Autosomal recessive spinocerebellar ataxias

Autosomal recessive spinocerebellar ataxias with axonal neuropathy (SCAN)

Autosomal recessive cerebellar ataxias (SCAR) are a heterogeneous group of inherited neurodegenerative disorders that affect the cerebellum, the spinocerebellar and sensory tracts of the spinal cord and often the sensory nerves. They may present as a pure cerebellar syndrome or are associated with neurological symptoms such as peripheral neuropathy, dystonia, chorea, cognitive impairment, optic atrophy, seizures or extra neurological symptoms such as cardiomyopathy and diabetes mellitus in Friedreich ataxia. The main clinical features are staggering gait with frequent falls, upper limb dysmetria, impairment of speech, dysphagia, and abnormalities of eye movement.

Neurodegenerative disease

(SCAR1/SCAN2) SETX [HSA:23064] [KO:K10706]
(SCAR2) PMPCA [HSA:23203] [KO:K01412]
(SCAR4) VPS13D [HSA:55187] [KO:K19527]
(SCAR7) TPP1 [HSA:1200] [KO:K01279]
(SCAR8) SYNE1 [HSA:23345] [KO:K19326]
(SCAR9) ADCK3 [HSA:56997] [KO:K08869]
(SCAR10) ANO10 [HSA:55129] [KO:K19327]
(SCAR11) SYT14 [HSA:255928] [KO:K19328]
(SCAR12) WWOX [HSA:51741] [KO:K19329]
(SCAR13) GRM1 [HSA:2911] [KO:K04603]
(SCAR14) SPTBN2 [HSA:6712] [KO:K23932]
(SCAR15) KIAA0226 [HSA:9711] [KO:K19330]
(SCAR16) STUB1 [HSA:10273] [KO:K09561]
(SCAR17) CWF19L1 [HSA:55280]
(SCAR18) GRID2 [HSA:2895] [KO:K05207]
(SCAR19) SLC9A1 [HSA:6548] [KO:K05742]
(SCAR20) SNX14 [HSA:57231] [KO:K17926]
(SCAR21) SCYL1 [HSA:57410] [KO:K08876]
(SCAR22) VWA3B [HSA:200403] [KO:K24509]
(SCAR23) TDP2 [HSA:51567] [KO:K19619]
(SCAR24) UBA5 [HSA:79876] [KO:K12164]
(SCAR25) ATG5 [HSA:9474] [KO:K08339]
(SCAR26) XRCC1 [HSA:7515] [KO:K10803]
(SCAR27) GDAP2 [HSA:54834]
(SCAR28) THG1L [HSA:54974] [KO:K10761]
(SCAN1) TDP1 [HSA:55775] [KO:K10862]
(SCAN3) COA7 [HSA:65260] [KO:K18180]

See also H00063 Spinocerebellar ataxia, H00067 Friedreich ataxia, and H00848 Ataxia with ocular apraxia.
SCAR19 is known as Lichtenstein-Knorr syndrome, and associates sensorineural hearing loss.

PMID:19440741

Anheim M, Fleury M, Monga B, Laugel V, Chaigne D, Rodier G, Ginglinger E, Boulay C, Courtois S, Drouot N, Fritsch M, Delaunoy JP, Stoppa-Lyonnet D, Tranchant C, Koenig M

Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management.

Neurogenetics 11:1-12 (2010)
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PMID:26657514

Choquet K, Zurita-Rendon O, La Piana R, Yang S, Dicaire MJ, Boycott KM, Majewski J, Shoubridge EA, Brais B, Tetreault M

Autosomal recessive cerebellar ataxia caused by a homozygous mutation in PMPCA.

Brain 139:e19 (2016)
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PMID:23418007

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Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).

Hum Mutat 34:706-13 (2013)
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PMID:17159980

Gros-Louis F, Dupre N, Dion P, Fox MA, Laurent S, Verreault S, Sanes JR, Bouchard JP, Rouleau GA

Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.

Nat Genet 39:80-5 (2007)
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PMID:18319074

Lagier-Tourenne C, Tazir M, Lopez LC, Quinzii CM, Assoum M, Drouot N, Busso C, Makri S, Ali-Pacha L, Benhassine T, Anheim M, Lynch DR, Thibault C, Plewniak F, Bianchetti L, Tranchant C, Poch O, DiMauro S, Mandel JL, Barros MH, Hirano M, Koenig M

ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency.

Am J Hum Genet 82:661-72 (2008)
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PMID:21092923

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Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia.

Am J Hum Genet 87:813-9 (2010)
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PMID:21835308

Doi H, Yoshida K, Yasuda T, Fukuda M, Fukuda Y, Morita H, Ikeda S, Kato R, Tsurusaki Y, Miyake N, Saitsu H, Sakai H, Miyatake S, Shiina M, Nukina N, Koyano S, Tsuji S, Kuroiwa Y, Matsumoto N

Exome sequencing reveals a homozygous SYT14 mutation in adult-onset, autosomal-recessive spinocerebellar ataxia with psychomotor retardation.

Am J Hum Genet 89:320-7 (2011)
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PMID:24369382

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The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation.

