KEGG   DISEASE: Spinocerebellar ataxia (SCA)
Entry
H00063                      Disease                                

Name
Spinocerebellar ataxia (SCA)
  Subgroup
Machado-Joseph disease [DS:H01478]
  Supergrp
Spinocerebellar degeneration [DS:H01616]
Description
The autosomal dominant spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative diseases characterised by loss of balance and motor coordination due to the primary dysfunction of the cerebellum. Compelling evidence points to major aetiological roles for transcriptional dysregulation, protein aggregation and clearance, autophagy, the ubiquitin-proteasome system, alterations of calcium homeostasis, mitochondria defects, toxic RNA gain-of-function mechanisms and eventual cell death with apoptotic features of neurons during SCA disease progression.
Category
Neurodegenerative disease
Brite
Human diseases [BR:br08402]
 Nervous system diseases
  Neurodegenerative diseases
   H00063  Spinocerebellar ataxia (SCA)
Human diseases in ICD-11 classification [BR:br08403]
 08 Diseases of the nervous system
  Movement disorders
   8A03  Ataxic disorders
    H00063  Spinocerebellar ataxia (SCA)
Pathway
hsa05017  Spinocerebellar ataxia
hsa04730  Long-term depression
hsa03008  Ribosome biogenesis in eukaryotes
Network
nt06410  Calcium signaling
nt06411  Potassium transport
nt06413  Autophagy
nt06415  PI3K signaling
nt06440  Transcription
nt06462  Spinocerebellar ataxia
  Element
N00954  Mutation-activated GRM1 to mGluR1-TRPC3 signaling pathway
N00955  Mutation-inactivated PRKCG to mGluR1-TRPC3 signaling pathway
N00956  Mutation-activated PRKCG to mGluR1-TRPC3 signaling pathway
N00957  Mutation-caused abberant ATXN2/3 to mGluR5-Ca2+ -apoptotic pathway
N00958  Mutation-activated ITPR1 to mGluR1-TRPC3 signaling pathway
N00959  ITPR1-reduced expression to mGluR1-TRPC3 signaling pathway
N00960  Mutation-caused aberrant SPTBN2 to mGluR1-TRPC3 signaling pathway
N00961  Mutation-activated TRPC3 to mGluR1-TRPC3 signaling pathway
N00962  Mutation-inactivated ATXN3 to autophagy-vesicle nucleation
N00964  DAB1-overexpression to RELN-VLDLR-PI3K signaling pathway
N00966  Mutation-caused aberrant ATXN1 to RORA-mediated transcription
N00968  Mutation-activated CACNA1A to VGCC-Ca2+ -apoptotic pathway
N00969  Mutation-inactivated CACNA1A to VGCC-Ca2- -apoptotic pathway
N00971  Mutation-caused aberrant PDYN to transport of calcium
N00973  Mutation-inactivated KCNC3 to transport of potassium
N00975  Mutation-inactivated KCND3 to transport of potassium
Gene
(SCA1) ATXN1 (CAG repeat expansion) [HSA:6310] [KO:K23616]
(SCA2) ATXN2 (CAG repeat expansion) [HSA:6311] [KO:K23625]
(SCA3) ATXN3 (CAG repeat expansion) [HSA:4287] [KO:K11863]
(SCA5) SPTBN2 [HSA:6712] [KO:K23932]
(SCA6) CACNA1A (CAG repeat expansion) [HSA:773] [KO:K04344]
(SCA7) ATXN7 (CAG repeat expansion) [HSA:6314] [KO:K11318]
(SCA8) ATXN8OS (CTG/CAG repeat expansion) [HSA:6315] [KO:K23933]
(SCA10) ATXN10 (ATTCT repeat expansion) [HSA:25814] [KO:K19323]
(SCA11) TTBK2 [HSA:146057] [KO:K08815]
(SCA12) PPP2R2B (CAG repeat expansion) [HSA:5521] [KO:K04354]
(SCA13) KCNC3 [HSA:3748] [KO:K04889]
(SCA14) PRKCG [HSA:5582] [KO:K19663]
(SCA15) ITPR1 (deletion) [HSA:3708] [KO:K04958]
(SCA17) TBP (CAG repeat expansion) [HSA:6908] [KO:K03120]
(SCA19/22) KCND3 [HSA:3752] [KO:K04893]
(SCA21) TMEM240 [HSA:339453]
(SCA23) PDYN [HSA:5173] [KO:K15840]
(SCA26) EEF2 [HSA:1938] [KO:K03234]
(SCA27) FGF14 [HSA:2259] [KO:K23920]
(SCA28) AFG3L2 [HSA:10939] [KO:K08956]
(SCA31) BEAN1 [HSA:146227] [KO:K19324]
(SCA35) TGM6 [HSA:343641] [KO:K05624]
(SCA36) NOP56 [HSA:10528] [KO:K14564]
