Friedreich's ataxia

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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 onset5–15 years
DurationLong-term
CausesGenetic
Diagnostic methodMedical history and physical examination
TreatmentPhysical therapy
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 sensation in the arms and legs and impaired speech that worsens over time. Many people also have a form of heart disease called hypertrophic cardiomyopathy. Symptoms typically start between 5 and 15 years of age. Most young people diagnosed with FRDA require a mobility aid such as a cane, walker or wheelchair by their teens. As the disease progresses, people lose their sight and hearing. Other complications include scoliosis and diabetes mellitus.

The condition is caused by mutations in the FXN gene on the chromosome 9, which produces a protein called 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. Physical symptoms, patient history and genetic testing confirms the diagnosis.

No effective treatment exists, but there are several therapies in trials. FRDA shortens life expectancy due to heart disease and some people can live into their sixties or older.

FRDA affects 1 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 the German physician Nikolaus Friedreich, who first described it in the 1860s.

Signs and symptoms[edit]

Symptoms typically start between the ages of 5 and 15, but in Late Onset FRDA they may occur after age 25 years. The progressive loss of coordination and muscle strength leads to loss of ambulation and the full-time use of a wheelchair. Most young people diagnosed with FRDA require mobility aids such as a cane, walker, or wheelchair by their teens or early 20s.[1] The disease is progressive with increasing staggering or stumbling gait and frequent falling. Lower extremities are more severely involved. Long-term observation shows that many people reach a plateau in symptoms in the patient's early adulthood. On average, after 10–15 years, people lose the ability to stand or walk without assistance. However, disease progression is variable, and people may be ambulatory decades after onset, while others require a wheelchair within a few years.[2]

Symptoms may include the following:

Genetics[edit]

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.[5]

In 96% of cases the mutant FXN gene has 90-1,300 GAA trinucleotide repeat expansions in intron 1 of both alleles.[6] This expansion causes epigenetic changes and formation of heterochromatin near the repeat.[5] The length of the shorter GAA repeat is correlated with age of onset and disease severity.[7] The formation of heterochromatin results in reduced transcription of the gene and low levels of frataxin.[8] People with FDRA tend to have 5-35% of the frataxin expressed in healthy individuals. Heterozygous carriers of the mutant FXN gene have frataxin levels reduced by 50%; however, this decrease is not enough to cause symptoms.[9]

In about 4% of cases the disease is caused by a (missense, nonsense, or intronic) point mutation, where the patient is heterozygotes with an expansion in one allele and a point mutation in the other.[10] A missense point mutation can have milder symptoms.[10] A detailed genetic work up is needed to determine this diagnosis.[11]

Depending on the point mutation a patient may end up with no frataxin, nonfunctional frataxin or frataxin that is not properly localized to the mitochondria.[12][13]

Pathophysiology[edit]

FRDA affects the nervous system, heart and pancreas and other systems.[14] Degeneration of nerve tissue in the spinal cord causes ataxia.[14] The sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum are particularly affected.[14] The disease primarily affects the spinal cord and peripheral nerves.[14] The spinal cord becomes thinner and nerve cells lose some myelin sheath.[14] The diameter of the spinal cord is smaller than that of unaffected individuals mainly due to smaller dorsal root ganglia.[15] The motor neurons of the spinal cord are affected to a lesser extent than sensory neurons.[14] In peripheral nerves there is a loss of large myelinated sensory fibers.[14]

Structures in the brain are also affected by FRDA, notably the dentate nucleus of the cerebellum.[15] In the heart, FRDA patients often develop some fibrosis, and over time many patients develop left ventricle hypertrophy and dilatation of the left ventricle.[15]

Frataxin[edit]

The exact role of frataxin remains unclear.[16] 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. Frataxin also regulates iron transfer in the mitochondria by providing a proper amount of reactive oxygen species (ROS) to maintain normal processes.[17] One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism.[5]

Without frataxin, the energy in the mitochondria falls, and excess iron creates extra ROS, leading to further cell damage.[18][17] 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.[18]

Diagnosis[edit]

Balance difficulty, loss of proprioception, an absence of reflexes, and signs of other neurological problems are common signs from a physical examination.

