Medicine:Friedreich's ataxia

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Short description: Rare autosomal-recessive human disease


Friedreich's ataxia
Other namesSpinocerebellar ataxia, FRDA, FA
Protein FXN PDB 1ekg.png
Frataxin
SpecialtyNeurology
SymptomsLack of coordination, balance issues, gait abnormality
ComplicationsCardiomyopathy, scoliosis, diabetes mellitus
Usual onset5–20 years
DurationLong-term
CausesGenetic
Diagnostic methodMedical history and physical examination
TreatmentNone
PrognosisShortened life expectancy
Frequency1 in 50,000 (United States)

Friedreich's ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of coordination in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 years of age. Many develop hypertrophic cardiomyopathy and require a mobility aid such as a cane, walker, or wheelchair in their teens. As the disease progresses, some affected people lose their sight and hearing. Other complications may include scoliosis and diabetes mellitus.

The condition is caused by mutations in the FXN gene on chromosome 9, which makes a protein called frataxin. In FRDA, cells produce less frataxin. Degeneration of nerve tissue in the spinal cord causes the ataxia; particularly affected are the sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum. The spinal cord becomes thinner, and nerve cells lose some myelin sheath.

In February 2023, the first approval of a treatment for FRDA was granted by the U.S. Food and Drug Administration (FDA). Approval in the EU is pending. There are several additional therapies in trial. FRDA shortens life expectancy due to heart disease, but some people can live into their 60s or older.

FRDA affects one in 50,000 people in the United States and is the most common inherited ataxia. Rates are highest in people of Western European descent. The condition is named after German physician Nikolaus Friedreich, who first described it in the 1860s.

Symptoms

Symptoms typically start between the ages of 5 and 15, but in late-onset FRDA, they may occur after age 25 years.[1] The symptoms are broad, but consistently involve gait and limb ataxia, dysarthria and loss of lower limb reflexes.[1]

Classical symptoms

There is some variability in symptom frequency, onset and progression. All individuals with FRDA develop neurological symptoms, including dysarthria and loss of lower limb reflexes, and more than 90% present with ataxia.[1] Cardiac issues are very common with early onset FRDA .[1] Most individuals develop heart problems such as enlargement of the heart, symmetrical hypertrophy, heart murmurs, atrial fibrillation, tachycardia, hypertrophic cardiomyopathy, and conduction defects. Scoliosis is present in about 60%. 7% of people with FRDA also have diabetes and having diabetes has an adverse impact on people with FA, especially those that show symptoms when young.[2][3]

Other symptoms

People who have been living with FRDA for a long time may develop other complications. 36.8% experience decreased visual acuity, which may be progressive and could lead to functional blindness.[3] Hearing loss is present in about 10.9% of cases.[3] Some patients report bladder and bowel symptoms.[4] Advanced stages of disease are associated with supraventricular tachyarrhythmias, most commonly atrial fibrillation.[1]

Other later stage symptoms can include, cerebellar effects such as nystagmus, fast saccadic eye movements, dysmetria and loss of coordination (truncal ataxia, and stomping gait).[1] Symptoms can involve the dorsal column such as the loss of vibratory sensation and proprioceptive sensation.[1]

The progressive loss of coordination and muscle strength leads to the full-time use of a wheelchair. Most young people diagnosed with FRDA require mobility aids such as a cane, walker, or wheelchair by early 20s.[5] The disease is progressive, with increasing staggering or stumbling gait and frequent falling. By the third decade, affected people lose the ability to stand or walk without assistance and require a wheelchair for mobility.[6]

Early-onset cases

Non-neurological symptoms such as scoliosis, pes cavus, cardiomyopathy and diabetes are more frequent amongst the early-onset cases.[1]

Genetics

image showing how two carriers can produce one in four offspring with FRDA. This is called an autosomal-recessive pattern of inheritance.
FRDA has an autosomal-recessive pattern of inheritance.

