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Spinocerebellar ataxia

{{Short description|Progressive neurological disease}}

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{{Infobox medical condition (new)

| name = Spinocerebellar ataxia

| image = brain-cerebellum.png

| caption = Cerebellum (in blue) of the human brain

| synonyms= Spinocerebellar atrophy or Spinocerebellar degeneration

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Spinocerebellar ataxia (SCA) is a progressive, degenerative,{{DorlandsDict|one/000009888|spinocerebellar ataxia}} 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. 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.{{cite web |title=Ataxias and Cerebellar or Spinocerebellar Degeneration Information Page |url=https://www.ninds.nih.gov/health-information/disorders/ataxia |website=National Institute on Neurological Disorders and Stroke}} Currently, research is being conducted at universities, such as the University of Minnesota, to elucidate many of the unknown characteristics of the disease.{{Cite web |title=Spinocerebellar Ataxia {{!}} Research Computing |url=https://rc.umn.edu/project/spinocerebellar-ataxia |access-date=2024-09-17 |website=rc.umn.edu}}

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.{{cite journal | vauthors = Rossi M, Perez-Lloret S, Doldan L, Cerquetti D, Balej J, Millar Vernetti P, Hawkes H, Cammarota A, Merello M | title = Autosomal dominant cerebellar ataxias: a systematic review of clinical features | journal = European Journal of Neurology | volume = 21 | issue = 4 | pages = 607–615 | date = April 2014 | pmid = 24765663 | doi = 10.1111/ene.12350 | hdl-access = free | s2cid = 74661673 | hdl = 11336/30194 }} As with other forms of ataxia, SCA frequently results in atrophy of the cerebellum,{{cite book |chapter=Spinocerebellar ataxia |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK22234/ |title=Genes and Disease [Internet] |publisher=National Center for Biotechnology Information |location=Bethesda MD |year=1998 |id=NBK22234 |url=https://www.ncbi.nlm.nih.gov/books/n/gnd/TOC/}}{{dead link|date=July 2025|bot=medic}}{{cbignore|bot=medic}} — Gives a concise description of SCA, along with a picture of shrunken degenerated cerebellum. 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.{{cite journal | vauthors = Shaikh AG, Kim JS, Froment C, Koo YJ, Dupre N, Hadjivassiliou M, Honnorat J, Kothari S, Mitoma H, Rodrigue X, Soong BW, Subramony SH, Strupp M, Schmahmann J, Manto M | title = Scale for Ocular motor Disorders in Ataxia (SODA) | journal = Journal of the Neurological Sciences | volume = 443 | pages = 120472 | date = December 2022 | pmid = 36403298 | doi = 10.1016/j.jns.2022.120472 | s2cid = 253156325 }}

The symptoms of an ataxia vary with the specific type and with the individual patient. Many subtypes of spinocerebellar ataxia result in cases where an individual retains full mental capacity but progressively loses physical control, but nearly half of the identified subtypes result in cognitive dysfunction, dementia, and mental retardation.{{cite journal | vauthors = Teive HA, Arruda WO | title = Cognitive dysfunction in spinocerebellar ataxias | journal = Dementia & Neuropsychologia | volume = 3 | issue = 3 | pages = 180–187 | date = 2009 | pmid = 29213626 | pmc = 5618971 | doi = 10.1590/S1980-57642009DN30300002 }}