Diagnostic tests to support a physical examination include

Other diagnoses include Charcot-Marie-Tooth type 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia type 1 and 2 and other early-onset ataxias.[20]

Management[edit]

As there is no cure physical therapy is ‘a way of life’ for the patient. Physical therapists have a critical role to play in educating patients and caregivers as to correct posture, muscle use and the identification and avoidance of features which aggravate spasticity such as tight clothing, poorly adjusted wheelchairs, pain and infection.[21]

Rehabilitation[edit]

Physical therapy should consist of intensive motor coordination, balance, and stabilization training to preserve gains.[22][23]

To address the ataxic gait pattern and loss of proprioception, physical therapists can use visual cueing during gait training to help facilitate a more efficient gait pattern.[23] Frenkel exercises and Proprioceptive Neuromuscular Facilitation stretching might help improve proprioception.[21] Low intensity strengthening exercises should be incorporated to maintain functional use of the upper and lower extremities.[24] Stabilization exercises of the trunk and lower back can help with postural control and the management of scoliosis,[23] especially if the patient requires a wheelchair. Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities.[24] 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.[22]

Speech therapy is recommended.[25][26]

Devices[edit]

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.[1]

Functional electrical stimulation or transcutaneous nerve stimulation devices may alleviate symptoms.[1]

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.[27][28]

Medication and surgery[edit]

Cardiac abnormalities can be controlled with ACE inhibitors such as enalapril, ramipril, lisinopril or trandolapril, sometimes used in conjunction with beta blockers. Patients with symptomatic heart failure might be prescribed eplerenone or digoxin to keep cardiac abnormalities under control.[1]

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 in patients suffering from equinus deformity.[1] Patients experiencing severe heart failure can have an automated implantable cardioverter-defibrillator implanted or a cardiac transplant.[1]

Prognosis[edit]

Every patient has a particular form of evolution of the disease.[27] In general, patients who were younger at diagnosis, and those with longer GAA triplet expansions, tend to have more severe symptoms.[1]

Congestive heart failure and cardiac arrhythmia are the leading cause of death.[29] However, patients with less severe symptoms can live into their sixties or older.[19]

Epidemiology[edit]

FRDA affects Indo-European populations. It is rare in East Asians, Sub-Saharan Africans, and Native Americans.

FRDA is the most prevalent inherited ataxia,[30] affecting about 1 in 50,000 people in the United States. Males and females are affected equally. The estimated carrier prevalence is 1:100.[1]

A 1990-1996 study of Europeans calculated the incidence rate was 2.8:100,000.[31] A later study estimated prevalence of 3-4 cases per 100,000 individuals.[32]

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.[33]

A study of Japanese patients with spinocerebellar degeneration found a rate of 2.4% making the prevalence rate of FRDA much rarer at 1:1,000,000.[34]

History[edit]

Nikolaus Friedreich

The condition is named after the 1860's German pathologist and neurologist, Nikolaus Friedreich.[35] Friedreich reported five patients in three papers in 1863 at the University of Heidelberg.[36][37][38] Further observations appeared in a paper in 1876.[39]

Frantz Fanon wrote his medical thesis on FRDA, in 1951.[40]

A 1984 Canadian study traced 40 cases to one common ancestral couple arriving in New France in 1634.[41]

FRDA was first linked to a GAA repeat expansion on chromosome 9 in 1996.[42]

Research[edit]

As of April 2019 the most advanced candidate for a curative treatment is RTA 408 (Omaveloxolone or Omav). Reata Pharmaceuticals developed a small molecule to target activation of a transcriptional factor, Nrf2.[43] Nrf2 is decreased in FRDA cells.[44]

