Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of type 1 autosomal dominant cerebellar ataxia (ADCA type 1), a neurodegenerative disorder, and is characterized by ataxia, external progressive ophthalmoplegia, and other neurological manifestations¹. Research suggests that length of ATXN2 expansions may affect the phenotype of SCA3².

Prevalence

2.1 100,000

1-5/100,000³. Most prevalent SCA subtype⁴. Found worldwide across ancestries/ethnicities⁵.

Age of Onset

Typical: 10-49⁵; 3⁶- 73^5,7.

HPO Terms

HP:0000508 Ptosis HP:0000520 Proptosis HP:0000544 External ophthalmoplegia HP:0000590 Progressive external ophthalmoplegia HP:0000623 Supranuclear ophthalmoplegia HP:0000639 Nystagmus HP:0000640 Gaze-evoked nystagmus HP:0000641 Dysmetric saccades HP:0000651 Diplopia HP:0000726 Dementia HP:0000750 Delayed speech and language development HP:0001151 Impaired horizontal smooth pursuit HP:0001251 Ataxia HP:0001257 Spasticity HP:0001260 Dysarthria HP:0001272 Cerebellar atrophy HP:0001300 Parkinsonism HP:0001332 Dystonia HP:0001347 Hyperreflexia HP:0001605 Vocal cord paralysis HP:0001751 Abnormal vestibular function HP:0002015 Dysphagia HP:0002063 Rigidity HP:0002067 Bradykinesia HP:0002070 Limb ataxia HP:0002071 Abnormality of extrapyramidal motor function HP:0002073 Progressive cerebellar ataxia HP:0002078 Truncal ataxia HP:0002171 Gliosis HP:0002172 Postural instability HP:0002198 Dilated fourth ventricle HP:0002312 Clumsiness HP:0002380 Fasciculations HP:0002495 Impaired vibratory sensation HP:0002503 Spinocerebellar tract degeneration HP:0002839 Urinary bladder sphincter dysfunction HP:0003202 Skeletal muscle atrophy HP:0003394 Muscle spasm HP:0003438 Absent Achilles reflex HP:0003487 Babinski sign HP:0003693 Distal amyotrophy HP:0004370 Abnormality of temperature regulation HP:0007089 Facial-lingual fasciculations HP:0007256 Abnormal pyramidal sign HP:0012332 Abnormal autonomic nervous system physiology HP:0012532 Chronic pain HP:0030454 Abnormal electrooculogram

Association

Mendelian

Locus

hg19 chr14:92537354-92537396

hg38 chr14:92071010-92071052

t2t chr14:86300519-86300603

Details

Benign alleles range from 11-44 repeats⁸, with intermediate alleles (45-59) associated with incomplete penetrance and non-classic phenotypes⁵. The threshold between incomplete and full penetrance is unclear, but presumed to occur at ~60 repeats^5,8. The interruption CAA has been observed⁹; AAG is present in hg38 reference sequence. The APOE ε4 allele appears to act as a disease modifier¹⁰; GLS expansions may also function as disease modifiers¹¹.

Mechanism

GoF

Polyglutamine expansion leading to gain of function; aggregated and mislocalized proteins in neurons^12,5. RAN translation has been demonstrated from the CUA/CUG transcript in cell-free and transfected-cell reporter systems¹³.

Detection

PCR fragment analysis or RP-PCR typically detect expansions, but homozygous PCR results may require Southern blotting to exclude allelic dropout of a larger expansion that failed to amplify⁵. Long-read sequencing can characterize full structure¹⁴.

Year

1994¹⁵

Location in Gene

Coding Exon 10

Gene Strand

Alleles

Ref. Motif

CTG

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

CTG

Pathogen. (gene)

CAG

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

TTG, AGG

Interrup. (gene)

CAA, CCT

gnomAD

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0007182

Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis.