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|date=September 2020}}

  • Many types of autosomal dominant cerebellar ataxias for which specific genetic information is available are now known. Synonyms for autosomal-dominant cerebellar ataxias (ADCA) used prior to the current understanding of the molecular genetics were Marie's ataxia, inherited olivopontocerebellar atrophy, cerebello-olivary atrophy, or the more generic term "spinocerebellar degeneration." (Spinocerebellar degeneration is a rare inherited neurological disorder of the central nervous system characterized by the slow degeneration of certain areas of the brain. There are three forms of spinocerebellar degeneration: Types 1, 2, 3. Symptoms begin during adulthood.){{citation needed|date=April 2015}}
  • There are five typical autosomal-recessive disorders in which ataxia is a prominent feature: Friedreich ataxia, ataxia-telangiectasia, ataxia with vitamin E deficiency, ataxia with oculomotor apraxia (AOA), spastic ataxia. Disorder subdivisions: Friedreich's ataxia, spinocerebellar ataxia, ataxia telangiectasia, vasomotor ataxia, vestibulocerebellar, ataxiadynamia, ataxiophemia, and olivopontocerebellar atrophy.{{citation needed|date=April 2015}}
  • There have been reported cases where a polyglutamine expansion may lengthen when passed down, which often can result in an earlier age-of-onset and a more severe disease phenotype for individuals who inherit the disease allele. This falls under the category of genetic anticipation.{{cite journal | vauthors = Khristich AN, Mirkin SM | title = On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability | journal = The Journal of Biological Chemistry | volume = 295 | issue = 13 | pages = 4134–4170 | date = March 2020 | pmid = 32060097 | pmc = 7105313 | doi = 10.1074/jbc.REV119.007678 | doi-access = free }}{{cite journal | vauthors = Figueroa KP, Gross C, Buena-Atienza E, Paul S, Gandelman M, Kakar N, Sturm M, Casadei N, Admard J, Park J, Zühlke C, Hellenbroich Y, Pozojevic J, Balachandran S, Händler K, Zittel S, Timmann D, Erdlenbruch F, Herrmann L, Feindt T, Zenker M, Klopstock T, Dufke C, Scoles DR, Koeppen A, Spielmann M, Riess O, Ossowski S, Haack TB, Pulst SM | title = A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy | journal = Nature Genetics | volume = 56 | issue = 6 | pages = 1080–1089 | date = June 2024 | pmid = 38684900 | doi = 10.1038/s41588-024-01719-5 }} Several types of SCA are characterized by repeat expansion of the trinucleotide sequence CAG in DNA that encodes a polyglutamine repeat tract in protein. The expansion of CAG repeats over successive generations appears to be due to slipped strand mispairing during DNA replication or DNA repair.{{cite journal | vauthors = Usdin K, House NC, Freudenreich CH | title = Repeat instability during DNA repair: Insights from model systems | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 50 | issue = 2 | pages = 142–167 | date = 2015 | pmid = 25608779 | pmc = 4454471 | doi = 10.3109/10409238.2014.999192 }}

Image:Autosomal dominant - en.svg|There are numerous types of autosomal-dominant cerebellar ataxias

Image:autorecessive.svg|There are five typical autosomal recessive disorders in which ataxia is a prominent feature

Diagnosis

=Classification=

A few SCAs remain unspecified and can not be precisely diagnosed, but in the last decade{{As of?|date=September 2023}} genetic testing has allowed precise identification of dozens of different SCAs and more tests are being added each year.{{Cite web |url=http://www.ataxia.org/pdf/Gene_Testing_for_Hereditary_Ataxia.pdf |title=FREQUENTLY ASKED QUESTIONS ABOUT... Gene Testing for Hereditary Ataxia |access-date=2017-01-25 |archive-url=https://web.archive.org/web/20150727154044/http://www.ataxia.org/pdf/Gene_Testing_for_Hereditary_Ataxia.pdf |archive-date=2015-07-27 |url-status=dead }} 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.[http://www.ataxia.org www.ataxia.org]{{full citation needed|date=April 2015}}

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|date=April 2015}}

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|date=April 2015}}

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

class="wikitable"

!SCA Type

!Average Onset
(Range in Years)

!Average Duration
(Range in Years)

!What the patient experiences

!Common origin

!Problems
with DNA

SCA1{{GeneTests|sca1}} (ATXN1)

|4th decade
(<10 to >60)

|15 years
(10–35)

|Hypermetric saccades, slow saccades, upper motor neuron
(note: saccades relates to eye movement)

| 

|CAG repeat, 6p (Ataxin 1)

