stringtranslate.com

Spinocerebellar ataxia

Spinocerebellar ataxia (SCA) is a progressive, degenerative,[1] genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of spinocerebellar ataxia at any given time. SCA is hereditary, progressive, degenerative, and often fatal. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder.[2]

Signs and symptoms

Spinocerebellar ataxia (SCA) is one of a group of genetic disorders characterized by slowly progressive incoordination of gait and is often associated with poor coordination of hands, speech, and eye movements. A review of different clinical features among SCA subtypes was recently published describing the frequency of non-cerebellar features, like parkinsonism, chorea, pyramidalism, cognitive impairment, peripheral neuropathy, seizures, among others.[3] As with other forms of ataxia, SCA frequently results in atrophy of the cerebellum,[4] loss of fine coordination of muscle movements leading to unsteady and clumsy motion, and other symptoms. Ocular deficits can be quantified using the SODA scale.[5]

The symptoms of an ataxia vary with the specific type and with the individual patient. In many cases a person with ataxia retains full mental capacity but progressively loses physical control.[citation needed]

Cause

The hereditary ataxias are categorized by mode of inheritance and causative gene or chromosomal locus. The hereditary ataxias can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.[citation needed]

Diagnosis

Classification

A few SCAs remain unspecified and can not be precisely diagnosed, but in the last decade[as of?] genetic testing has allowed precise identification of dozens of different SCAs and more tests are being added each year.[9] In 2008, a genetic ataxia blood test developed to test for 12 types of SCA, Friedreich's ataxia, and several others. However, since not every SCA has been genetically identified some SCAs are still diagnosed by neurological examination, which may include a physical exam, family history, MRI scanning of the brain and spine, and spinal tap.[10]

Many SCAs below fall under the category of polyglutamine diseases, which are caused when a disease-associated protein (i.e., ataxin-1, ataxin-3, etc.) contains a large number of repeats of glutamine residues, termed a polyQ sequence or a "CAG trinucleotide repeat" disease for either the one-letter designation or codon for glutamine respectively. The threshold for symptoms in most forms of SCA is around 35, though for SCA3 it extends beyond 50. Most polyglutamine diseases are dominant due to the interactions of resulting polyQ tail.[citation needed]

The first ataxia gene was identified in 1993 and called "Spinocerebellar ataxia type 1" (SCA1); later genes were called SCA2, SCA3, etc. Usually, the "type" number of "SCA" refers to the order in which the gene was found. At this time, there are at least 49 different gene mutations that have been found.[citation needed]

The following is a list of some of the many types of Spinocerebellar ataxia.

Others include SCA18, SCA20, SCA21, SCA23, SCA26, SCA28, and SCA29.

Four X-linked types have been described ( 302500, 302600, 301790, 301840), but only the first of these has so far been tied to a gene (SCAX1).

Treatment

Medication

There is no cure for spinocerebellar ataxia, which is currently considered to be a progressive and irreversible disease, although not all types cause equally severe disability.[24]

In general, treatments are directed towards alleviating symptoms, not the disease itself. Many patients with hereditary or idiopathic forms of ataxia have other symptoms in addition to ataxia. Medications or other therapies might be appropriate for some of these symptoms, which could include tremor, stiffness, depression, spasticity, and sleep disorders, among others. Both onset of initial symptoms and duration of disease are variable. If the disease is caused by a polyglutamine trinucleotide repeat CAG expansion, a longer expansion may lead to an earlier onset and a more radical progression of clinical symptoms. Typically, a person with this disease will eventually be unable to perform daily tasks (ADLs).[25] However, rehabilitation therapists can help patients to maximize their ability of self-care and delay deterioration to certain extent.[26] Researchers are exploring multiple avenues for a cure including RNA interference(RNAi) technology, the use of stem cells, and several other avenues.[27]

On January 18, 2017, BioBlast Pharma announced completion of Phase 2a clinical trials of their medication, trehalose, in the treatment of SCA3. BioBlast has received FDA Fast Track status and orphan drug status for their treatment. The information provided by BioBlast in their research indicates that they hope this treatment may prove efficacious in other SCA treatments that have similar pathology related to PolyA and PolyQ diseases.[28][29]