Marilena,Lauerer, Jennifer,Faber, Nicolas,Casadei, Magda M,Santana, Georg,Auburger, Michaela,Pogoda, Jakob,Admard, Lea,Kaupp, Patricia Laura,Kos, Mafalda,Raposo, Manuela,Lima, Luis Pereira,de Almeida, Hector,Garcia-Moreno, Paola,Giunti, Jeroen,de Vries, Bart P,van de Warrenburg, Judith,van Gaalen, Marcus,Grobe-Einsler, Berkan,Koyak, Kathrin,Reetz, Friedrich,Erdlenbruch, Heike,Jacobi, Jon,Infante, Holger,Hengel, Ludger,Schöls, Thomas,Klockgether, Olaf,Rieß, Jeannette,Hübener-Schmid

Acta neuropathologica communications · 2025-07-19

pmid:40684213

Profiling of Short-Tandem-Repeat Disease Alleles in 12,632 Human Whole Genomes.

Haibao,Tang, Ewen F,Kirkness, Christoph,Lippert, William H,Biggs, Martin,Fabani, Ernesto,Guzman, Smriti,Ramakrishnan, Victor,Lavrenko, Boyko,Kakaradov, Claire,Hou, Barry,Hicks, David,Heckerman, Franz J,Och, C Thomas,Caskey, J Craig,Venter, Amalio,Telenti

American journal of human genetics · 2017-11-02

pmid:29100084

Spinocerebellar Ataxia

Jenish,Bhandari, Pawan K.,Thada, Debopam,Samanta

StatPearls · 2026-01-01

genereviews:NBK557816

5genereviews:NBK1196

Analysis of Short Tandem Repeat Expansions in a Cohort of 12,496 Exomes from Patients with Neurological Diseases Reveals Variable Genotyping Rate Dependent on Exome Capture Kits.

Clarissa,Rocca, David,Murphy, Chris,Clarkson, Matteo,Zanovello, Delia,Gagliardi, Queen Square,Genomics, Rauan,Kaiyrzhanov, Javeria,Alvi, Reza,Maroofian, Stephanie,Efthymiou, Tipu,Sultan, Jana,Vandrovcova, James,Polke, Robyn,Labrum, Henry,Houlden, Arianna,Tucci

Genes · 2025-01-28

pmid:40004498

Mitochondrial DNA haplogroups and age at onset of Machado-Joseph disease/spinocerebellar ataxia type 3: a study in patients from multiple populations.

A,Ramos, M,Planchat, A R,Vieira Melo, M,Raposo, U,Shamim, V,Suroliya, A K,Srivastava, M,Faruq, H,Morino, R,Ohsawa, H,Kawakami, L,Bannach Jardim, M L,Saraiva-Pereira, J,Vasconcelos, C,Santos, M,Lima

European journal of neurology · 2018-12-07

pmid:30414314

The Frequency of Intermediate Alleles in Patients with Cerebellar Phenotypes.

Elena,Capacci, Silvia,Bagnoli, Giulia,Giacomucci, Costanza Maria,Rapillo, Alessandra,Govoni, Valentina,Bessi, Cristina,Polito, Irene,Giotti, Alice,Brogi, Elisabetta,Pelo, Sandro,Sorbi, Benedetta,Nacmias, Camilla,Ferrari

Cerebellum (London, England) · 2023-10-31

pmid:37906407

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing.

Igor,Stevanovski, Sanjog R,Chintalaphani, Hasindu,Gamaarachchi, James M,Ferguson, Sandy S,Pineda, Carolin K,Scriba, Michel,Tchan, Victor,Fung, Karl,Ng, Andrea,Cortese, Henry,Houlden, Carol,Dobson-Stone, Lauren,Fitzpatrick, Glenda,Halliday, Gianina,Ravenscroft, Mark R,Davis, Nigel G,Laing, Avi,Fellner, Marina,Kennerson, Kishore R,Kumar, Ira W,Deveson

Science advances · 2022-03-04

pmid:35245110

Apolipoprotein E epsilon4 allele is associated with better performance language and visual memory in spinocerebellar ataxia type 3.