SCA2{{GeneTests|sca2}} (ATXN2)

|3rd–4th decade
(<10 to >60)

|10 years
(1–30)

|Diminished velocity saccades
areflexia (absence of neurologic reflexes)

|Cuba

|CAG repeat, 12q

SCA3{{GeneTests|sca3}} (MJD) (ATXN3)

|4th decade
(10–70)

|10 years
(1–20)

|Also called Machado-Joseph disease (MJD){{NINDS|spinocerebellar-ataxias-including-machado-joseph-disease|Spinocerebellar Ataxias including Machado-Joseph Disease}}
Gaze-evoked nystagmus (a rapid, involuntary, oscillatory motion of the eyeball)
upper motor neuron
slow saccades

|Azores
(Portugal)

|CAG repeat, 14q

SCA4 (PLEKHG4)

|4th–7th decade
(19–72)

|Decades

|areflexia (absence of neurologic reflexes)

| 

|Chromosome 16q

SCA5 (SPTBN2)

|3rd–4th decade
(10–68)

|>25 years

|Pure cerebellar

| 

|Chromosome 11

SCA6{{GeneTests|sca6}} (CACNA1A)

|5th–6th decade
(19–71)

|>25 years

|Downbeating nystagmus, positional vertigo
Symptoms can appear for the first time as late as 65 years old.

| 

|CAG repeat, 19p
Calcium channel gene

SCA7{{GeneTests|sca7}} (ATXN7)

|3rd–4th decade
(0.5–60)

|20 years
(1–45; early onset correlates with shorter duration)

|Macular degeneration, upper motor neuron, slow saccades

| 

|CAG repeat, 3p (Ataxin 7)

SCA8{{GeneTests|sca8}} (IOSCA)

|39 yrs
(18–65)

|Normal lifespan

|Horizontal nystagmus (a rapid, involuntary, oscillatory motion of the eyeball), instability, lack of coordination

| 

|CTG repeat,{{cite journal | vauthors = Mosemiller AK, Dalton JC, Day JW, Ranum LP | title = Molecular genetics of spinocerebellar ataxia type 8 (SCA8) | journal = Cytogenetic and Genome Research | volume = 100 | issue = 1–4 | pages = 175–183 | year = 2003 | pmid = 14526178 | doi = 10.1159/000072852 | s2cid = 2292926 }} 13q

SCA10{{GeneTests|sca10}} (ATXN10)

|36 years

|9 years

|ataxia, seizures

|Mexico

|Chromosome 22q linked
pentanucleotide repeat

SCA11 (TTBK2)

|30 yrs
(15–70)

|Normal lifespan

|Mild, remain ambulatory (able to walk about on one's own)

| 

|15q

SCA12{{GeneTests|sca12}} (PPP2R2B)

|33 yrs
(8–55)

| 

|Head and hand tremor,
akinesia (loss of normal motor function, resulting in impaired muscle movement)

| 

|CAG repeat, 5q

SCA13 (KCNC3)

|Childhood or adulthood depending on mutation

|Depending on KCNC3 (a kind of gene)

|Intellectual disability

| 

|19q

SCA14{{GeneTests|sca14}} (PRKCG)

|28 yrs
(12–42)

|Decades
(1–30)

|Myoclonus (a sudden twitching of muscles or parts of muscles, without any rhythm or pattern, occurring in various brain disorders)

| 

|19q

SCA16 (ITPR1)

|39 yrs
(20–66)

|1–40 years

|Head and hand tremor

| 

|8q

SCA17 (TBP)

|

|

|

| 

|&nb|CAG repeat, 6q (TATA-binding protein)

SCA19, SCA22 (KCND3{{cite book| vauthors = Perlman SL |title=Evaluation and Management of Ataxic Disorders: An Overview for Physicians|date=2016|publisher=National Ataxia Foundation|location=Minneapolis|isbn=978-0-943218-14-4|lccn = 2007923539|page=6}})

| 

| 

|Mild cerebellar syndrome, dysarthria

| 

| 

SCA25

|1.5–39 yrs

|Unknown

|ataxia with sensory neuropathy, vomiting and gastrointestinal pain.