FRDA is an autosomal-recessive disorder that affects a gene (FXN) on chromosome 9, which produces an important protein called frataxin.[7]

In 96% of cases, the mutant FXN gene has 90–1,300 GAA trinucleotide repeat expansions in intron 1 of both alleles.[8] This expansion causes epigenetic changes and formation of heterochromatin near the repeat.[7] The length of the shorter GAA repeat is correlated with the age of onset and disease severity.[9] The formation of heterochromatin results in reduced transcription of the gene and low levels of frataxin.[10] People with FDRA might have 5-35% of the frataxin protein compared to healthy individuals. Heterozygous carriers of the mutant FXN gene have 50% lower frataxin levels, but this decrease is not enough to cause symptoms.[11]

In about 4% of cases, the disease is caused by a (missense, nonsense, or intronic) point mutation, with an expansion in one allele and a point mutation in the other.[12] A missense point mutation can have milder symptoms.[12] Depending on the point mutation, cells can produce no frataxin, nonfunctional frataxin, or frataxin that is not properly localized to the mitochondria.[13][14]

Pathophysiology

FRDA affects the nervous system, heart, pancreas, and other systems.[15][16]

Degeneration of nerve tissue in the spinal cord causes ataxia.[15] The sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum are particularly affected.[15] The disease primarily affects the spinal cord and peripheral nerves.

The spinal cord becomes thinner and nerve cells lose some myelin sheath.[15] The diameter of the spinal cord is smaller than that of unaffected individuals mainly due to smaller dorsal root ganglia.[16] The motor neurons of the spinal cord are affected to a lesser extent than sensory neurons.[15] In peripheral nerves, a loss of large myelinated sensory fibers occurs.[15]

Structures in the brain are also affected by FRDA, notably the dentate nucleus of the cerebellum.[16] The heart often develops some fibrosis, and over time, develops left-ventricle hypertrophy and dilatation of the left ventricle.[16]

Frataxin

The exact role of frataxin remains unclear.[17] Frataxin assists iron-sulfur protein synthesis in the electron transport chain to generate adenosine triphosphate, the energy molecule necessary to carry out metabolic functions in cells. It also regulates iron transfer in the mitochondria by providing a proper amount of reactive oxygen species (ROS) to maintain normal processes.[18] One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism.[19]

Without frataxin, the energy in the mitochondria falls, and excess iron creates extra ROS, leading to further cell damage.[18] 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.[19]

Diagnosis

Balance difficulty, loss of proprioception, an absence of reflexes, and signs of other neurological problems are common signs from a physical examination.[6][20] Diagnostic tests are made to confirm a physical examination such as electromyogram, nerve conduction studies, electrocardiogram, echocardiogram, blood tests for elevated glucose levels and vitamin E levels, and scans such as X-ray radiograph for scoliosis.[21] MRI and CT scans of brain and spinal cord are done to rule out other neurological conditions.[22] Finally, a genetic test is conducted to confirm.[22]

Other diagnoses might include Charcot-Marie-Tooth types 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia types 1 and 2, and other early-onset ataxias.[23]

Management of Symptoms

Physicians and patients can reference the clinical management guidelines for Friedreich ataxia.[24] These Guidelines are intended to assist qualified healthcare professionals in making informed treatment decisions about the care of individuals with Friedreich ataxia.[25]

Therapeutics

Omaveloxolone received FDA approval under the brand name Skyclarys for the treatment of Friedreich's ataxia in February 2023.[26] Approval in the EU is pending.[27]

Rehabilitation

Physical therapists play a critical role in educating on correct posture, muscle use, and the identification and avoidance of features that aggravate spasticities such as tight clothing, poorly adjusted wheelchairs, pain, and infection.[28]

Physical therapy typically includes intensive motor coordination, balance, and stabilization training to preserve gains.[29] Low-intensity strengthening exercises are incorporated to maintain functional use of the upper and lower extremities.[29] Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities.[29] Other physical therapy goals include 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.[29] Speech therapy can improve voice quality.[30]

Devices

Well-fitted orthoses can promote correct posture, support normal joint alignment, stabilize joints during walking, improve range of motion and gait, reduce spasticity, and prevent foot deformities and scoliosis.[5]

Functional electrical stimulation or transcutaneous nerve stimulation devices may alleviate symptoms.[5]

As progression of ataxia continues, assistive devices such as a cane, walker, or wheelchair may be required for mobility and independence. A standing frame can help reduce the secondary complications of prolonged use of a wheelchair.[31][32]

Managing Cardiac Involvement

Cardiac abnormalities can be controlled with ACE inhibitors such as enalapril, ramipril, lisinopril, or trandolapril, sometimes used in conjunction with beta blockers. Affected people who also have symptomatic congestive heart failure may be prescribed eplerenone or digoxin to keep cardiac abnormalities under control.[5]