Reata has shown in preclinical studies that RT408 and the company's predecessor molecules boost mitochondrial energy production, increase the number and efficiency of mitochondria[45] Reata is completing a Phase 2/3 clinical trial. The study, MOXIe, is a randomized, placebo-controlled Phase 2/3 trial. Part 1 (finished in 2017) was a randomized, placebo-controlled, double-blind, dose-escalation study to evaluate the safety of RTA 408 in patients. This first phase also suggested that 80–160 mg/day could be an effective dose for a Part 2 efficacy study.[46]

Part 2 of MOXIe is still ongoing and results are anticipated by Q1 2020. It is a 48 week, randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of 150 mg omaveloxone.[47][48]

Frataxin replacements or stabilizers[edit]

  • EPO mimetics are orally available peptide imitations of erythropoietin. They are small molecules erythropoietin receptor agonists designed to activate the tissue-protective erythropoietin receptor.[58] STATegics plans to start a preclinical PK-PD study with a lead compound.[59]
  • Ubiquitin competitors. Since carriers of FRDA are asymptomatic but have a reduced level of frataxin it might be enough to just prevent existing frataxin degradation and increase levels of frataxin.[60] Fratagene Therapeutics is developing a small molecule called RNF126 to inhibit an enzyme which degrades frataxin.[61][62]

FXN gene expression[edit]

  • BNM 290 is a second generation HDAC inhibitor which came from an acquisition by Biogen of Repligen's RG2833. HDAC inhibitors interfere with the histone deacetylase which functions to keep the DNA of a gene tightly coiled and silence protein expression. BioMarin planned to file an Investigational New Drug application in 2018.[63]
  • Jupiter Orphan Therapeutics is using resveratrol to improve mitochondrial function. In 2016, IND enabling studies were started in Australia for a modified compound normally found in the skins of red grapes.[64]
  • RNA-based approach to try to unsilence FXN gene and increase the expression of frataxin. This could be an effect of epigenetics and identifying novel non-coding RNA (ncRNA) responsible for directing the localized epigenetic silencing of the FXN gene.
  • Nicotinamide (vitamin B3) was found effective in preclinical FRDA models and well-tolerated by patients. An open-label, dose-escalation study demonstrated that higher doses boosted frataxin expression but failed to establish any clinical benefit in a 12 month study.[9]
  • Etravirine, an antiviral drug used to treat HIV, was found in a drug repositioning screening to increase frataxin levels in peripheral cells derived from Friedreich's ataxia patients.[65]
  • Dimethyl fumarate has been shown to increase frataxin levels in FA patient-derived cells, mouse models, and humans. Multiple sclerosis patients treated with DMF showed an 85% increase in frataxin expression over 3 months.[66]

Gene therapy[edit]

  • An adeno-associated virus vector was used to reduce mitochondrial cardiomyopathy in a mice model in 2014.[67]
  • Lentivirus-mediated delivery of the FXN gene has been shown to increase frataxin expression and prevent DNA damage in human and mouse fibroblasts.[68]
  • 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.[69]

Society and culture[edit]

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.[70]

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.[71]

Dynah Haubert is a lawyer with FRDA who works for Disability Rights Pennsylvania (DRP). She spoke at the 2016 Democratic National Convention about her support for Hillary Clinton and her work supporting Americans with disabilities.[72]

Geraint Williams in an athlete affected by FRDA who is known for scaling Mount Kilimanjaro in an adaptive wheelchair.[73]

Shobhika Kalra is an activist with FRDA who helped build over 1000 wheelchair ramps across the UAE, with the goal to make Dubai fully wheelchair-friendly by 2020.[74]

References[edit]