Xuanyu,Chen, Kunxin,Lin, Zhixian,Ye, Liangliang,Qiu, Yusen,Qiu, Ruying,Yuan, Xintong,Yu, Chunyu,Huang, Bi,Cheng, Wei,Lin, Tianmin,Lai, Wanjin,Chen, Ning,Wang, Shirui,Gan, Qiuni,Su, Ying,Fu

European journal of neurology · 2025-01-01

pmid:39731318

Genetic Analysis of GCA Repeats in the GLS Gene: Implications for Undiagnosed Ataxia and Spinocerebellar Ataxia 3 in Mainland China.

Lijing,Lei, Linliu,Peng, Linlin,Wan, Zhao,Chen, Chunrong,Wang, Huirong,Peng, Rong,Qiu, Beisha,Tang, Hong,Jiang

Movement disorders : official journal of the Movement Disorder Society · 2024-12-19

pmid:39699045

Clinical and neuroimaging review of triplet repeat diseases.

Ryo,Kurokawa, Mariko,Kurokawa, Akihiko,Mitsutake, Moto,Nakaya, Akira,Baba, Yasuhiro,Nakata, Toshio,Moritani, Osamu,Abe

Japanese journal of radiology · 2022-09-28

pmid:36169768

Upstream non-AUG initiation and ribosomal -1 frameshifting in ATXN8OS CTA/CTG repeat-associated translation.

Soyoka,Sakamoto, Hayato,Ito, Mayuka,Hasumi, Tatsuya,Morisaki, Makito,Hirano, Tatsuya,Niwa, Yoshitaka,Nagai, Timothy J,Stasevich, Hideki,Taguchi

Nucleic acids research · 2026-07-17

pmid:42483834

Long-read sequencing identifies ATXN3 repeat expansions, and transcriptomics reveals disease progression biomarkers and druggable targets for spinocerebellar ataxia type 3.

Chang,Liu, Xin,Wang, Chao,Xu, Xiaoxiang,Liu, Liyan,Ke, Ying,Li, Hang,Zhang, Jianqiang,Tan, Senwei,Tan, Zitong,Zhang, Liang,Cheng, Yaqiong,Ren, Lei,Shi

BMC neurology · 2025-09-01

pmid:40890629

CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.

Y,Kawaguchi, T,Okamoto, M,Taniwaki, M,Aizawa, M,Inoue, S,Katayama, H,Kawakami, S,Nakamura, M,Nishimura, I,Akiguchi

Nature genetics · 1994-11-01

pmid:7874163

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Establishing Sensory Neurons as Therapeutic Targets in Peripheral Neuropathy Driven by Polyglutamine Expanded Murine ATXN3.

Juan P,Mato, John M,Hayes, Jacen,Emerson, Maeha,Sridharan, Toluwani,Adelaja, Arsal,Naeem, Alexandra F,Putka, Hayley S,McLoughlin

Annals of neurology · 2026-07-31

pmid:42538636

How Early Should I Refer My Patient? The Benefits of a Quick Ophthalmic Referral in Spinocerebellar Ataxias, a Case Series and Literature Review.

Andrea B,Fiscal-Carvajal, José L,De-León-Guerra, Cristian E,Salinas-Aguirre, Marisol,Ibarra-Ramírez, Marissa L,Fernández-de-Luna, Ingrid E,Estrada-Bellmann, Joel,Arenas-Estala, Luis D,Campos-Acevedo, Jibran,Mohamed-Noriega

Brain sciences · 2026-07-17

pmid:42512530

Alterations in Skin Microbiota in Patients with Spinocerebellar Ataxia Type 3: A Pilot Study.

Jingzi,Peng, Lang,Sun, Zhao,Chen, Linlin,Wan, Chunrong,Wang, LinLiu,Peng, Daji,Chen, Zhe,Long, Yiqing,Gong, Yan,Tan, Qi,Wu, Rong,Qiu, Beisha,Tang, Hong,Jiang

Current neuropharmacology · 2026-07-07

pmid:42439334

Mapping the Disrupted Connectome in Spinocerebellar Ataxia Type 3: A Network-Based Statistics Study Identifying Novel Therapeutic Targets for Neuromodulation.