Surgical Intervention

Surgery may correct deformities caused by abnormal muscle tone. Titanium screws and rods inserted in the spine help prevent or slow the progression of scoliosis. Surgery to lengthen the Achilles tendon can improve independence and mobility to alleviate equinus deformity.[5] An automated implantable cardioverter-defibrillator can be implanted after a severe heart failure.[5]

Omaveloxolone was approved for medical use in the United States in February 2023.[33]

Prognosis

The disease evolves differently in different people.[31] In general, those diagnosed at a younger age or with longer GAA triplet expansions tend to have more severe symptoms.[5]

Congestive heart failure and abnormal heart rhythms are the leading causes of death,[34] but people with fewer symptoms can live into their 60s or older.[22]

Epidemiology

FRDA affects Indo-European populations. It is rare in East Asians, sub-Saharan Africans, and Native Americans. FRDA is the most prevalent inherited ataxia, affecting approximately 1 in 40,000 with European descent.[15] Males and females are affected equally. The estimated carrier prevalence is 1:100.[5] A 1990–1996 study of Europeans calculated the incidence rate was 2.8:100,000.[35] The prevalence rate of FRDA in Japan is 1:1,000,000.[36]

FRDA follows the same pattern as haplogroup R1b. Haplogroup R1b is the most frequently occurring paternal lineage in Western Europe. FRDA and Haplogroup R1b are more common in northern Spain, Ireland, and France, rare in Russia and Scandinavia, and follow a gradient through central and eastern Europe. A population carrying the disease went through a population bottleneck in the Franco-Cantabrian region during the last ice age.[37]

History

Photo of Nikolaus Friedreich
Nikolaus Friedreich

The condition is named after the 1860s German pathologist and neurologist, Nikolaus Friedreich.[38] Friedreich reported the disease in 1863 at the University of Heidelberg.[39][40][41] Further observations appeared in a paper in 1876.[42]

Frantz Fanon wrote his medical thesis on FRDA, in 1951.[43]

A 1984 Canadian study traced 40 cases to one common ancestral couple arriving in New France in 1634.[44]

FRDA was first linked to a GAA repeat expansion on chromosome 9 in 1996.[45]

Research

Currently there is no cure for Friedreich's ataxia, and treatment development is currently directed toward slowing, stopping, or reversing disease progression. In 2019, Reata Pharmaceuticals reported positive results in a phase 2 trial of RTA 408 (Omaveloxolone or Omav) to target activation of a transcriptional factor, Nrf2.[46] Nrf2 is decreased in FRDA cells.[47][48][49][50] In May 2022, the FDA accepted a new drug application for omaveloxolone and granted it priority review.[51] Omaveloxolone received FDA approval under the brand name Skyclarys for the treatment of Friedreich's ataxia in February 2023.[26] Approval in the EU is pending.[27]

There are several additional therapies in trial. Patients can enroll in a registry to make clinical trial recruiting easier. The Friedreich's Ataxia Global Patient Registry is the only worldwide registry of Friedreich's ataxia patients to characterize the symptoms and establish the rate of disease progression.[52] The Friedreich's Ataxia App is the only global community app which enables novel forms of research.[53]

As of May 2021, research continues along the following paths.

Improve mitochondrial function and reduce oxidative stress

Modulation of frataxin controlled metabolic pathways

  • Dimethyl fumarate has been shown to increase frataxin levels in FRDA cells, mouse models, and humans. DMF showed an 85% increase in frataxin expression over 3 months in multiple sclerosis .[56]

Frataxin replacements or stabilizers

  • EPO mimetics are orally available peptide imitations of erythropoietin. They are small molecules erythropoietin receptor agonists designed to activate the tissue-protective erythropoietin receptor.[57][58]
  • Etravirine, an antiviral drug used to treat HIV, was found in a drug repositioning screening to increase frataxin levels in peripheral cells.[59] Fratagene Therapeutics is developing a small molecule called RNF126 to inhibit an enzyme which degrades frataxin.[60]

Increase frataxin gene expression

  • Resveratrol might improve mitochondrial function.[61]
  • Nicotinamide (vitamin B3) was found effective in preclinical FRDA models and well tolerated.[11]
  • An RNA-based approach might unsilence the FXN gene and increase the expression of frataxin. Non-coding RNA (ncRNA) could be responsible for directing the localized epigenetic silencing of the FXN gene.
  • Lentivirus-mediated delivery of the FXN gene has been shown to increase frataxin expression and prevent DNA damage in human and mouse fibroblasts.[62]
  • CRISPR Therapeutics received a grant from the Friedreich's Ataxia Research Alliance to investigate gene editing as a potential treatment for the disease in 2017.[63]