  1. ^ a b c d e f g h "Friedreich ataxia clinical management guidelines". Friedreich Ataxia Research Alliance (USA). 2014. Archived from the original on 20 October 2018. Retrieved 23 October 2018.
  2. ^ 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.
  3. ^ "Friedreich Ataxia Fact Sheet". Archived from the original on January 23, 2019. Retrieved February 10, 2019.
  4. ^ 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.
  5. ^ a b c Klockgether T (August 2011). "Update on degenerative ataxias". Current Opinion in Neurology. 24 (4): 339–45. doi:10.1097/WCO.0b013e32834875ba. PMID 21734495.
  6. ^ Clark E, Johnson J, Dong YN, Mercado-Ayon, Warren N, Zhai M, McMillan E, Salovin A, Lin H, Lynch DR (Nov 2018). "Role of frataxin protein deficiency and metabolic dysfunction in Friedreich ataxia, an autosomal recessive mitochondrial disease". Neuronal Signaling. 2 (4): NS20180060. doi:10.1042/NS20180060.
  7. ^ Durr (1996). "Clinical and Genetic Abnormalities in Patients with Friedreich's Ataxia". New England Journal of Medicine. 335 (16): 1169–1175. doi:10.1056/nejm199610173351601. PMID 8815938.
  8. ^ 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.
  9. ^ a b 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.
  10. ^ a b Cosse, Mireille; dRr, Alexandra; Schmitt, Michele; Dahl, Niklas; Trouillas, Paul; Allinson, Patricia; Kostrzewa, Markus; Nivelon-Chevallier, Annie; Gustavson, Karl-Henrik; KohlschTter, Alfried; miLler, Ulrich; Mandel, Jean-Louis; Brice, Alexis; Koenig, Michel; Cavalcanti, Francesca; Tammaro, Angela; De Michele, Giuseppe; Filla, Alessandro; Cocozza, Sergio; Labuda, Malgorzata; Montermini, Laura; Poirier, Jose; Pandolfo, Massimo (1999). "Friedreich's ataxia: Point mutations and clinical presentation of compound heterozygotes". Annals of Neurology. 45 (2): 200–206. doi:10.1002/1531-8249(199902)45:2<200::AID-ANA10>3.0.CO;2-U.
  11. ^ a b Brigatti, Karlla W.; Deutsch, Eric C.; Lynch, David R.; Farmer, Jennifer M. (2012). "Novel Diagnostic Paradigms for Friedreich Ataxia". Journal of Child Neurology. 27 (9): 1146–1151. doi:10.1177/0883073812448440. PMC 3674546. PMID 22752491.
  12. ^ Lazaropoulos, Michael; Dong, Yina; Clark, Elisia; Greeley, Nathaniel R.; Seyer, Lauren A.; Brigatti, Karlla W.; Christie, Carlton; Perlman, Susan L.; Wilmot, George R.; Gomez, Christoper M.; Mathews, Katherine D.; Yoon, Grace; Zesiewicz, Theresa; Hoyle, Chad; Subramony, Sub H.; Brocht, Alicia F.; Farmer, Jennifer M.; Wilson, Robert B.; Deutsch, Eric C.; Lynch, David R. (2015). "Frataxin levels in peripheral tissue in Friedreich ataxia". Annals of Clinical and Translational Neurology. 2 (8): 831–842. doi:10.1002/acn3.225. PMC 4554444. PMID 26339677.
  13. ^ Galea, Charles A.; Huq, Aamira; Lockhart, Paul J.; Tai, Geneieve; Corben, Louise A.; Yiu, Eppie M.; Gurrin, Lyle C.; Lynch, David R.; Gelbard, Sarah; Durr, Alexandra; Pousset, Francoise; Parkinson, Michael; Labrum, Robyn; Giunti, Paola; Perlman, Susan L.; Delatycki, Martin B.; Evans-Galea, Marguerite V. (2016). "Compound heterozygousFXNmutations and clinical outcome in friedreich ataxia". Annals of Neurology. 79 (3): 485–495. doi:10.1002/ana.24595. PMID 26704351.
  14. ^ a b c d e f g 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.
  15. ^ a b c Koeppen AH (15 April 2011). "Friedreich's ataxia: Pathology, pathogenesis, and molecular genetics". Journal of the Neurological Sciences. 303 (1–2): 1–12. doi:10.1016/j.jns.2011.01.010. PMC 3062632. PMID 21315377.
