of progressive and selective atrophy of large glutamatergic neurons and grumose degeneration of corticonuclear synaptic terminals that contain gamma-aminobutyric acid (GABA). Small GABA-ergic neurons and their projection fibers in the dentato-olivary tract survive. Atrophy of Betz cells and corticospinal tracts constitute a second lesion.
Low frataxin levels lead to insufficient biosynthesis of iron–sulfur clusters that are required for mitochondrial electron transport and assembly of functional aconitase and iron dysmetabolism of the entire cell. In normal individuals, the FXN gene encodes frataxin, a mitochondrial matrix protein. This globular protein consists of two α helices and seven β strands and is highly conserved, occurring in all eukaryotes and some prokaryotes. Frataxin has a variety of known functions. Frataxin assists iron-sulfur protein synthesis in the electron transport chain to ultimately generate adenosine triphosphate (ATP), the energy molecule necessary to carry out metabolic functions in cells. Frataxin also regulates iron transfer in the mitochondria for providing a proper amount of reactive oxygen species (ROS) to maintain normal processes. Without frataxin, the energy in the mitochondria falls, and excess iron causes extra ROS to be created, leading to further cell damage.
Mitochondrial DNA (mtDNA) is especially exposed to attack by ROS since it is located within the mitochondria. Because several enzymes of the electron transport chain are encoded in mtDNA, ROS-induced damage to mtDNA may cause further increases in ROS production and oxidative stress. Elevated levels of DNA double-strand breaks have been reported in Friedreich’s ataxia patient fibroblasts and fibroblasts from a mouse model of Friedreich’s ataxia. Using a lentivirus gene delivery system to deliver the frataxin gene to Friedreich’s ataxia patient and mouse model cells, it was possible to obtain long-term over-expression of frataxin mRNA and frataxin protein levels. This over-expression was associated with a substantially reduced level of DNA double-strand breaks. It appears that frataxin is normally involved in the repair of DNA damage, which may be important for preventing neurodegeneration.
A diagnosis of Friedreich's ataxia requires investigation of the medical history and a thorough physical examination, in particular looking for balance difficulty, loss of proprioception, an absence of reflexes, and signs of other neurological problems. Genetic testing provides a conclusive diagnosis. Other tests that may aid in the diagnosis or management of the disorder include:
- Electromyogram (EMG), which measures the electrical activity of muscle cells
- Nerve conduction studies, which measure the speed with which nerves transmit impulses
- Electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart
- Echocardiogram, which records the position and motion of the heart muscle
- Blood tests to check for elevated glucose levels and vitamin E levels
- Magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions
Therapeutic strategies and disease insight have expanded rapidly over recent years, providing new opportunities for disease relief.
Rehabilitation therapy is a cornerstone of present-day ataxia therapy and there is evidence that this therapy improves symptoms in the short-term and that, with continued exercise, benefits can be maintained long-term.
Physical therapy should consist of intensive motor coordination, balance, and stabilization training. To address the ataxic gait pattern and loss of proprioception typically seen in persons with Friedreich’s ataxia, physical therapists can use visual cueing during gait training to help facilitate a more efficient gait pattern. Frenkel exercises and PNF techniques were developed to improve proprioception and have been shown to be effective in ataxic patients. Low intensity strengthening exercises should also be incorporated to maintain functional use of the upper and lower extremities. Stabilization exercises of the trunk and low back can help with postural control and the management of scoliosis, especially if the person is non-ambulatory and requires the use of a wheelchair. Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities. Other goals can be set according to the needs and wishes of the patient, including increased transfer and locomotion independence; muscle strengthening; increased physical resilience; “safe fall” strategy; learning to use mobility aids; learning how to reduce the body’s energy expenditure; and developing specific breathing patterns.
Outside of therapy, patients should be encouraged to keep up continuous coordination and balance training to preserve gains. Balance and coordination training using visual feedback can be incorporated into activities of daily living. Exercises should reflect functional tasks such as cooking, transfers and self-care. The focus is to preserve the patient's level of functioning: if a person is able to walk, they should do it as much as possible.