Society and culture

Photo of Kyle Bryant training on his recumbent bicycle
Kyle Bryant training on his recumbent bicycle

The Cake Eaters is a 2007 independent drama film that stars Kristen Stewart as a young woman with FRDA.[64]

The Ataxian is a documentary that tells the story of Kyle Bryant, an athlete with FRDA who completes a long-distance bike race in an adaptive "trike" to raise money for research.[65]

Dynah Haubert spoke at the 2016 Democratic National Convention about supporting Americans with disabilities.[66]

Geraint Williams in an athlete affected by FRDA who is known for scaling Mount Kilimanjaro in an adaptive wheelchair.[67]

Shobhika Kalra is an activist with FRDA who helped build over 1000 wheelchair ramps across the United Arab Emirates in 2018 to try to make Dubai fully wheelchair-friendly by 2020.[68]

Butterflies Still Fly is a 2023 film, based on a true story, directed by Joseph Nenci. Italo is a light-hearted journalist, darkened by a personal drama that distracts him from work. He encounters with Giorgia, a young girl suffering from Friedreich's Ataxia, who will change his life.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Cook, A.; Giunti, P. (2017). "Friedreich's ataxia: Clinical features, pathogenesis and management". British Medical Bulletin 124 (1): 19–30. doi:10.1093/bmb/ldx034. PMID 29053830. 
  2. ↑ McCormick, Ashley; Farmer, Jennifer; Perlman, Susan; Delatycki, Martin; Wilmot, George; Matthews, Katherine; Yoon, Grace; Hoyle, Chad et al. (2017). "Impact of diabetes in the Friedreich ataxia clinical outcome measures study". Annals of Clinical and Translational Neurology 4 (9): 622–631. doi:10.1002/acn3.439. PMID 28904984. 
  3. ↑ 3.0 3.1 3.2 Reetz, Kathrin; Dogan, Imis; Hohenfeld, Christian; Didszun, Claire; Giunti, Paola; Mariotti, Caterina; Durr, Alexandra; Boesch, Sylvia et al. (2018). "Nonataxia symptoms in Friedreich Ataxia". Neurology 91 (10): e917–e930. doi:10.1212/WNL.0000000000006121. PMID 30097477. https://dipot.ulb.ac.be/dspace/bitstream/2013/296726/3/DF74D77F-A0D4-4D4E-A532-0860F91C1D47.pdf. 
  4. ↑ "Friedreich Ataxia Fact Sheet". https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Friedreichs-Ataxia-Fact-Sheet. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 "Friedreich ataxia clinical management guidelines". Friedreich Ataxia Research Alliance (USA). 2014. http://curefa.org/clinical-care-guidelines. 
  6. ↑ 6.0 6.1 Parksinson, MH; Boesch, S; Nachbauer, W; Mariotti, C; Giunti, P (August 2013). "Clinical features of Friedreich's ataxia: classical and atypical phenotypes". Journal of Neurochemistry 126 (Supplement 1): 103–17. doi:10.1111/jnc.12317. PMID 23859346. 
  7. ↑ 7.0 7.1 "Update on degenerative ataxias". Current Opinion in Neurology 24 (4): 339–45. August 2011. doi:10.1097/WCO.0b013e32834875ba. PMID 21734495. 
  8. ↑ "Role of frataxin protein deficiency and metabolic dysfunction in Friedreich ataxia, an autosomal recessive mitochondrial disease". Neuronal Signaling 2 (4): NS20180060. Nov 2018. doi:10.1042/NS20180060. PMID 32714592. 
  9. ↑ "Clinical and genetic abnormalities in patients with Friedreich's ataxia". The New England Journal of Medicine 335 (16): 1169–75. October 1996. doi:10.1056/nejm199610173351601. PMID 8815938. 
  10. ↑ "The Friedreich ataxia GAA triplet repeat: premutation and normal alleles". Human Molecular Genetics 6 (8): 1261–6. August 1997. doi:10.1093/hmg/6.8.1261. PMID 9259271. 
  11. ↑ 11.0 11.1 "Friedreich Ataxia: current status and future prospects". Cerebellum & Ataxias 4: 4. 2017. doi:10.1186/s40673-017-0062-x. PMID 28405347. 