  16. ^ Marmolino, Daniele (2011). "Friedreich's ataxia: Past, present and future". Brain Research Reviews. 67 (1–2): 311–330. doi:10.1016/j.brainresrev.2011.04.001. PMID 21550666.
  17. ^ a b 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.
  18. ^ a b Pandolfo M (October 2008). "Friedreich ataxia". Archives of Neurology. 65 (10): 1296–303. doi:10.1001/archneur.65.10.1296. PMID 18852343.
  19. ^ a b c "Friedreich's Ataxia Fact Sheet". National Institute of Neurological Disorders and Stroke. Archived from the original on 2017-08-26. Retrieved 2017-08-26. This article incorporates text from this source, which is in the public domain.
  20. ^ "Friedreich ataxia NIH page". NIH Rare diseases. Archived from the original on March 31, 2019. Retrieved March 17, 2019.
  21. ^ a b 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.
  22. ^ a b Chien H, Barsottini O (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.
  23. ^ a b c 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.
  24. ^ a b "Facts About Friedreich's Ataxia (FA)". Muscular Dystrophy Association. 2011. Archived from the original on 2011-09-27. Retrieved 2011-05-16.
  25. ^ Vogel AP, Folker J, Poole ML (October 2014). "Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes" (PDF). The Cochrane Database of Systematic Reviews. 10 (10): CD008953. doi:10.1002/14651858.CD008953.pub2. PMID 25348587.
  26. ^ 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.
  27. ^ a b 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. Archived from the original on 2018-10-31. Retrieved 2018-10-31.
  28. ^ 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. PMID 28039539.
  29. ^ Doğan-Aslan, Meryem (January 2018). "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. doi:10.5606/tftrd.2018.2213. PMC 6657791. PMID 31453516. Archived (PDF) from the original on 2018-10-30. Retrieved 2018-10-29.
  30. ^ 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.
  31. ^ Dürr, Alexandra; Cossée, Mireille; Agid, Yves; Campuzano, Victoria; Mignard, Claude; Penet, Christiane; Mandel, Jean-Louis; Brice, Alexis; Koenig, Michel (1996). "Clinical and Genetic Abnormalities in Patients with Friedreich's Ataxia". New England Journal of Medicine. 335 (16): 1169–1175. doi:10.1056/NEJM199610173351601. PMID 8815938.
  32. ^ Schulz, Jörg B.; Boesch, Sylvia; Bürk, Katrin; Dürr, Alexandra; Giunti, Paola; Mariotti, Caterina; Pousset, Francoise; Schöls, Ludger; Vankan, Pierre; Pandolfo, Massimo (2009). "Diagnosis and treatment of Friedreich ataxia: A European perspective". Nature Reviews Neurology. 5 (4): 222–234. doi:10.1038/nrneurol.2009.26. PMID 19347027.
  33. ^ 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. Bibcode:2006JNeur..26.9606G. doi:10.1111/jnc.12215. PMID 23859338.
  34. ^ Kita, K. (1993). "Spinocerebellar degeneration in Japan--the feature from an epidemiological study". Clinical Neurology. 33 (12): 1279–1284.
  35. ^ synd/1406 at Who Named It?
  36. ^ 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.
  37. ^ 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.
  38. ^ 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.
  39. ^ 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.
  40. ^ Adam Shatz, "Where Life Is Seized" Archived 2017-01-12 at the Wayback Machine, London Review of Books, 19 January 2017
  41. ^ 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. 11 (4 Suppl): 506–9. doi:10.1017/S0317167100034971. PMID 6391645.