In addition, Dr. Beverly Davidson has been working on a methodology using RNAi technology to find a potential cure for over 2 decades.[30] Her research began in the mid-1990s and progressed to work with mouse models about a decade later and most recently has moved to a study with non-human primates. The results from her most recent research "are supportive of clinical application of this gene therapy".[31]

Finally, another gene transfer technology discovered in 2011 has also been shown by Boudreau et al. to hold great promise and offers yet another avenue to a potential future cure.[32]

N-Acetyl-Leucine

N-Acetyl-Leucine is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc (Oxford, United Kingdom).[33]

N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration (FDA)[34] and the European Medicines Agency (EMA)[35] for the treatment of various genetic diseases, including spinocerebellar ataxias. N-Acetyl-Leucine has also been granted Orphan Drug Designations in the US and EU for the related inherited cerebellar ataxia ataxia-telangiectasia U.S. Food & Drug Administration (FDA)[36] and the European Medicines Agency (EMA).[37]

Published case series studies have demonstrated the effects of acute treatment with N-Acetyl-Leucine for the treatment of inherited cerebellar ataxias, including spinocerebellar ataxias.[38][39] These studies further demonstrated that the treatment is well tolerated, with a good safety profile.[citation needed]A multinational clinical trial investigating N-Acetyl-L-Leucine for the treatment of a related inherited cerebellar ataxia, ataxia-telangiectasia, began in 2019.[40]

IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of Niemann-Pick disease type C[41] and GM2 gangliosidosis (Tay-Sachs and Sandhoff disease).[42] Future opportunities to develop N-Acetyl-Leucine include Lewy body dementia,[43] amyotrophic lateral sclerosis, restless leg syndrome, multiple sclerosis, and migraine.[44]

Rehabilitation

Physical therapists can assist patients in maintaining their level of independence through therapeutic exercise programmes. One recent research report demonstrated a gain of two SARA points (Scale for the Assessment and Rating of Ataxia) from physical therapy.[45] In general, physical therapy emphasises postural balance and gait training for ataxia patients.[46] General conditioning such as range-of-motion exercises and muscle strengthening would also be included in therapeutic exercise programmes. Research showed that spinocerebellar ataxia 2 (SCA2) patients[47] with a mild stage of the disease gained significant improvement in static balance and neurological indices after six months of a physical therapy exercise training program.[48] Occupational therapists may assist patients with incoordination or ataxia issues through the use of adaptive devices. Such devices may include a cane, crutches, walker, or wheelchair for those with impaired gait. Other devices are available to assist with writing, feeding, and self care if hand and arm coordination are impaired. A randomised clinical trial revealed that an intensive rehabilitation program with physical and occupational therapies for patients with degenerative cerebellar diseases can significantly improve functional gains in ataxia, gait, and activities of daily living. Some level of improvement was shown to be maintained 24 weeks post-treatment.[49] Speech language pathologists may use both behavioral intervention strategies as well as augmentative and alternative communication devices to help patients with impaired speech.[citation needed]