| 

|2p

SCA27{{OMIM|609307}} (FGF14)

|15–20 yrs

|Unknown

|ataxia with poor cognition, dyskinesias and tremor.

| 

|FGF14 13q34

SCA35

|40–48 years

|Unknown

|gait and limb ataxia, dysarthria, ocular dysmetria, intention tremor, pseudobulbar palsy, spasmodic torticollis, extensor plantar responses, reduced proprioception and hyperreflexia

|China

|transglutaminase 6 (TGM6) located at chromosome 20p13

SCA36

|5th and 6th decade (adulthood)

|Decades

|ataxia, hyperrheflexia, dysarthria, fasciculations of the tongue with subsequent wasting of the tongue

|

|NOP56

SCA37

|Adulthood

|Decades

|dysarthria, slowly progressive gait and limb ataxia with severe dysmetria in the lower extremities, mild dysmetria in the upper extremities, dysphagia, and abnormal ocular movements

|

|DAB1

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

Four X-linked types have been described ({{OMIM|302500||none}}, {{OMIM|302600||none}}, {{OMIM|301790||none}}, {{OMIM|301840||none}}), but only the first of these has so far been tied to a gene (SCAX1).

class="wikitable"
Name

! OMIM

! RareDiseases

! Other

Anemia, sideroblastic spinocerebellar ataxia; Pagon Bird Detter syndrome

| {{OMIM|301310

none}}

| {{RareDiseases|668}}

|

Friedreich's ataxia; Spinocerebellar ataxia, Friedreich

| {{OMIM|229300

none}}

| {{RareDiseases|6468}}

|

Infantile onset Spinocerebellar ataxia

| {{OMIM|605361

none}}

| {{RareDiseases|4062}}

|

Spinocerebellar ataxia 1

| {{OMIM|164400

none}}

| {{RareDiseases|4071}}

|

Spinocerebellar ataxia 2

| {{OMIM|183090

none}}

| {{RareDiseases|4072}}

|

Spinocerebellar ataxia 3; Machado Joseph disease

| {{OMIM|109150

none}}

| {{RareDiseases|6801}}

|

Spinocerebellar ataxia 4

| {{OMIM|600223

none}}

| {{RareDiseases|9970}}

|

Spinocerebellar ataxia 5

| {{OMIM|600224

none}}

| {{RareDiseases|4953}}

|

Spinocerebellar ataxia 7

| {{OMIM|164500

none}}

| {{RareDiseases|4955}}

|

Spinocerebellar ataxia 8

| {{OMIM|603680

none}}

| {{RareDiseases|4956}}

|

Spinocerebellar ataxia 13

| {{OMIM|605259

none}}

| {{RareDiseases|9611}}

|

Spinocerebellar ataxia 18

| {{OMIM|607458

none}}

| {{RareDiseases|9976}}

|

Spinocerebellar ataxia 19

| {{OMIM|607346

none}}

| {{RareDiseases|9969}}

|

Spinocerebellar ataxia 20

| {{OMIM|608687

none}}

| {{RareDiseases|9997}}

|

Spinocerebellar ataxia 21

| {{OMIM|607454

none}}

| {{RareDiseases|9999}}

|

Spinocerebellar ataxia 23

| {{OMIM|610245

none}}

| {{RareDiseases|9950}}

|

Spinocerebellar ataxia 25

| {{OMIM|608703

none}}

| {{RareDiseases|9996}}

|

Spinocerebellar ataxia 26

| {{OMIM|609306

none}}

| {{RareDiseases|9995}}

|

Spinocerebellar ataxia 28

| {{OMIM|610246

none}}

| {{RareDiseases|9951}}

|

Spinocerebellar ataxia 30

| {{OMIM|117360

none}}

| {{RareDiseases|9975}}

|

Spinocerebellar ataxia 35

| {{OMIM|613908

none}}

| {{RareDiseases

}

|

|-

| {{Anchor|Autosomal recessive}}Spinocerebellar ataxia amyotrophy deafness syndrome