Video game therapy, or exergaming, is a promising new tool for the treatment of FDRA. Physiotherapy exercises complemented by whole-body and coordinative training on commercially available video game technology have been found to be beneficial for both early onset and advanced, multisystem degenerative ataxia patients. Video game-based training involves motivational reward incentives and stimulating exercise environments that can stimulate and train patients’ real-world activities and anticipatory coordination capacities. Many patients find video games to be a convenient, cost-effective, and motivational way to engage in rehabilitation exercises.
Patients also often undertake speech therapy since dysarthria (a motor speech disorder) occurs in almost all Friedreich's ataxia patients. However, the dysarthria is not always ataxic and the dysarthria can be mixed. The speech intelligibility in speakers with dysarthria and Friedreich's Ataxia can be mild to severely reduced. Speech therapy seeks to improve speech outcomes and/or compensate for communication deficits. Dysphagia (difficulty swallowing) is also a common symptom of Friedreich's ataxia, and speech therapy can support patients to eat and drink in a safer way.
Good quality, well-fitted orthoses can support normal joint alignment, promote correct posture, stabilize joints during walking, and improve range of motion. This is important to help manage spasticity, and to prevent foot deformities and scoliosis.
Wearable proprioceptive stabilizers like the Equistasi are neurological rehabilitation devices meant to exert focal mechanical vibration on muscles and joints. Research indicates that this may improve limb and gait ataxia in patients affected by FDRA and similar conditions.
Orthopedic shoes have been shown to improve gait in ambulatory individuals. In severe cases in which the rehabilitation treatment applications are insufficient, use of supportive devices enables the patient to function more easily within the present functional level. As progression of ataxia occurs, assistive devices such as a cane, walker, or wheelchair may be required for mobility and independence. Other assistive technology, such as a standing frame, can help reduce the secondary complications of prolonged use of a wheelchair.
Although there are not yet any curative pharmacological therapies for Friedreich's Ataxia, many of its side effects respond well to medication. In particular, the cardiac abnormalities associated with Friedreich's Ataxia can often be controlled with ACE inhibitors such as enalapril, ramipril, lisinopril or trandolapril, sometimes used in conjunction with beta blockers. Patients who have already developed symptomatic heart failure might be prescribed eplerenone or digoxin to keep it under control.
Patients with Friedreich's Ataxia may require some surgical interventions with the aim to help the patient maintain functional independence for as long as possible.
If physical and pharmacological interventions have proven ineffective, surgical solutions may be considered to correct deformities caused by abnormal muscle tone. Titanium screws and rods inserted in the spine help prevent or slow the progression of scoliosis. In patients suffering from the equinus deformity, surgically lengthening the Achilles tendon has been shown to improve independence and mobility.
Patients experiencing severe heart failure that does not respond to maximal medical management may be considered for implantation of an automated implantable cardioverter-defibrillator or, in some cases, a cardiac transplant.
Every patient has a particular form of evolution of the disease. In general, patients who were younger at diagnosis, and those who have longer GAA triplet expansions, tend to have more severe symptoms. Studies investigating FRDA have often provided inconclusive and contradicting results arising from inhomogeneity in trial populations, nonvalidated measures used in older studies, and low availability of study participants It is hoped that the use and development of model clinical instruments and technologies such as computerized gait monitoring, speech evaluation, and imaging along with molecular indices will add precision and new avenues for capturing ataxic symptoms and physiologic functions, thereby resulting in more precise and extended measurement of disease progression.
A further confounding factor is that treatments that affect the course of the disease are continuously being developed. Where decline to complete disability was once thought to be inevitable, recent research proves that a period of inpatient rehabilitation may reverse or halt the downward decline in function seen in most patients and that, with continued exercise, benefits can be maintained indefinitely.
The estimated life expectancy has been found to be about 40-50 years. Congestive heart failure and cardiac arrhythmia are the leading cause of death.However, some people with less severe features of FDRA live into their sixties or older.
There is currently no FDA-approved disease-modifying agent to correct Friedreich's Ataxia at the genetic or cellular level, and much research has been focused on discovering such an agent.
RG2833, a histone deacetylase inhibitor developed by Repligen, was acquired by BioMarin Pharmaceutical in January 2014. A phase Ib clinical trial with RG2833 has been successfully completed in 2014 and research continues.