References

  1. ^ "spinocerebellar ataxia" at Dorland's Medical Dictionary
  2. ^ "Ataxias and Cerebellar or Spinocerebellar Degeneration Information Page". National Institute on Neurological Disorders and Stroke.
  3. ^ Rossi, M; Perez-Lloret, S; Doldan, L; Cerquetti, D; Balej, J; Millar Vernetti, P; Hawkes, H; Cammarota, A; Merello, M (2014). "Autosomal dominant cerebellar ataxias: A systematic review of clinical features". European Journal of Neurology. 21 (4): 607–15. doi:10.1111/ene.12350. hdl:11336/30194. PMID 24765663. S2CID 74661673.
  4. ^ "Spinocerebellar ataxia". Genes and Disease [Internet]. Bethesda MD: National Center for Biotechnology Information. 1998. NBK22234. — Gives a concise description of SCA, along with a picture of shrunken degenerated cerebellum.
  5. ^ Shaikh, A; Ji Soo, Kim (2022). "Scale for Ocular motor Disorders in Ataxia (SODA)". Journal of the Neurological Sciences. 443: 120472. doi:10.1016/j.jns.2022.120472. PMID 36403298. S2CID 253156325.
  6. ^ Khristich AN, Mirkin SM (March 2020). "On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability". J. Biol. Chem. 295 (13): 4134–4170. doi:10.1074/jbc.REV119.007678. PMC 7105313. PMID 32060097.
  7. ^ Figueroa, Karla P.; Gross, Caspar; Buena-Atienza, Elena; Paul, Sharan; Gandelman, Mandi; Kakar, Naseebullah; Sturm, Marc; Casadei, Nicolas; Admard, Jakob; Park, Joohyun; Zühlke, Christine; Hellenbroich, Yorck; Pozojevic, Jelena; Balachandran, Saranya; Händler, Kristian (2024-04-29). "A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy". Nature Genetics: 1–10. doi:10.1038/s41588-024-01719-5. ISSN 1546-1718.
  8. ^ Usdin K, House NC, Freudenreich CH (2015). "Repeat instability during DNA repair: Insights from model systems". Crit. Rev. Biochem. Mol. Biol. 50 (2): 142–67. doi:10.3109/10409238.2014.999192. PMC 4454471. PMID 25608779.
  9. ^ "FREQUENTLY ASKED QUESTIONS ABOUT... Gene Testing for Hereditary Ataxia" (PDF). Archived from the original (PDF) on 2015-07-27. Retrieved 2017-01-25.
  10. ^ www.ataxia.org[full citation needed]
  11. ^ sca1 at NIH/UW GeneTests
  12. ^ sca2 at NIH/UW GeneTests
  13. ^ sca3 at NIH/UW GeneTests
  14. ^ Spinocerebellar Ataxias including Machado-Joseph Disease at NINDS
  15. ^ sca6 at NIH/UW GeneTests
  16. ^ sca7 at NIH/UW GeneTests
  17. ^ sca8 at NIH/UW GeneTests
  18. ^ Mosemiller, A.K.; Dalton, J.C.; Day, J.W.; Ranum, L.P.W. (2003). "Molecular genetics of spinocerebellar ataxia type 8 (SCA8)". Cytogenetic and Genome Research. 100 (1–4): 175–83. doi:10.1159/000072852. PMID 14526178. S2CID 2292926.
  19. ^ sca10 at NIH/UW GeneTests
  20. ^ sca12 at NIH/UW GeneTests
  21. ^ sca14 at NIH/UW GeneTests
  22. ^ a b Perlman, Susan L. (2016). Evaluation and Management of Ataxic Disorders: An Overview for Physicians. Minneapolis: National Ataxia Foundation. p. 6. ISBN 978-0-943218-14-4. LCCN 2007923539.
  23. ^ Online Mendelian Inheritance in Man (OMIM): 609307
  24. ^ Jiang, Bingcheng; Glover, J.N. Mark; Weinfeld, Michael (January 2017). "Neurological disorders associated with DNA strand-break processing enzymes". Mechanisms of Ageing and Development. 161 (Pt A): 130–140. doi:10.1016/j.mad.2016.07.009. PMC 5266678. PMID 27470939.
  25. ^ Cruts, Marc; Engelborghs, Sebastiaan; van der Zee, Julie; Van Broeckhoven, Christine (1993). "C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia". In Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E.; Bean, Lora J.H.; Stephens, Karen; Amemiya, Anne (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID 25577942.
  26. ^ Synofzik, Matthis; Ilg, Winfried (2014). "Motor Training in Degenerative Spinocerebellar Disease: Ataxia-Specific Improvements by Intensive Physiotherapy and Exergames". BioMed Research International. 2014: 583507. doi:10.1155/2014/583507. PMC 4022207. PMID 24877117.
  27. ^ "Archived copy". Archived from the original on 2016-11-19. Retrieved 2017-01-26.{{cite web}}: CS1 maint: archived copy as title (link)