  12. ↑ 12.0 12.1 "Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes". Annals of Neurology 45 (2): 200–6. February 1999. doi:10.1002/1531-8249(199902)45:2<200::AID-ANA10>3.0.CO;2-U. PMID 9989622. 
  13. ↑ "Frataxin levels in peripheral tissue in Friedreich ataxia". Annals of Clinical and Translational Neurology 2 (8): 831–42. August 2015. doi:10.1002/acn3.225. PMID 26339677. 
  14. ↑ "Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia". Annals of Neurology 79 (3): 485–95. March 2016. doi:10.1002/ana.24595. PMID 26704351. 
  15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 Delatycki, Martin B.; Bidichandani, Sanjay I. (2019). "Friedreich ataxia- pathogenesis and implications for therapies". Neurobiology of Disease 132: 104606. doi:10.1016/j.nbd.2019.104606. PMID 31494282. 
  16. ↑ 16.0 16.1 16.2 16.3 Hanson, Emily; Sheldon, Mark; Pacheco, Brenda; Alkubeysi, Mohammed; Raizada, Veena (2019). "Heart disease in Friedreich's ataxia". World Journal of Cardiology 11 (1): 1–12. doi:10.4330/wjc.v11.i1.1. PMID 30705738. 
  17. ↑ Maio, Nunziata; Jain, Anshika; Rouault, Tracey A. (2020). "Mammalian iron–sulfur cluster biogenesis: Recent insights into the roles of frataxin, acyl carrier protein and ATPase-mediated transfer to recipient proteins". Current Opinion in Chemical Biology 55: 34–44. doi:10.1016/j.cbpa.2019.11.014. PMID 31918395. 
  18. ↑ 18.0 18.1 "Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia". Human Molecular Genetics 23 (25): 6848–62. December 2014. doi:10.1093/hmg/ddu408. PMID 25113747. 
  19. ↑ 19.0 19.1 "Role of Frataxin, a Protein Implicated in Friedreich Ataxia, in Making Iron-Sulfur Clusters♦". Journal of Biological Chemistry 288 (52): 36787. 2013. doi:10.1074/jbc.P113.525857. 
  20. ↑ Corben, LA; Lynch, D; Pandolfo, M; Schulz, JB; Delatycki, MB; Clinical Management Guidelines Writing Group (November 2014). "Consensus clinical management guidelines for Friedreich ataxia". Orphanet Journal of Rare Diseases 9: 184. doi:10.1186/s13023-014-0184-7. PMID 25928624. 
  21. ↑ "Novel diagnostic paradigms for Friedreich ataxia". Journal of Child Neurology 27 (9): 1146–51. September 2012. doi:10.1177/0883073812448440. PMID 22752491. 
  22. ↑ 22.0 22.1 22.2 "Friedreich's Ataxia Fact Sheet". National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Friedreichs-Ataxia-Fact-Sheet.  This article incorporates text from this source, which is in the public domain.
  23. ↑ "Friedreich ataxia NIH page". https://rarediseases.info.nih.gov/diseases/6468/friedreich-ataxia. 
  24. ↑ "FDRA Guidelines". https://frdaguidelines.org/. 
  25. ↑ Corben, L. A.; Collins, V.; Milne, S.; Farmer, J.; Musheno, A.; Lynch, D.; Subramony, S.; Pandolfo, M. et al. (2022). "Clinical management guidelines for Friedreich ataxia: Best practice in rare diseases". Orphanet Journal of Rare Diseases 17 (1): 415. doi:10.1186/s13023-022-02568-3. PMID 36371255. 
  26. ↑ 26.0 26.1 "FDA approves first treatment for Friedreich's ataxia". FDA. 28 February 2023. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia. Retrieved 8 May 2023. 
  27. ↑ 27.0 27.1 "Public Health - European Commission". https://ec.europa.eu/health/documents/community-register/html/o2037.htm. 
  28. ↑ "Emerging therapies in Friedreich's ataxia". Neurodegenerative Disease Management 6 (1): 49–65. Feb 2016. doi:10.2217/nmt.15.73. PMID 26782317. 
  29. ↑ 29.0 29.1 29.2 29.3 Chien, Hsin Fen; Barsottini, Orlando Graziani Povoas, eds (10 December 2016). Movement Disorders Rehabilitation. Springer, Cham. pp. 83–95. doi:10.1007/978-3-319-46062-8. ISBN 978-3-319-46062-8. 