  42. ^ 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. Bibcode:1996Sci...271.1423C. doi:10.1126/science.271.5254.1423. PMID 8596916.
  43. ^ Reisman SA, Lee CY, Meyer CJ, Proksch JW, Sonis ST, Ward KW (May 2014). "Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis". Radiation Research. 181 (5): 512–20. Bibcode:2014RadR..181..512R. doi:10.1667/RR13578.1. PMID 24720753.
  44. ^ Shan, Yuxi; Schoenfeld, Robert A.; Hayashi, Genki; Napoli, Eleonora; Akiyama, Tasuku; Iodi Carstens, Mirela; Carstens, Earl E.; Pook, Mark A.; Cortopassi, Gino A. (2013). "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): 1481–1493. doi:10.1089/ars.2012.4537. PMC 3797453. PMID 23350650.
  45. ^ Reisman SA, Lee CY, Meyer CJ, Proksch JW, Ward KW (Jul 2014). "Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin". Archives of Dermatological Research. 306 (5): 447–54. doi:10.1007/s00403-013-1433-7. PMID 24362512.
  46. ^ Lynch, D. R.; Farmer, J.; Hauser, L.; Blair, I. A.; Wang, Q. Q.; Mesaros, C.; Snyder, N.; Boesch, S.; Chin, M.; Delatycki, M. B.; Giunti, P.; Goldsberry, A.; Hoyle, C.; McBride, M. G.; Nachbauer, W.; O'Grady, M.; Perlman, S.; Subramony, S. H.; Wilmot, G. R.; Zesiewicz, T.; Meyer, C. (2019). "Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia". Annals of Clinical and Translational Neurology. 6 (1): 15–26. doi:10.1002/acn3.660. PMC 6331199. PMID 30656180.
  47. ^ "RTA 408 Capsules in Patients With Friedreich's Ataxia - MOXIe".
  48. ^ "Part 2 of the Phase II MOXIe study (RTA 408 or omaveloxolone)".
  49. ^ 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.
  50. ^ 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.
  51. ^ Zesiewicz, T.; Heerinckx, F.; De Jager, R.; Omidvar, O.; Kilpatrick, M.; Shaw, J.; Shchepinov, M. S. (2018). "Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia". Movement Disorders. 33 (6): 1000–1005. doi:10.1002/mds.27353. PMID 29624723.
  52. ^ "Safety and Efficacy of EPI-743 in Patients With Friedreich's Ataxia".
  53. ^ Sadun, Alfredo A.; Chicani, C. F.; Ross-Cisneros, F. N.; Barboni, P.; Thoolen, M.; Shrader, W. D.; Kubis, K.; Carelli, V.; Miller, G. (2012). "Effect of EPI-743 on the Clinical Course of the Mitochondrial Disease Leber Hereditary Optic Neuropathy". Archives of Neurology. 69 (3): 331–8. doi:10.1001/archneurol.2011.2972. PMID 22410442.
  54. ^ Enns, Gregory M.; Kinsman, Stephen L.; Perlman, Susan L.; Spicer, Kenneth M.; Abdenur, Jose E.; Cohen, Bruce H.; Amagata, Akiko; Barnes, Adam; Kheifets, Viktoria; Shrader, William D.; Thoolen, Martin; Blankenberg, Francis; Miller, Guy (2012). "Initial experience in the treatment of inherited mitochondrial disease with EPI-743". Molecular Genetics and Metabolism. 105 (1): 91–102. doi:10.1016/j.ymgme.2011.10.009. PMID 22115768.
  55. ^ Martinelli, Diego; Catteruccia, Michela; Piemonte, Fiorella; Pastore, Anna; Tozzi, Giulia; Dionisi-Vici, Carlo; Pontrelli, Giuseppe; Corsetti, Tiziana; Livadiotti, Susanna; Kheifets, Viktoria; Hinman, Andrew; Shrader, William D.; Thoolen, Martin; Klein, Matthew B.; Bertini, Enrico; Miller, Guy (2012). "EPI-743 reverses the progression of the pediatric mitochondrial disease—Genetically defined Leigh Syndrome". Molecular Genetics and Metabolism. 107 (3): 383–388. doi:10.1016/j.ymgme.2012.09.007. PMID 23010433.
  56. ^ "Bioelectron Pipeline".
  57. ^ "Epicatechin to Treat Friedreich's Ataxia".
  58. ^ Miller, James L.; Rai, Myriam; Frigon, Normand L.; Pandolfo, Massimo; Punnonen, Juha; Spencer, Jeffrey R. (2017). "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. doi:10.1016/j.neuropharm.2017.05.011. PMID 28504123.