|

| {{RareDiseases|2451}}

| [https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=1990&Disease_Disease_Search_diseaseGroup=Spinocerebellar-ataxia-amyotrophy-deafness-&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Gemignani-syndrome&title=Gemignani%20syndrome&search=Disease_Search_Simple ORPHA:2074] at Orphanet

|-

| Spinocerebellar ataxia, autosomal recessive 1

| {{OMIM|606002||none}}

| {{RareDiseases|4949}}

|

|-

| Spinocerebellar ataxia, autosomal recessive 3

| {{OMIM|271250||none}}

| {{RareDiseases|9971}}

|

|-

| Spinocerebellar ataxia, autosomal recessive 4

| {{OMIM|607317||none}}

| {{RareDiseases|4952}}

|

|-

| Spinocerebellar ataxia, autosomal recessive 5

| {{OMIM|606937||none}}

| {{RareDiseases|9977}}

|

|-

| Spinocerebellar ataxia, autosomal recessive 6

| {{OMIM|608029||none}}

| {{RareDiseases|4954}}

|

|-

| Spinocerebellar ataxia, autosomal recessive 21 - mutation in SCYL1

| {{OMIM|616719}}

|

| [https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=24170&Disease_Disease_Search_diseaseGroup=Spinocerebellar-ataxia--autosomal-recessive-21&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Acute-infantile-liver-failure-cerebellar-ataxia-peripheral-sensory-motor-neuropathy-syndrome&title=Acute%20infantile%20liver%20failure-cerebellar%20ataxia-peripheral%20sensory%20motor%20neuropathy%20syndrome&search=Disease_Search_Simple ORPHA:466794]

|-

| Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy

| {{OMIM|607250||none}}

| {{RareDiseases|10000}}

|

|-

| Spinocerebellar ataxia, X-linked, 2

| {{OMIM|302600||none}}

| {{RareDiseases|9978}}

|

|-

| Spinocerebellar ataxia, X-linked, 3

| {{OMIM|301790||none}}

| {{RareDiseases|9981}}

|

|-

| Spinocerebellar ataxia, X-linked, 4

| {{OMIM|301840||none}}

| {{RareDiseases|9980}}

|

|}

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.{{cite journal | vauthors = Jiang B, Glover JN, Weinfeld M | title = Neurological disorders associated with DNA strand-break processing enzymes | journal = Mechanisms of Ageing and Development | volume = 161 | issue = Pt A | pages = 130–140 | date = January 2017 | pmid = 27470939 | pmc = 5266678 | doi = 10.1016/j.mad.2016.07.009 }}

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).{{Cite book | vauthors = Cruts M, Engelborghs S, van der Zee J, Van Broeckhoven C |chapter=C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK268647/ | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A |title=GeneReviews |date=1993|publisher=University of Washington, Seattle |pmid=25577942 }} However, rehabilitation therapists can help patients to maximize their ability of self-care and delay deterioration to certain extent.{{cite journal | vauthors = Synofzik M, Ilg W | title = Motor training in degenerative spinocerebellar disease: ataxia-specific improvements by intensive physiotherapy and exergames | journal = BioMed Research International | volume = 2014 | pages = 583507 | date = 2014 | pmid = 24877117 | pmc = 4022207 | doi = 10.1155/2014/583507 | doi-access = free }} Researchers are exploring multiple avenues for a cure including RNA interference

(RNAi) technology, the use of stem cells, and several other avenues.{{cite web |url=http://www.ataxia.org/events/2016-Presentations/Sunday/Update%20on%20SCA%20Research%20-%20Wilmot.pptx | vauthors = Wilmot G | publisher = National Ataxia Foundation |title= Update on SCA Research |access-date=2017-01-26 |url-status=dead |archive-url=https://web.archive.org/web/20161119043550/http://ataxia.org/events/2016-Presentations/Sunday/Update%20on%20SCA%20Research%20-%20Wilmot.pptx |archive-date=2016-11-19 }}