(SCA37) DAB1 [HSA:1600] [KO:K20054]
(SCA38) ELOVL5 [HSA:60481] [KO:K10244]
(SCA40) CCDC88C [HSA:440193]
(SCA41) TRPC3 [HSA:7222] [KO:K04966]
(SCA42) CACNA1G [HSA:8913] [KO:K04854]
(SCA43) MME [HSA:4311] [KO:K01389]
(SCA44) GRM1 [HSA:2911] [KO:K04603]
(SCA45) FAT2 [HSA:2196] [KO:K16506]
(SCA46) PLD3 [HSA:23646] [KO:K16860]
(SCA47) PUM1 [HSA:9698] [KO:K17943]
Comment
Disease class: polyglutamine disease
Affected region: cerebellum, dentate nucleus, brain stem (SCA1); cerebellum, brain stem, frontotemporal lobes (frontal lobe and temporal lobe) (SCA2); cerebellum, basal ganglia, brain stem, spinal cord (SCA3); cerebellum (SCA5); cerebellum, dentate nucleus, inferior olive (SCA6); cerebellum, inferior olive, dentate nucleus, pontine nuclei (also the retina) (SCA7); cerebral cortex, cerebellum (SCA12); cerebellum, inferior olive (SCA17)
Microscopic lesion: neuronal inclusions (SCA1, SCA2, SCA3, SCA7, SCA17); cytoplasmic inclusions (SCA6)
Other DBs
ICD-11: 8A03.16
ICD-10: G31.9
MeSH: D020754
OMIM: 164400 183090 109150 600224 183086 164500 608768 603516 604432 604326 605259 605361 606658 607136 607346 607454 610245 609306 609307 610246 117210 613908 614153 615945 615957 616053 616410 616795 617018 617691 617769 617770 617931
Reference
PMID:19050414 (drug)
  Authors
Zesiewicz TA, Sullivan KL
  Title
Treatment of ataxia and imbalance with varenicline (chantix): report of 2 patients with spinocerebellar ataxia (types 3 and 14).
  Journal
Clin Neuropharmacol 31:363-5 (2008)
DOI:10.1097/WNF.0b013e31818736a9
Reference
PMID:18317266 (SCA3)
  Authors
Rub U, Brunt ER, Deller T
  Title
New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease).
  Journal
Curr Opin Neurol 21:111-6 (2008)
DOI:10.1097/WCO.0b013e3282f7673d
Reference
  Authors
Soong BW, Paulson HL
  Title
Spinocerebellar ataxias: an update.
  Journal
Curr Opin Neurol 20:438-46 (2007)
DOI:10.1097/WCO.0b013e3281fbd3dd
Reference
PMID:17590087 (SCA15)
  Authors
van de Leemput J, Chandran J, Knight MA, Holtzclaw LA, Scholz S, Cookson MR, Houlden H, Gwinn-Hardy K, Fung HC, Lin X, Hernandez D, Simon-Sanchez J, Wood NW, Giunti P, Rafferty I, Hardy J, Storey E, Gardner RJ, Forrest SM, Fisher EM, Russell JT, Cai H, Singleton AB
  Title
Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans.
  Journal
PLoS Genet 3:e108 (2007)
DOI:10.1371/journal.pgen.0030108
Reference
PMID:17390258 (SCA3)
  Authors
Paulson HL
  Title
Dominantly inherited ataxias: lessons learned from Machado-Joseph disease/spinocerebellar ataxia type 3.
  Journal
Semin Neurol 27:133-42 (2007)
DOI:10.1055/s-2007-971172
Reference
PMID:16927298 (SCA5)
  Authors
Bauer P, Schols L, Riess O
  Title
Spectrin mutations in spinocerebellar ataxia (SCA).
  Journal
Bioessays 28:785-7 (2006)
DOI:10.1002/bies.20443
Reference
PMID:15876340 (Drug)
  Authors
Liu CS, Hsu HM, Cheng WL, Hsieh M
  Title
Clinical and molecular events in patients with Machado-Joseph disease under lamotrigine therapy.
  Journal
Acta Neurol Scand 111:385-90 (2005)
DOI:10.1111/j.1600-0404.2005.00405.x
Reference
  Authors
Rudnicki DD, Margolis RL.
  Title
Repeat expansion and autosomal dominant neurodegenerative disorders: consensus and controversy.
  Journal
Expert Rev Mol Med 5:1-24 (2003)
DOI:10.1017/S1462399403006598
Reference
  Authors
Albin RL
  Title
Dominant ataxias and Friedreich ataxia: an update.
  Journal
Curr Opin Neurol 16:507-14 (2003)
DOI:10.1097/01.wco.0000084230.82329.d5
Reference
PMID:10525976 (SCA1, SCA2, SCA3)
  Authors
Burk K, Fetter M, Abele M, Laccone F, Brice A, Dichgans J, Klockgether T
  Title
Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3.