  30. ↑ Lowit, Anja; Egan, Aisling; Hadjivassiliou, Marios (2020). "Feasibility and Acceptability of Lee Silverman Voice Treatment in Progressive Ataxias". The Cerebellum 19 (5): 701–714. doi:10.1007/s12311-020-01153-3. PMID 32588316. 
  31. ↑ 31.0 31.1 "Physical Therapy and Rehabilitation for Ataxic Patients". Balneo Research Journal 4 (2): 81–84. 2013. doi:10.12680/balneo.2013.1044. 
  32. ↑ "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. March 2017. doi:10.1007/s10072-016-2800-x. PMID 28039539. 
  33. ↑ "Reata Pharmaceuticals Announces FDA Approval of Skyclarys (Omavaloxolone), the First and Only Drug Indicated for Patients with Friedreich's Ataxia". Reata Pharmaceuticals Inc. (Press release). 28 February 2023. Archived from the original on 1 March 2023. Retrieved 28 February 2023.
  34. ↑ "Demographic and clinical features and rehabilitation outcomes of patients with Friedreich ataxia: A retrospective study". Turkish Journal of Physical Medicine and Rehabilitation 64 (3): 230–238. September 2018. doi:10.5606/tftrd.2018.2213. PMID 31453516. PMC 6657791. http://ftrdergisi.com/uploads/pdf/pdf_4066.pdf. Retrieved 29 October 2018. 
  35. ↑ "Clinical and genetic abnormalities in patients with Friedreich's ataxia". The New England Journal of Medicine 335 (16): 1169–75. October 1996. doi:10.1056/NEJM199610173351601. PMID 8815938. 
  36. ↑ "[Spinocerebellar degeneration in Japan--the feature from an epidemiological study]". Rinsho Shinkeigaku = Clinical Neurology 33 (12): 1279–84. December 1993. PMID 8174325. 
  37. ↑ "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. August 2013. doi:10.1111/jnc.12215. PMID 23859338. 
  38. ↑ Nicolaus Friedreich at Who Named It?
  39. ↑ "Ueber degenerative Atrophie der spinalen Hinterstränge" (in de). Arch Pathol Anat Phys Klin Med 26 (3–4): 391–419. 1863. doi:10.1007/BF01930976. 
  40. ↑ "Ueber degenerative Atrophie der spinalen Hinterstränge" (in de). Arch Pathol Anat Phys Klin Med 26 (5–6): 433–459. 1863. doi:10.1007/BF01878006. 
  41. ↑ "Ueber degenerative Atrophie der spinalen Hinterstränge" (in de). Arch Pathol Anat Phys Klin Med 27 (1–2): 1–26. 1863. doi:10.1007/BF01938516. 
  42. ↑ "Ueber Ataxie mit besonderer Berücksichtigung der hereditären Formen" (in de). Arch Pathol Anat Phys Klin Med 68 (2): 145–245. 1876. doi:10.1007/BF01879049. https://zenodo.org/record/2412480. 
  43. ↑ Adam Shatz, "Where Life Is Seized" , London Review of Books, 19 January 2017
  44. ↑ "Origin of Friedreich's disease in Quebec". The Canadian Journal of Neurological Sciences 11 (4 Suppl): 506–9. November 1984. doi:10.1017/S0317167100034971. PMID 6391645. 
  45. ↑ "Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion". Science 271 (5254): 1423–7. March 1996. doi:10.1126/science.271.5254.1423. PMID 8596916. Bibcode: 1996Sci...271.1423C. 
  46. ↑ "Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis". Radiation Research 181 (5): 512–20. May 2014. doi:10.1667/RR13578.1. PMID 24720753. Bibcode: 2014RadR..181..512R. 
  47. ↑ "Frataxin deficiency leads to defects in expression of antioxidants and Nrf2 expression in dorsal root ganglia of the Friedreich's ataxia YG8R mouse model". Antioxidants & Redox Signaling 19 (13): 1481–93. November 2013. doi:10.1089/ars.2012.4537. PMID 23350650. .
  48. ↑ "A Phase 2 Study of the Safety, Efficacy, and Pharmacodynamics of RTA 408 in the Treatment of Friedreich's Ataxia (MOXIe)". 1 October 2020. https://clinicaltrials.gov/ct2/show/NCT02255435. 
  49. ↑ "FARA – Part 2 of the Phase II MOXIe study (RTA 408 or omaveloxolone)". https://www.curefa.org/clinical-trials/clinical-trials-active-enrolling/part-2-of-the-phase-ii-moxie-study-rta-408-or-omaveloxolone. 