Protection of cells from damage with the use of deuterated compounds has been attempted by Retrotope. Its first drug RT001 is a deuterated synthetic homologue of ethyl linoleate, a polyunsaturated fatty acid (11,11-D2-ethyl linoleate). Polyunsaturated fatty acids (PUFAs)are essential nutrients which are the major component of lipid membranes, particularly in mitochondria. Their high susceptibility to oxidation by reactive oxygen species through the chain reaction can be substantially reduced by the replacement of hydrogen (H) atoms with the isotope deuterium (D), yielding D-PUFAs. RT001 has been compared with non-deuterated linoleic acid ethyl ester in a randomized, double-blind, controlled trial in 18 FRDA patients for 4 weeks. Primary endpoints were safety, tolerability, and pharmacokinetics. Secondary endpoints included the FARS, a timed foot-walk test and cardiopulmonary exercise testing. The study met its primary safety and tolerability endpoints. An improvement in peak workload and VO2 max in the RT001 group compared to placebo, as well as a positive trend in the neurological scales in the drug group were detected, thus further development is planned.
Research in gene therapy is another treatment under development. One study in mouse models showed that gene replacement therapy completely reversed the cardiac symptoms of Friedreich's Ataxia at the functional, cellular, and molecular levels. This provides a promising outlook in the future treatment of Friedreich's ataxia.
Treatment strategies proven to be inefficient
Nicotinamide (vitamin B3) represents was found effective in preclinical FA models and well-tolerated by FA patients. An open-label, dose-escalation study demonstrated that higher doses boosted frataxin expression and attenuated abnormal heterochromatin, but failed to establish any clinical benefit in a study of 12 months. The trial is being extended.
A Cochrane review on treatment of patients with Friedreich ataxia with antioxidants concluded that there is limited but not persuasive evidence of efficacy. An antioxidant Idebenone was removed from the Canadian market in 2013 due to lack of effectiveness.
Horizon Pharma's development plan of interferon gamma-1B for treatment of FA was given fast track designation by the Food and Drug Administration in 2015. However, in the Phase 3 trial released in December 2016, the results did not meet primary endpoints.  The trial is to be repeated with new endpoints.
Friedreich's ataxia is the most prevalent inherited ataxia, affecting about 1 in 50,000 people in the United States. Males and females are affected equally. The estimated carrier prevalence is 1:110.
A 1984 Canadian study was able to trace 40 cases of classical Friedreich's disease from 14 French-Canadian kindreds previously thought to be unrelated to one common ancestral couple arriving in New France in 1634: Jean Guyon and Mathurine Robin.
Epidemiological data shows that prevalence of Friedriech's ataxia follows patterns in the prevalence of haplogroup R1b. Both are more common in northern Spain, Ireland and France, rare in Russia and Scandinavia, and both follow a gradient through central and eastern Europe. This data provides an image of the prehistory of Friedreich's ataxia; a population carrying the disease went through a population bottleneck in the Franco-Cantabrian region during the last ice age. The correlation also provides a useful tool for predicting the prevalence of Friedreich's ataxia.
Friedreich, working as a professor of pathology at the University of Heidelberg, reported five patients with the condition in a series of three papers in 1863. Further observations appeared in a subsequent paper in 1876.
Friedreich's ataxia was first linked to a GAA repeat expansion on chromosome 9 in 1996.
- "Friedreich ataxia clinical management guidelines". Friedreich Ataxia Research Alliance (USA). 2014. Retrieved 23 October 2018.
- synd/1406 at Who Named It?
- Thoren C (June 1962). "Diabetes mellitus in Friedreich's ataxia". Acta Paediatrica. Supplementum. 135: 239–47. doi:10.1111/j.1651-2227.1962.tb08680.x. PMID 13921008.
- Pandolfo M (March 2009). "Friedreich ataxia: the clinical picture". Journal of Neurology. 256 Suppl 1 (1 Suppl): 3–8. doi:10.1007/s00415-009-1002-3. PMID 19283344.
- Klockgether T (August 2011). "Update on degenerative ataxias". Current Opinion in Neurology. 24 (4): 339–45. doi:10.1097/WCO.0b013e32834875ba. PMID 21734495.
- Marmolino D (June 2011). "Friedreich's ataxia: past, present and future". Brain Research Reviews. 67 (1–2): 311–30. doi:10.1016/j.brainresrev.2011.04.001. PMID 21550666.