  59. ^ "STATegics, Inc. Announces a New Grant from Friedreich's Ataxia Research Alliance" (PDF).
  60. ^ "FARA - Rare Disease Day 2017 – Friedreich ataxia: Researchers from Fratagene Therapeutics and the University of Rome "Tor Vergata" identify a new therapeutic target".
  61. ^ Rufini, Alessandra; Fortuni, Silvia; Arcuri, Gaetano; Condò, Ivano; Serio, Dario; Incani, Ottaviano; Malisan, Florence; Ventura, Natascia; Testi, Roberto (2011). "Preventing the ubiquitin–proteasome-dependent degradation of frataxin, the protein defective in Friedreich's ataxia". Human Molecular Genetics. 20 (7): 1253–1261. doi:10.1093/hmg/ddq566. PMID 21216878.
  62. ^ Benini, Monica; Fortuni, Silvia; Condò, Ivano; Alfedi, Giulia; Malisan, Florence; Toschi, Nicola; Serio, Dario; Massaro, Damiano Sergio; Arcuri, Gaetano; Testi, Roberto; Rufini, Alessandra (2017). "E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia". Cell Reports. 18 (8): 2007–2017. doi:10.1016/j.celrep.2017.01.079. PMC 5329121. PMID 28228265.
  63. ^ "BioMarin Highlights Breadth of Innovative Development Pipeline at R&D Day on October 18 in New York".
  64. ^ "Jupiter Orphan Therapeutics, Inc. Enters into a Global Licensing Agreement with Murdoch Childrens Research Institute" (PDF).
  65. ^ Alfedi G, Luffarelli R, Condò I, Pedini G, Mannucci L, Massaro DS, Benini M, Toschi N, Alaimo G, Panarello L, Pacini L, Fortuni S, Serio D, Malisan F, Testi R, Rufini A (January 2019). "Drug Repositiolning Screening Identifies Etravirine as a Potential Therapeutic for Friedreich's Ataxia". Movement Disorders. 34 (3): 323–334. doi:10.1002/mds.27604. PMID 30624801.
  66. ^ Jasoliya, Mittal; Sacca, Francesco; Sahdeo, Sunil; Chedin, Frederic; Pane, Chiara; Brescia Morra, Vincenzo; Filla, Alessandro; Pook, Mark; Cortopassi, Gino (June 2019). "Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich's Ataxia". PLOS ONE. 14 (6): e0217776. Bibcode:2019PLoSO..1417776J. doi:10.1371/journal.pone.0217776. PMC 6546270. PMID 31158268.
  67. ^ Perdomini, Morgane; Belbellaa, Brahim; Monassier, Laurent; Reutenauer, Laurence; Messaddeq, Nadia; Cartier, Nathalie; Crystal, Ronald G.; Aubourg, Patrick; Puccio, Hélène (2014). "Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia". Nature Medicine. 20 (5): 542–547. doi:10.1038/nm.3510. PMID 24705334.
  68. ^ 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.
  69. ^ Melão, Alice (2017-10-19). "CRISPR Therapeutics Receives FARA Grant to Develop Gene Editing Therapies for Friedreich's Ataxia". Friedreich's Ataxia News. Retrieved 21 April 2019.
  70. ^ Holden, Stephen (March 13, 2009). "The Cake Eaters". The New York Times. Retrieved 2009-07-08.
  71. ^ "Devastating Diagnosis Pushes Local Man To Live Bigger". CBS Sacramento. 2015-05-30. Archived from the original on 2015-06-16. Retrieved 2015-06-12.
  72. ^ "How the DNC Is Subtly Rebuking Donald Trump's Mockery of a Disabled Reporter". Slate. 2016-07-27. Archived from the original on 2018-12-15. Retrieved 2018-12-14.
  73. ^ "Man with rare nerve condition climbs Mount Kilimanjaro to raise money for charity". ITV. Archived from the original on 15 December 2018. Retrieved 14 December 2018.
  74. ^ "Shobhika Kalra: Meet the Dubai woman in wheelchair who helped build 1,000 ramps across UAE". GULF NEWS. Archived from the original on 2018-12-15. Retrieved 2018-12-14.

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