  28. ^ "Bioblast Announces Phase 2a Results of Trehalose in Patients with Spinocerebellar Ataxia Type 3 (SCA3)". Investors Hub. Retrieved 14 October 2017.
  29. ^ "The Orphan Genetic Disease Company: Bioblast Pharma Ltd. June 2016" (PDF). Bioblast Pharma Ltd. Retrieved 14 October 2017.
  30. ^ Veritas, Gene (17 August 2013). "RNA Interference for Treating Huntington's Disease: An Interview with Dr. Beverly Davidson". Vimeo. Retrieved 14 October 2017.
  31. ^ Keiser, M. S.; Kordower, J. H.; Gonzalez-Alegre, P; Davidson, B. L. (2015). "Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy". Brain. 138 (12): 3555–3566. doi:10.1093/brain/awv292. PMC 4840549. PMID 26490326.
  32. ^ Boudreau, Ryan L; Spengler, Ryan M; Davidson, Beverly L (December 2011). "Rational Design of Therapeutic siRNAs: Minimizing Off-targeting Potential to Improve the Safety of RNAi Therapy for Huntington's Disease". Molecular Therapy. 19 (12): 2169–2177. doi:10.1038/mt.2011.185. PMC 3242660. PMID 21952166.
  33. ^ "IntraBio". Archived from the original on 2019-08-01. Retrieved 2019-08-01.
  34. ^ "Search Orphan Drug Designations and Approvals". www.accessdata.fda.gov. Retrieved 2019-08-01.
  35. ^ FRANCISCO, Estela Miranda (2018-12-20). "EU/3/18/2059". European Medicines Agency. Retrieved 2019-08-01.
  36. ^ "Search Orphan Drug Designations and Approvals". www.accessdata.fda.gov. Retrieved 2019-08-01.
  37. ^ "Search Orphan Drug Designations and Approvals". www.accessdata.fda.gov. Retrieved 2019-08-01.
  38. ^ Cross, Jo (April 2006). "MEDLINE, PubMed, PubMed Central, and the NLM". Editors' Bulletin. 2 (1): 1–5. doi:10.1080/17521740701702115.
  39. ^ Schniepp, Roman; Strupp, Michael; Wuehr, Max; Jahn, Klaus; Dieterich, Marianne; Brandt, Thomas; Feil, Katharina (December 2016). "Acetyl-DL-leucine improves gait variability in patients with cerebellar ataxia—a case series". Cerebellum & Ataxias. 3 (1): 8. doi:10.1186/s40673-016-0046-2. PMC 4828858. PMID 27073690.
  40. ^ Clinical trial number NCT03759678 for "N-Acetyl-L-Leucine for Ataxia-Telangiectasia (A-T)" at ClinicalTrials.gov
  41. ^ Clinical trial number NCT03759639 for "N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC)" at ClinicalTrials.gov
  42. ^ Clinical trial number NCT03759665 for "N-Acetyl-L-Leucine for GM2 Gangliosdisosis (Tay-Sachs and Sandhoff Disease)" at ClinicalTrials.gov
  43. ^ "IntraBio". Archived from the original on 2019-08-01. Retrieved 2019-08-01.
  44. ^ Strupp, Michael; Bayer, Otmar; Feil, Katharina; Straube, Andreas (February 2019). "Prophylactic treatment of migraine with and without aura with acetyl-dl-leucine: a case series". Journal of Neurology. 266 (2): 525–529. doi:10.1007/s00415-018-9155-6. PMID 30547273. S2CID 56148131.
  45. ^ Synofzik, Matthis; Ilg, Winfried (2014). "Motor Training in Degenerative Spinocerebellar Disease: Ataxia-Specific Improvements by Intensive Physiotherapy and Exergames". BioMed Research International. 2014: 583507. doi:10.1155/2014/583507. PMC 4022207. PMID 24877117.
  46. ^ Marsden, J.; Harris, C. (2011). "Cerebellar ataxia: Pathophysiology and rehabilitation". Clinical Rehabilitation. 25 (3): 195–216. doi:10.1177/0269215510382495. PMID 21321055. S2CID 40374830.
  47. ^ "SCA2 information sheet from www.ataxia.org" (PDF). Archived from the original (PDF) on 2012-07-12. Retrieved 2012-05-10.
  48. ^ Trujillo-Martín, M.Mar; Serrano-Aguilar, Pedro; Monton-Álvarez, Fernando; Carrillo-Fumero, Romen (2009). "Effectiveness and safety of treatments for degenerative ataxias: A systematic review". Movement Disorders. 24 (8): 1111–24. doi:10.1002/mds.22564. PMID 19412936. S2CID 11008654.
  49. ^ Miyai, I.; Ito, M.; Hattori, N.; Mihara, M.; Hatakenaka, M.; Yagura, H.; Sobue, G.; Nishizawa, M.; Cerebellar Ataxia Rehabilitation Trialists Collaboration (2011). "Cerebellar Ataxia Rehabilitation Trial in Degenerative Cerebellar Diseases". Neurorehabilitation and Neural Repair. 26 (5): 515–22. doi:10.1177/1545968311425918. PMID 22140200. S2CID 23764699.

Further reading

External links