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.{{cite web|title=Bioblast Announces Phase 2a Results of Trehalose in Patients with Spinocerebellar Ataxia Type 3 (SCA3)|url=http://ih.advfn.com/p.php?pid=nmona&article=73638650|website=Investors Hub|access-date=14 October 2017}}{{cite web|title=The Orphan Genetic Disease Company: Bioblast Pharma Ltd. June 2016|url=https://bioblastpharma.com/sites/default/files/pdfs/BioBlast-Corporate-Presentation.pdf|publisher=Bioblast Pharma Ltd.|access-date=14 October 2017}}

In addition, Dr. Beverly Davidson has been working on a methodology using RNAi technology to find a potential cure for over 2 decades.{{cite web| vauthors = Veritas G |title=RNA Interference for Treating Huntington's Disease: An Interview with Dr. Beverly Davidson|url=https://vimeo.com/72561489|website=Vimeo|access-date=14 October 2017|date=17 August 2013}} 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".{{cite journal | vauthors = Keiser MS, Kordower JH, Gonzalez-Alegre P, Davidson BL | title = Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy | journal = Brain | volume = 138 | issue = Pt 12 | pages = 3555–3566 | date = December 2015 | pmid = 26490326 | pmc = 4840549 | doi = 10.1093/brain/awv292 }}

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.{{cite journal | vauthors = Boudreau RL, Spengler RM, Davidson BL | title = Rational design of therapeutic siRNAs: minimizing off-targeting potential to improve the safety of RNAi therapy for Huntington's disease | journal = Molecular Therapy | volume = 19 | issue = 12 | pages = 2169–2177 | date = December 2011 | pmid = 21952166 | pmc = 3242660 | doi = 10.1038/mt.2011.185 }}

= 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).{{Cite web|url=http://intrabio.com/for-medical-professionals/|title=IntraBio|access-date=2019-08-01|archive-date=2019-08-01|archive-url=https://web.archive.org/web/20190801041947/http://intrabio.com/for-medical-professionals/|url-status=dead}}

N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration (FDA){{Cite web|url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=640818|archive-url=https://web.archive.org/web/20210428042901/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=640818|url-status=dead|archive-date=April 28, 2021|title=Search Orphan Drug Designations and Approvals|website=www.accessdata.fda.gov|access-date=2019-08-01}} and the European Medicines Agency (EMA){{Cite web|url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3182059|title=EU/3/18/2059| vauthors = Francisco EM |date=2018-12-20|website=European Medicines Agency|access-date=2019-08-01}} 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){{Cite web|url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=631918|archive-url=https://web.archive.org/web/20210427183332/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=631918|url-status=dead|archive-date=April 27, 2021|title=Search Orphan Drug Designations and Approvals|website=www.accessdata.fda.gov|access-date=2019-08-01}} and the European Medicines Agency (EMA).{{Cite web|url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=653218|archive-url=https://web.archive.org/web/20210428082859/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=653218|url-status=dead|archive-date=April 28, 2021|title=Search Orphan Drug Designations and Approvals|website=www.accessdata.fda.gov|access-date=2019-08-01}}

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.{{cite journal | vauthors = Cross J |title=MEDLINE, PubMed, PubMed Central, and the NLM |journal=Editors' Bulletin |date=April 2006 |volume=2 |issue=1 |pages=1–5 |doi=10.1080/17521740701702115 |doi-access=free }}{{cite journal | vauthors = Schniepp R, Strupp M, Wuehr M, Jahn K, Dieterich M, Brandt T, Feil K | title = Acetyl-DL-leucine improves gait variability in patients with cerebellar ataxia-a case series | journal = Cerebellum & Ataxias | volume = 3 | issue = 1 | pages = 8 | date = December 2016 | pmid = 27073690 | pmc = 4828858 | doi = 10.1186/s40673-016-0046-2 | doi-access = free }} These studies further demonstrated that the treatment is well tolerated, with a good safety profile.{{citation needed|date=December 2020}}