  Journal
J Neurol 246:789-97 (1999)
DOI:10.1007/s004150050456
Reference
  Authors
Kobayashi H, Abe K, Matsuura T, Ikeda Y, Hitomi T, Akechi Y, Habu T, Liu W, Okuda H, Koizumi A
  Title
Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement.
  Journal
Am J Hum Genet 89:121-30 (2011)
DOI:10.1016/j.ajhg.2011.05.015
Reference
  Authors
Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, van Dijk F, Verschuuren-Bemelmans C, Hageman G, van de Vlies P, Kusters B, van de Warrenburg BP, Kremer B, Wijmenga C, Sinke RJ, Swertz MA, Kampinga HH, Boddeke E, Verbeek DS
  Title
Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19.
  Journal
Ann Neurol 72:870-80 (2012)
DOI:10.1002/ana.23700
Reference
  Authors
Delplanque J, Devos D, Huin V, Genet A, Sand O, Moreau C, Goizet C, Charles P, Anheim M, Monin ML, Buee L, Destee A, Grolez G, Delmaire C, Dujardin K, Dellacherie D, Brice A, Stevanin G, Strubi-Vuillaume I, Durr A, Sablonniere B
  Title
TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment.
  Journal
Brain 137:2657-63 (2014)
DOI:10.1093/brain/awu202
Reference
  Authors
Hekman KE, Yu GY, Brown CD, Zhu H, Du X, Gervin K, Undlien DE, Peterson A, Stevanin G, Clark HB, Pulst SM, Bird TD, White KP, Gomez CM
  Title
A conserved eEF2 coding variant in SCA26 leads to loss of translational fidelity and increased susceptibility to proteostatic insult.
  Journal
Hum Mol Genet 21:5472-83 (2012)
DOI:10.1093/hmg/dds392
Reference
  Authors
Guo YC, Lin JJ, Liao YC, Tsai PC, Lee YC, Soong BW
  Title
Spinocerebellar ataxia 35: novel mutations in TGM6 with clinical and genetic characterization.
  Journal
Neurology 83:1554-61 (2014)
DOI:10.1212/WNL.0000000000000909
Reference
  Authors
Di Gregorio E, Borroni B, Giorgio E, Lacerenza D, Ferrero M, Lo Buono N, Ragusa N, Mancini C, Gaussen M, Calcia A, Mitro N, Hoxha E, Mura I, Coviello DA, Moon YA, Tesson C, Vaula G, Couarch P, Orsi L, Duregon E, Papotti MG, Deleuze JF, Imbert J, Costanzi C, Padovani A, Giunti P, Maillet-Vioud M, Durr A, Brice A, Tempia F, Funaro A, Boccone L, Caruso D, Stevanin G, Brusco A
  Title
ELOVL5 mutations cause spinocerebellar ataxia 38.
  Journal
Am J Hum Genet 95:209-17 (2014)
DOI:10.1016/j.ajhg.2014.07.001
Reference
  Authors
Tsoi H, Yu AC, Chen ZS, Ng NK, Chan AY, Yuen LY, Abrigo JM, Tsang SY, Tsui SK, Tong TM, Lo IF, Lam ST, Mok VC, Wong LK, Ngo JC, Lau KF, Chan TF, Chan HY
  Title
A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.
  Journal
J Med Genet 51:590-5 (2014)
DOI:10.1136/jmedgenet-2014-102333
Reference
  Authors
Becker EB, Fogel BL, Rajakulendran S, Dulneva A, Hanna MG, Perlman SL, Geschwind DH, Davies KE
  Title
Candidate screening of the TRPC3 gene in cerebellar ataxia.
  Journal
Cerebellum 10:296-9 (2011)
DOI:10.1007/s12311-011-0253-6
Reference
  Authors
Chemin J, Monteil A, Perez-Reyes E, Bourinet E, Nargeot J, Lory P
  Title
Specific contribution of human T-type calcium channel isotypes (alpha(1G), alpha(1H) and alpha(1I)) to neuronal excitability.
  Journal
J Physiol 540:3-14 (2002)
DOI:10.1113/jphysiol.2001.013269
Reference
  Authors
Depondt C, Donatello S, Rai M, Wang FC, Manto M, Simonis N, Pandolfo M
  Title
MME mutation in dominant spinocerebellar ataxia with neuropathy (SCA43).
  Journal
Neurol Genet 2:e94 (2016)
DOI:10.1212/NXG.0000000000000094
Reference
  Authors
Matilla-Duenas A, Sanchez I, Corral-Juan M, Davalos A, Alvarez R, Latorre P
  Title
Cellular and molecular pathways triggering neurodegeneration in the spinocerebellar ataxias.
  Journal
Cerebellum 9:148-66 (2010)
DOI:10.1007/s12311-009-0144-2
Reference
  Authors
Sullivan R, Yau WY, O'Connor E, Houlden H
  Title
Spinocerebellar ataxia: an update.
  Journal
J Neurol 266:533-544 (2019)
DOI:10.1007/s00415-018-9076-4
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