  50. ↑ "Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia". Annals of Clinical and Translational Neurology 6 (1): 15–26. January 2019. doi:10.1002/acn3.660. PMID 30656180. 
  51. ↑ "Omaveloxolone Gets Priority Review for Friedreich Ataxia". 31 May 2022. https://www.empr.com/home/news/drugs-in-the-pipeline/omaveloxolone-gets-priority-review-for-friedreich-ataxia/. 
  52. ↑ "FA Global Patient Registry (FAGPR)". 5 October 2017. https://friedreichsataxianews.com/news-posts/2017/10/05/friedreichs-ataxia-global-patient-registry-key-to-moving-research-into-treatments-fara-says/. 
  53. ↑ "The FA App". https://curefa.org/news/introducing-the-fa-app. 
  54. ↑ "Initial experience in the treatment of inherited mitochondrial disease with EPI-743". Molecular Genetics and Metabolism 105 (1): 91–102. January 2012. doi:10.1016/j.ymgme.2011.10.009. PMID 22115768. 
  55. ↑ "Emerging therapeutics for the treatment of Friedreich's ataxia". Expert Opinion on Orphan Drugs 6: 57–67. 2018. doi:10.1080/21678707.2018.1409109. 
  56. ↑ "Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich's Ataxia". PLOS ONE 14 (6): e0217776. June 2019. doi:10.1371/journal.pone.0217776. PMID 31158268. Bibcode: 2019PLoSO..1417776J. 
  57. ↑ "Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo". Neuropharmacology 123: 34–45. September 2017. doi:10.1016/j.neuropharm.2017.05.011. PMID 28504123. 
  58. ↑ "STATegics, Inc. Announces a New Grant from Friedreich's Ataxia Research Alliance". http://stategics.com/doc/STATegics_Press_Release_FARA_Jan_08_2013_FINAL.pdf. 
  59. ↑ "Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia". Movement Disorders 34 (3): 323–334. March 2019. doi:10.1002/mds.27604. PMID 30624801. 
  60. ↑ "E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia". Cell Reports 18 (8): 2007–2017. February 2017. doi:10.1016/j.celrep.2017.01.079. PMID 28228265. 
  61. ↑ "Jupiter Orphan Therapeutics, Inc. Enters into a Global Licensing Agreement with Murdoch Childrens Research Institute". http://www.curefa.org/pdf/sci-news/JOT-MurdochPR-01-12-2016.pdf. 
  62. ↑ "Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts". Gene Therapy 23 (12): 846–856. December 2016. doi:10.1038/gt.2016.61. PMID 27518705. 
  63. ↑ Melão, Alice (19 October 2017). "CRISPR Therapeutics Receives FARA Grant to Develop Gene Editing Therapies for Friedreich's Ataxia". https://friedreichsataxianews.com/2017/10/19/crispr-therapeutics-receives-grant-to-develop-gene-editing-therapies-for-friedreichs-ataxia/. 
  64. ↑ Holden, Stephen (13 March 2009). "The Cake Eaters". The New York Times. https://movies.nytimes.com/2009/03/13/movies/13cake.html. 
  65. ↑ "Devastating Diagnosis Pushes Local Man To Live Bigger". CBS Sacramento. 30 May 2015. http://sacramento.cbslocal.com/2015/05/30/devastating-diagnosis-pushes-local-man-to-live-bigger/. 
  66. ↑ "How the DNC Is Subtly Rebuking Donald Trump's Mockery of a Disabled Reporter". 27 July 2016. https://slate.com/human-interest/2016/07/dnc-rebukes-trump-for-mocking-the-disabled.html. 
  67. ↑ "Man with rare nerve condition climbs Mount Kilimanjaro to raise money for charity". 25 November 2018. https://www.itv.com/news/wales/2018-11-25/man-with-rare-nerve-condition-climbs-mount-kilimanjaro-to-raise-money-for-charity/. 
  68. ↑ "Shobhika Kalra: Meet the Dubai woman in wheelchair who helped build 1,000 ramps across UAE". 30 October 2018. https://gulfnews.com/world/shobhika-kalra-meet-the-dubai-woman-in-wheelchair-who-helped-build-1000-ramps-across-uae-1.2295954. 

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