A multinational clinical trial investigating N-Acetyl-L-Leucine for the treatment of a related inherited cerebellar ataxia, ataxia-telangiectasia, began in 2019.{{ClinicalTrialsGov|NCT03759678|N-Acetyl-L-Leucine for Ataxia-Telangiectasia (A-T)}}

IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of Niemann-Pick disease type C{{ClinicalTrialsGov|NCT03759639|N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC)}} and GM2 gangliosidosis (Tay-Sachs and Sandhoff disease).{{ClinicalTrialsGov|NCT03759665|N-Acetyl-L-Leucine for GM2 Gangliosdisosis (Tay-Sachs and Sandhoff Disease)}} Future opportunities to develop N-Acetyl-Leucine include Lewy body dementia,{{Cite web|url=http://intrabio.com/2018/12/02/intrabio-announces-clinical-results-for-treatment-of-dementia/|title=IntraBio|access-date=2019-08-01|archive-date=2019-08-01|archive-url=https://web.archive.org/web/20190801041945/http://intrabio.com/2018/12/02/intrabio-announces-clinical-results-for-treatment-of-dementia/|url-status=dead}} amyotrophic lateral sclerosis, restless leg syndrome, multiple sclerosis, and migraine.{{cite journal | vauthors = Strupp M, Bayer O, Feil K, Straube A | title = Prophylactic treatment of migraine with and without aura with acetyl-DL-leucine: a case series | journal = Journal of Neurology | volume = 266 | issue = 2 | pages = 525–529 | date = February 2019 | pmid = 30547273 | doi = 10.1007/s00415-018-9155-6 | s2cid = 56148131 }}

=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.{{cite journal | vauthors = Synofzik M, Ilg W | title = Motor training in degenerative spinocerebellar disease: ataxia-specific improvements by intensive physiotherapy and exergames | journal = BioMed Research International | volume = 2014 | pages = 583507 | date = 2014 | pmid = 24877117 | pmc = 4022207 | doi = 10.1155/2014/583507 | doi-access = free }} In general, physical therapy emphasises postural balance and gait training for ataxia patients.{{cite journal | vauthors = Marsden J, Harris C | title = Cerebellar ataxia: pathophysiology and rehabilitation | journal = Clinical Rehabilitation | volume = 25 | issue = 3 | pages = 195–216 | date = March 2011 | pmid = 21321055 | doi = 10.1177/0269215510382495 | s2cid = 40374830 }} 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{{cite web |title=SCA2 information sheet from www.ataxia.org |url=http://www.ataxia.org/pdf/NAF%20Web%20Content%20Publication%20SCA2.pdf |access-date=2012-05-10 |archive-url=https://web.archive.org/web/20120712190355/http://www.ataxia.org/pdf/NAF%20Web%20Content%20Publication%20SCA2.pdf |archive-date=2012-07-12 |url-status=dead }} 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.{{cite journal | vauthors = Trujillo-Martín MM, Serrano-Aguilar P, Monton-Alvarez F, Carrillo-Fumero R | title = Effectiveness and safety of treatments for degenerative ataxias: a systematic review | journal = Movement Disorders | volume = 24 | issue = 8 | pages = 1111–1124 | date = June 2009 | pmid = 19412936 | doi = 10.1002/mds.22564 | s2cid = 11008654 | hdl = 10261/212902 | hdl-access = free }} 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.{{cite journal | vauthors = Miyai I, Ito M, Hattori N, Mihara M, Hatakenaka M, Yagura H, Sobue G, Nishizawa M | title = Cerebellar ataxia rehabilitation trial in degenerative cerebellar diseases | journal = Neurorehabilitation and Neural Repair | volume = 26 | issue = 5 | pages = 515–522 | date = June 2012 | pmid = 22140200 | doi = 10.1177/1545968311425918 | s2cid = 23764699 | author9 = Cerebellar Ataxia Rehabilitation Trialists Collaboration | doi-access = free }} 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|date=December 2020}}