- Montermini L, Andermann E, Labuda M, Richter A, Pandolfo M, Cavalcanti F, Pianese L, Iodice L, Farina G, Monticelli A, Turano M, Filla A, De Michele G, Cocozza S (August 1997). "The Friedreich ataxia GAA triplet repeat: premutation and normal alleles". Human Molecular Genetics. 6 (8): 1261–6. doi:10.1093/hmg/6.8.1261. PMID 9259271.
- Friedreich Ataxia at eMedicine
- Delatycki MB, Williamson R, Forrest SM (January 2000). "Friedreich ataxia: an overview". Journal of Medical Genetics. 37 (1): 1–8. doi:10.1136/jmg.37.1.1. PMC 1734457. PMID 10633128.
- Pandolfo M (October 2008). "Friedreich ataxia". Archives of Neurology. 65 (10): 1296–303. doi:10.1001/archneur.65.10.1296. PMID 18852343.
- Sahdeo S, Scott BD, McMackin MZ, Jasoliya M, Brown B, Wulff H, Perlman SL, Pook MA, Cortopassi GA (December 2014). "Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia". Human Molecular Genetics. 23 (25): 6848–62. doi:10.1093/hmg/ddu408. PMC 4245046. PMID 25113747.
- Khonsari H, Schneider M, Al-Mahdawi S, Chianea YG, Themis M, Parris C, Pook MA, Themis M (December 2016). "Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts". Gene Ther. 23 (12): 846–856. doi:10.1038/gt.2016.61. PMC 5143368. PMID 27518705.
- "Friedreich's Ataxia Fact Sheet". National Institute of Neurological Disorders and Stroke. This article incorporates text from this source, which is in the public domain.
- Aranca TV, Jones TM, Shaw JD, Staffetti JS, Ashizawa T, Kuo SH, Fogel BL, Wilmot GR, Perlman SL, Onyike CU, Ying SH, Zesiewicz TA (Feb 2016). "Emerging therapies in Friedreich's ataxia". Neurodegenerative Disease Management. 6 (1): 49–65. doi:10.2217/nmt.15.73. PMC 4768799. PMID 26782317.
- Powers, Wendy (2007-01-01). "Holding Steady: How physical therapy can help patients with Friedreich's Ataxia". Advance. 18 (1): 26. Archived from the original on 2011-07-26. Retrieved 2011-05-16.
- "Facts About Friedreich's Ataxia (FA)". Muscular Dystrophy Association. 2011. Archived from the original on 2011-09-27. Retrieved 2011-05-16.
- Chien H, Barsottini O (10 December 2016). Movement Disorders Rehabilitation. Springer, Cham. pp. 83–95. ISBN 978-3-319-46062-8.
- Vogel AP, Folker J, Poole ML (October 2014). "Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes". The Cochrane Database of Systematic Reviews. 10 (10): CD008953. doi:10.1002/14651858.CD008953.pub2. PMID 25348587.
- Vogel AP, Brown SE, Folker JE, Corben LA, Delatycki MB (February 2014). "Dysphagia and swallowing-related quality of life in Friedreich ataxia". Journal of Neurology. 261 (2): 392–9. doi:10.1007/s00415-013-7208-4. PMID 24371004.
- Leonardi L, Aceto MG, Marcotulli C, Arcuria G, Serrao M, Pierelli F, Paone P, Filla A, Roca A, Casali C (March 2017). "A wearable proprioceptive stabilizer for rehabilitation of limb and gait ataxia in hereditary cerebellar ataxias: a pilot open-labeled study". Neurological Sciences. 38 (3): 459–463. doi:10.1007/s10072-016-2800-x.
- Ojoga F, Marinescu S (2013). "Physical Therapy and Rehabilitation for Ataxic Patients". Balneo Research Journal. 4 (2): 81–84. doi:10.12680/balneo.2013.1044.
- Michele GD, Filla A (October 2015). "Friedreich ataxia today—preparing for the final battle". Nature Reviews Neurology. 11: 188–190.
- "Demographic and clinical features and rehabilitation outcomes of patients with Friedreich ataxia: A retrospective study" (PDF). y Turkish Society of Physical Medicine and Rehabilitation. 64 (3): 230–238. January 2018. doi:10.5606/tftrd.2018.2213.