Lan,Ou, Chaoyang,Zhou, Xingang,Wang, Linfeng,Shi, Peiling,Ou, Chaodong,Xiang, Hui,Chen, Xi,Chen, Bijia,Wang, Wei,Chen, Jian,Wang, Zhiliang,Long, Chen,Liu

CNS neuroscience & therapeutics · 2026-07-01

pmid:42403360

Repeat expansions in Parkinson's disease and parkinsonism across ancestries: insights from a global genetic cohort.

Lara M,Lange, Catalina,Cerquera-Cleves, Ai Huey,Tan, Shen-Yang,Lim, Njideka U,Okubadejo, Chin-Hsien,Lin, Pin-Shiuan,Chen, Jung Hwan,Shin, Azlina,Ahmad-Annuar, Laurel A,Screven, Viorica,Chelban, Allison A,Dilliot, André,Fienemann, Kamalini Ghosh,Galvelis, Henry,Houlden, Hirotaka,Iwaki, Zane,Jaunmuktane, Patrick W,Cullinane, Thomas,Warner, Johanna,Junker, Yuliia,Kanana, Ignacio J Keller,Sarmiento, Christine,Klein, Pin-Jui,Kung, Hampton L,Leonard, Niccoló E,Mencacci, Mike A,Nalls, Raquel,Real, Samia Ben,Sassi, Joanne,Trinh, Dan,Vitale, Ana,Westenberger, Lesley Y,Wu, Andrew B,Singleton, Huw R,Morris, Katja,Lohmann, Cornelis,Blauwendraat, Peter,Heutink, Zih-Hua,Fang

medRxiv : the preprint server for health sciences · 2026-06-22

pmid:42396269

Replication analysis of the PRKN V380L (rs1801582) variant in a Japanese cohort of spinocerebellar ataxia type 3.

Ekaterina,Nadbitova, Nobuyuki,Takei, Sachiko,Hirokawa, Yuya,Hatano, Tomohiko,Ishihara, Osamu,Onodera, Yuka Mitsuhashi,Koike

BMC neurology · 2026-06-23

pmid:42337487

Spinocerebellar ataxia type 10 in a Guatemalan family: Characterization and preliminary evaluation of neurofilament light chain as a biomarker.

Tomasz,Chmiela, Ignacio,Pozo Cabanell, Leonard,Petrucelli, Mercedes,Prudencio, Zbigniew K,Wszolek

Parkinsonism & related disorders · 2026-06-18

pmid:42320256

The fT3/fT4 ratio as a candidate marker of motor progression in SCA3.

Mengyuan,Dong, Ziyan,Ding, Zhao,Chen, Na,Wan, Linliu,Peng, Qinlin,Huang, Jian,Hu, Ziting,Cui, Rongfan,Peng, Daren,Zeng, Ying,Zou, Yiqing,Gong, Yan,Tan, Daji,Chen, Qian,Jiang, Jiawei,He, Zhuan,Pei, Siyu,Ding, Xiaokai,Shen, Qi,Wu, Qi,Deng, Hongyu,Yuan, Chunrong,Wang, Linlin,Wan, Lang,He, Huirong,Peng, Yuting,Shi, Rong,Qiu, Hong,Jiang

Neurobiology of disease · 2026-06-06

pmid:42251968

White matter structural network alterations in spinocerebellar ataxia type 3: A graph theory analysis.

Qiannan,Wang, Jingna,Zhang, Liang,Qiao, Li,Wang, Linqiong,Sang, Ye,Zhang, Yalan,Liao, Jingjing,Liu, Mingguo,Qiu, Bijia,Wang, Chen,Liu

Neuroscience · 2026-05-25

pmid:42191105

Locus SCA3 ATXN3

Disease

Locus

Alleles

gnomAD

References

Additional Literature