References

{{Reflist}}

Further reading

{{refbegin}}

  • {{cite book | vauthors = Perlman S | chapter = Hereditary Ataxia Overview |date=23 January 2014 |pmid=20301317 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1138/ | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A |title=GeneReviews [Internet] |publisher=University of Washington, Seattle |location=Seattle WA |id=NBK1138 }}
  • {{cite book | vauthors = Moreira MC, Koenig M | chapter = Ataxia with Oculomotor Apraxia Type 2 |date=December 8, 2011 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1154/ | veditors = Adam MP, Feldman J, Mirzaa GM, etal |title=GeneReviews [Internet] |publisher=University of Washington, Seattle |pmid=20301333 |id=NBK1154 }}
  • {{cite book | vauthors = Pulst SM | chapter = Spinocerebellar Ataxia Type 13 |pmid=20301404 |id=NBK1225 |date=1 March 2012 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1225/ |title=GeneReviews [Internet] |publisher=University of Washington, Seattle |location=Seattle WA}}
  • {{cite book | vauthors = Brussino A, Brusco A, Dürr A | chapter = Spinocerebellar Ataxia Type 28 |pmid=21595125 |id=NBK54582 |date=7 February 2013 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK54582/ | veditors = Adam MP, Feldman J, Mirzaa GM, etal |title=GeneReviews [Internet] |publisher=University of Washington, Seattle |location=Seattle WA}}
  • {{cite journal | vauthors = Nikonishyna YV, Ortner NJ, Kaserer T, Hoffmann J, Biskup S, Dafotakis M, Reetz K, Schulz JB, Striessnig J, Dohrn MF | title = Novel CACNA1A Variant p.Cys256Phe Disrupts Disulfide Bonds and Causes Spinocerebellar Ataxia | journal = Movement Disorders | volume = 37 | issue = 2 | pages = 401–404 | date = February 2022 | pmid = 34647648 | doi = 10.1002/mds.28835 | publisher = Movement disorders: official journal of the Movement Disorder Society | s2cid = 238859984 | doi-access = free }}

{{refend}}

External links

  • {{OMIM|606002|Spinocerebellar Ataxia, Autosomal Recessive 1; SCAR1 }}
  • {{OMIM|608465|Senataxin; SETX}}
  • {{NINDS|ataxia-and-cerebellar-or-spinocerebellar-degeneration|Ataxia and Cerebellar or Spinocerebellar Degeneration}}
  • {{NINDS|spinocerebellar-ataxias-including-machado-joseph-disease|Spinocerebellar Ataxias including Machado-Joseph Disease}}
  • {{NINDS|multiple-system-atrophy|Multiple System Atrophy}}
  • {{MedlinePlusEncyclopedia|000758|Olivopontocerebellar atrophy}}
  • {{RareDiseases|9963|Spinocerebellar ataxia 27}}
  • {{RareDiseases|4958|Spinocerebellar ataxia dysmorphism}}

{{Medical resources

| DiseasesDB = 12339

| ICD10 = {{ICD10|G|11|1|g|10}}

| ICD9 = {{ICD9|334}}

| ICDO =

| OMIM = 164400

| MedlinePlus =

| eMedicineSubj =

| eMedicineTopic =

| MeshID = D020754

}}

{{Diseases of the nervous system}}

{{Trinucleotide repeat disorders}}

{{Inherited disorders of trafficking}}

{{Authority control}}

{{DEFAULTSORT:Spinocerebellar Ataxia}}

Category:Autosomal dominant disorders

Category:Systemic atrophies primarily affecting the central nervous system

Category:Neurodegenerative disorders

Category:Cytoskeletal defects

Category:Rare diseases