Brain 137:411-9 (2014)
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PMID:22901947

Guergueltcheva V, Azmanov DN, Angelicheva D, Smith KR, Chamova T, Florez L, Bynevelt M, Nguyen T, Cherninkova S, Bojinova V, Kaprelyan A, Angelova L, Morar B, Chandler D, Kaneva R, Bahlo M, Tournev I, Kalaydjieva L

Autosomal-recessive congenital cerebellar ataxia is caused by mutations in metabotropic glutamate receptor 1.

Am J Hum Genet 91:553-64 (2012)
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PMID:20826435

Assoum M, Salih MA, Drouot N, H'Mida-Ben Brahim D, Lagier-Tourenne C, AlDrees A, Elmalik SA, Ahmed TS, Seidahmed MZ, Kabiraj MM, Koenig M

Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia.

Brain 133:2439-47 (2010)
DOI:10.1093/brain/awq181

PMID:24312598

Shi Y, Wang J, Li JD, Ren H, Guan W, He M, Yan W, Zhou Y, Hu Z, Zhang J, Xiao J, Su Z, Dai M, Wang J, Jiang H, Guo J, Zhou Y, Zhang F, Li N, Du J, Xu Q, Hu Y, Pan Q, Shen L, Wang G, Xia K, Zhang Z, Tang B

Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.

PLoS One 8:e81884 (2013)
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PMID:27016154

Evers C, Kaufmann L, Seitz A, Paramasivam N, Granzow M, Karch S, Fischer C, Hinderhofer K, Gdynia G, Elsasser M, Pinkert S, Schlesner M, Bartram CR, Moog U

Exome sequencing reveals a novel CWF19L1 mutation associated with intellectual disability and cerebellar atrophy.

Am J Med Genet A 170:1502-9 (2016)
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PMID:24078737

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Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans.

Neurology 81:1378-86 (2013)
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PMID:25205112

Guissart C, Li X, Leheup B, Drouot N, Montaut-Verient B, Raffo E, Jonveaux P, Roux AF, Claustres M, Fliegel L, Koenig M

Mutation of SLC9A1, encoding the major Na(+)/H(+) exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome.

Hum Mol Genet 24:463-70 (2015)
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PMID:25848753

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Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.

Nat Genet 47:528-34 (2015)
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PMID:17571074

Schmidt WM, Kraus C, Hoger H, Hochmeister S, Oberndorfer F, Branka M, Bingemann S, Lassmann H, Muller M, Macedo-Souza LI, Vainzof M, Zatz M, Reis A, Bittner RE

Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration.

EMBO Rep 8:691-7 (2007)
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PMID:17948061

Hirano R, Interthal H, Huang C, Nakamura T, Deguchi K, Choi K, Bhattacharjee MB, Arimura K, Umehara F, Izumo S, Northrop JL, Salih MA, Inoue K, Armstrong DL, Champoux JJ, Takashima H, Boerkoel CF

Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation?

EMBO J 26:4732-43 (2007)
DOI:10.1038/sj.emboj.7601885

PMID:26157035

Kawarai T, Tajima A, Kuroda Y, Saji N, Orlacchio A, Terasawa H, Shimizu H, Kita Y, Izumi Y, Mitsui T, Imoto I, Kaji R

A homozygous mutation of VWA3B causes cerebellar ataxia with intellectual disability.

J Neurol Neurosurg Psychiatry 87:656-62 (2016)
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PMID:24658003

Gomez-Herreros F, Schuurs-Hoeijmakers JH, McCormack M, Greally MT, Rulten S, Romero-Granados R, Counihan TJ, Chaila E, Conroy J, Ennis S, Delanty N, Cortes-Ledesma F, de Brouwer AP, Cavalleri GL, El-Khamisy SF, de Vries BB, Caldecott KW

TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function.

Nat Genet 46:516-21 (2014)
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PMID:26872069

Duan R, Shi Y, Yu L, Zhang G, Li J, Lin Y, Guo J, Wang J, Shen L, Jiang H, Wang G, Tang B

UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia.

PLoS One 11:e0149039 (2016)
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PMID:29718187

Higuchi Y, Okunushi R, Hara T, Hashiguchi A, Yuan J, Yoshimura A, Murayama K, Ohtake A, Ando M, Hiramatsu Y, Ishihara S, Tanabe H, Okamoto Y, Matsuura E, Ueda T, Toda T, Yamashita S, Yamada K, Koide T, Yaguchi H, Mitsui J, Ishiura H, Yoshimura J, Doi K, Morishita S, Sato K, Nakagawa M, Yamaguchi M, Tsuji S, Takashima H

Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.

Brain 141:1622-1636 (2018)
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PMID:28002403

Hoch NC, Hanzlikova H, Rulten SL, Tetreault M, Komulainen E, Ju L, Hornyak P, Zeng Z, Gittens W, Rey SA, Staras K, Mancini GM, McKinnon PJ, Wang ZQ, Wagner JD, Yoon G, Caldecott KW

XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.

Nature 541:87-91 (2017)
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PMID:30084953

Eidhof I, Baets J, Kamsteeg EJ, Deconinck T, van Ninhuijs L, Martin JJ, Schule R, Zuchner S, De Jonghe P, Schenck A, van de Warrenburg BP

GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia.

Brain 141:2592-2604 (2018)
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PMID:27307223

Edvardson S, Elbaz-Alon Y, Jalas C, Matlock A, Patel K, Labbe K, Shaag A, Jackman JE, Elpeleg O

A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay.

Neurogenetics 17:219-225 (2016)
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