- "BioMarin Announces Agreement With Repligen for Pre-clinical Compounds (NASDAQ:BMRN)". Investors.bmrn.com. 2014-01-21. Archived from the original on 2015-07-05. Retrieved 2015-07-04.
- Bürk K (2017). "Friedreich Ataxia: current status and future prospects". Cerebellum & Ataxias. 4: 4. doi:10.1186/s40673-017-0062-x. PMC 5383992. PMID 28405347.
- Indelicato E, Bosch S (2018). "Emerging therapeutics for the treatment of Friedreich's ataxia". Expert Opinion on Orphan Drugs. 6: 57–67. doi:10.1080/21678707.2018.1409109.
- Zesiewicz T, Heerinckx F, De Jager R, Omidvar O, Kilpatrick M, Shaw J, Shchepinov MS (April 2018). "Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia". Movement Disorders. 6 (1): 57–67. doi:10.1002/mds.27353. PMID 29624723.
- Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M (August 2016). "Pharmacological treatments for Friedreich ataxia". The Cochrane Database of Systematic Reviews (8): CD007791. doi:10.1002/14651858.CD007791.pub4. PMID 27572719.
- "CATENA (idebenone) - Voluntary withdrawal of CATENA from the Canadian market - For the Public - Recalls & alerts - Healthy Canadians Website". Healthycanadians.gc.ca. Retrieved 2015-07-04.
- Dulaney, Chelsey (2015-04-10). "Horizon Pharma's Friedreich's Ataxia Drug Gets Fast-Track Designation". The Wall Street Journal. Retrieved 2015-07-04.
- http://www.fiercebiotech.com/biotech/horizon-slumps-after-phase-3-friedreich-s-ataxia-trial-flops[full citation needed]
- Lodi R, Tonon C, Calabrese V, Schapira AH (2006). "Friedreich's ataxia: from disease mechanisms to therapeutic interventions". Antioxidants & Redox Signaling. 8 (3–4): 438–43. doi:10.1089/ars.2006.8.438. PMID 16677089.
- Barbeau A, Sadibelouiz M, Roy M, Lemieux B, Bouchard JP, Geoffroy G (November 1984). "Origin of Friedreich's disease in Quebec". The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques. 11 (4 Suppl): 506–9. PMID 6391645.
- Vankan P (August 2013). "Prevalence gradients of Friedreich's ataxia and R1b haplotype in Europe co-localize, suggesting a common Palaeolithic origin in the Franco-Cantabrian ice age refuge". Journal of Neurochemistry. 126 Suppl 1: 11–20. doi:10.1111/jnc.12215. PMID 23859338.
- Friedreich N (1863). "Ueber degenerative Atrophie der spinalen Hinterstränge" [About degenerative atrophy of the spinal posterior column]. Arch Pathol Anat Phys Klin Med (in German). 26 (3–4): 391–419. doi:10.1007/BF01930976.
- Friedreich N (1863). "Ueber degenerative Atrophie der spinalen Hinterstränge" [About degenerative atrophy of the spinal posterior column]. Arch Pathol Anat Phys Klin Med (in German). 26 (5–6): 433–459. doi:10.1007/BF01878006.
- Friedreich N (1863). "Ueber degenerative Atrophie der spinalen Hinterstränge" [About degenerative atrophy of the spinal posterior column]. Arch Pathol Anat Phys Klin Med (in German). 27 (1–2): 1–26. doi:10.1007/BF01938516.
- Friedreich N (1876). "Ueber Ataxie mit besonderer Berücksichtigung der hereditären Formen" [About ataxia with special reference to hereditary forms]. Arch Pathol Anat Phys Klin Med (in German). 68 (2): 145–245. doi:10.1007/BF01879049.
- Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (March 1996). "Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion". Science. 271 (5254): 1423–7. doi:10.1126/science.271.5254.1423. PMID 8596916.
- Adam Shatz, "Where Life Is Seized", London Review of Books, 19 January 2017
- friedreichs_ataxia at NINDS
- friedreich at NIH/UW GeneTests
- NCBI Genes and Disease: Friedreich's ataxia at National Center for Biotechnology Information