{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:40:10Z","timestamp":1760722810417,"version":"build-2065373602"},"reference-count":30,"publisher":"BMJ","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[1998,2]]},"abstract":"<jats:p>In some neurodegenerative diseases, genetic anticipation correlates with expansions of the CAG\/CTG repeat sequence above the normal range through the generations of a pedigree. Among these neurodegenerative diseases are late onset autosomal dominant cerebellar ataxias (ADCA). ADCA are genetically heterogeneous disorders with different cloned genes for spinocerebellar ataxia type 1 (SCA1), type 2 (SCA2), type 3 or Machado-Joseph disease (SCA3\/MJD), and type 6 (SCA6). Another related dominant ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), also shows CAG\/CTG repeat expansions. Genetic anticipation has been reported for all of them except for the recently cloned SCA6 gene. Other, as yet undetected SCA genes may show the same features. We have used the repeat expansion detection (RED) method to detect repeat expansions directly in DNA samples from ADCA patients not resulting from known genes. Our sample consists of 19 affected index cases, corresponding to 52.8% of our ADCA families without CAG\/CTG repeat expansions in the SCA1, SCA2, SCA3\/MJD, SCA6, or DRPLA genes. Eighty-nine percent of the index cases had expansions of a CAG\/CTG sequence greater than 40 repeats by RED, while these were observed in only 26.9% of 78 healthy subjects from the general population (p &lt; 0.0001). The distribution of RED fragments in controls and ADCA patients also shows significant differences with the Mann-Whitney U test (U = 376.5, p = 0.0007). Moreover, there was a significant inverse correlation between the size of expansion and the age of onset (r = -0.54, p = 0.018). These results show CAG\/CTG repeat expansions of over 40 repeats in our sample of ADCA families not resulting from known SCA genes.<\/jats:p>","DOI":"10.1136\/jmg.35.2.99","type":"journal-article","created":{"date-parts":[[2008,11,10]],"date-time":"2008-11-10T15:37:21Z","timestamp":1226331441000},"page":"99-102","source":"Crossref","is-referenced-by-count":4,"title":["Uncloned expanded CAG\/CTG repeat sequences in autosomal dominant cerebellar ataxia (ADCA) detected by the repeat expansion detection (RED) method."],"prefix":"10.1136","volume":"35","author":[{"given":"M A","family":"Pujana","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V","family":"Volpini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Gratac\u00f3s","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Corral","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I","family":"Banchs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Gen\u00eds","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Cervera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"X","family":"Estivill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[1998,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/0092-8674(92)90302-S","article-title":"Dynamic mutations: a new class of mutations causing human disease","volume":"70","author":"Richards, R.I.; Sutherland, G.R.","year":"1992","unstructured":"Richards RI, Sutherland GR. Dynamic mutations: a new class of mutations causing human disease. Cell 1992;70:709-12.","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1002\/ana.410320517","article-title":"Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG\/CTG repeat in androgen receptor gene","volume":"32","author":"Doyu, M.; Sobue, G.; Mukai, E.","year":"1992","unstructured":"Doyu M, Sobue G, Mukai E, et al. Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG\/CTG repeat in androgen receptor gene. Ann Neurol 1992;32:707-10.","journal-title":"Ann Neurol"},{"key":"ref_3","first-page":"1","article-title":"Clinical features and classification of inherited ataxias","volume":"61","author":"Harding, A.E.","year":"1993","unstructured":"Harding AE. Clinical features and classification of inherited ataxias. Adv Neurol 1993;61:1-13.","journal-title":"Adv Neurol"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/ng0894-513","article-title":"Identification and characterization of the gene causing type 1 spinocerebellar ataxia","volume":"7","author":"Banfi, S.; Servadio, A.; Chung, M.","year":"1994","unstructured":"Banfi S, Servadio A, Chung M, et al. Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nat Genet 1994;7:513-20.","journal-title":"Nat Genet"},{"key":"ref_5","first-page":"285","article-title":"et al (group 1)","volume":"13","author":"Imbert, G.; Saudou, F.; Yvert, G.","year":"1996","unstructured":"Imbert G, Saudou F, Yvert G, et al (group 1); Cancel G, Abbas N, Diirr A, et al (group 2). Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG\/CTG\/glutamine repeats. Nat Genet 1996;13:285-91.","journal-title":"Nat Genet; Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG\/CTG\/glutamine repeats"},{"key":"ref_6","first-page":"269","article-title":"Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2","volume-title":"Nat Genet","volume":"13","author":"Pulst, S.M.; Nechiporuk, A.; Nechiporuk, T.","year":"1996","unstructured":"Pulst SM, Nechiporuk A, Nechiporuk T, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 1996;13:269-76."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/ng1196-277","article-title":"Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT","volume":"13","author":"Sanpei, K.; Takano, H.; Igarashi, S.","year":"1996","unstructured":"Sanpei K, Takano H, Igarashi S, et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 1996;13:277-84.","journal-title":"Nat Genet"},{"key":"ref_8","first-page":"221","volume":"8","author":"Genet, Nat","year":"1994","unstructured":"Nat Genet 1994;8:221-7."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/ng0197-62","article-title":"Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the a,,-voltage-dependent calcium channel","volume":"15","author":"Zhuchenko 0, Bailey J, Bonnen P","year":"1997","unstructured":"Zhuchenko 0, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the a,,-voltage-dependent calcium channel. Nat Genet 1997;15:62-9.","journal-title":"Nat Genet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/ng0194-9","article-title":"Unstable expansion of CAG\/CTG repeat in hereditary dentatorubralpallidoluysian atrophy (DRPLA)","volume":"6","author":"true","year":"1994","unstructured":"Koide R, Ikeuchi T, Onodera 0, et al. Unstable expansion of CAG\/CTG repeat in hereditary dentatorubralpallidoluysian atrophy (DRPLA). Nat Genet 1994;6:9-13.","journal-title":"Nat Genet"},{"key":"ref_11","first-page":"13","article-title":"Dentatorubral and pallidoluysian atrophy: expansion of an unstable CAG\/ CTG trinucleotide on chromosome 12p","volume":"6","author":"Nagafuchi, S.; Yanagisawa, H.; Sato, K.","year":"1994","unstructured":"Nagafuchi S, Yanagisawa H, Sato K, et al. Dentatorubral and pallidoluysian atrophy: expansion of an unstable CAG\/ CTG trinucleotide on chromosome 12p. Nat Genet 1994;6:13-18.","journal-title":"Nat Genet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1093\/hmg\/2.12.2123","article-title":"Presymptomatic analysis of spinocerebellar ataxia type 1 (SCAl) via the expansion of the SCAl CAG\/CTG-repeat in a large pedigree displaying anticipation and parental male bias","volume":"2","author":"Matilla, T.; Volpini, V.; Genis, D.","year":"1993","unstructured":"Matilla T, Volpini V, Genis D, et al. Presymptomatic analysis of spinocerebellar ataxia type 1 (SCAl) via the expansion of the SCAl CAG\/CTG-repeat in a large pedigree displaying anticipation and parental male bias. Hum Mol Genet 1993;2:2123-8.","journal-title":"Hum Mol Genet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1002\/ana.410370610","article-title":"Dentatorubralpallidoluysian atrophy (DRPLA): clinical features are closely related to unstable expansions of trinucleotide","volume":"37","author":"Ikeuchi, T.; Koide, R.; Tanaka, H.","year":"1995","unstructured":"Ikeuchi T, Koide R, Tanaka H, et al. Dentatorubralpallidoluysian atrophy (DRPLA): clinical features are closely related to unstable expansions of trinucleotide (CAG\/CTG) repeat. Ann Neurol 1995;37:769-75.","journal-title":"(CAG\/CTG) repeat. Ann Neurol"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1093\/hmg\/4.5.807","article-title":"Molecular features of the CAG\/CTG repeats and clinical manifestation of Machado-Joseph disease","volume":"4","author":"Maruyama, H.; Nakamura, S.; Matsuyama, Z.","year":"1995","unstructured":"Maruyama H, Nakamura S, Matsuyama Z, et al. Molecular features of the CAG\/CTG repeats and clinical manifestation of Machado-Joseph disease. Hum Mol Genet 1995;4: 807-12.","journal-title":"Hum Mol Genet"},{"key":"ref_15","first-page":"84","article-title":"The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3pl 2-p21.1","volume-title":"Nat Genet","volume":"10","author":"Benomar, A.; Krols, L.; Stevanin, G.","year":"1995","unstructured":"Benomar A, Krols L, Stevanin G, et al. The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3pl 2-p21.1. Nat Genet 1995;10:84-8."},{"key":"ref_16","first-page":"89","article-title":"Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p","volume-title":"Nat Genet","volume":"10","author":"Gouw, L.G.; Kaplan, C.D.; Haines, J.H.","year":"1995","unstructured":"Gouw LG, Kaplan CD, Haines JH, et al. Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nat Genet 1995;10:89-93."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/ng1194-280","article-title":"Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11","volume":"8","author":"Ranum, L.P.W.; Schut, L.J.; Lundgren, J.K.; Orr, T.H.; Livingston, D.M.","year":"1994","unstructured":"Ranum LPW, Schut LJ, Lundgren JK, Orr TH, Livingston DM. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet 1994;8:280-4.","journal-title":"Nat Genet"},{"key":"ref_18","first-page":"392","article-title":"Am _7 Hum Genet","volume":"59","year":"1996","unstructured":"Am _7 Hum Genet 1996;59:392-9."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/378403a0","article-title":"Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias","volume":"378","author":"Trottier, Y.; Lutz, Y.; Stevanin, G.","year":"1995","unstructured":"Trottier Y, Lutz Y, Stevanin G, et al. Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 1995;378: 403-6.","journal-title":"Nature"},{"key":"ref_20","first-page":"965","article-title":"An expanded CAG\/CTG repeat sequence in spinocerebellar ataxia type 7","volume":"6","author":"Lindblad, K.; Savontaus, M.L.; Stevanin, G.","year":"1996","unstructured":"Lindblad K, Savontaus ML, Stevanin G, et al. An expanded CAG\/CTG repeat sequence in spinocerebellar ataxia type 7. GenomeRes 1996;6:965-71.","journal-title":"GenomeRes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/ng0693-135","article-title":"Direct detection of novel expanded trinucleotide repeats in the human genome","volume":"4","author":"Schalling, M.; Hudson, T.J.; Buetow, K.H.; Housman, D.E.","year":"1993","unstructured":"Schalling M, Hudson TJ, Buetow KH, Housman DE. Direct detection of novel expanded trinucleotide repeats in the human genome. Nat Genet 1993;4:135-9.","journal-title":"Nat Genet"},{"key":"ref_22","first-page":"7783","article-title":"Trinucleotide repeats in human genome: size distributions for all possible triplets and detection of expanded disease alleles in a group of Huntington disease individuals by the repeat expansion detection method","volume":"6","author":"Hofferbert, S.; Schanen, N.C.; Chehab, F.; Francke, U.","year":"1997","unstructured":"Hofferbert S, Schanen NC, Chehab F, Francke U. Trinucleotide repeats in human genome: size distributions for all possible triplets and detection of expanded disease alleles in a group of Huntington disease individuals by the repeat expansion detection method. Hum Mol Genet 1997;6:7783.","journal-title":"Hum Mol Genet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1212\/WNL.45.9.1760","article-title":"No evidence for association of familial Parkinson's disease with CAG\/CTG repeat expansion","volume":"45","author":"Carero-Valenzuela, R.; Lindblad, K.; Payami, H.","year":"1995","unstructured":"Carero-Valenzuela R, Lindblad K, Payami H, et al. No evidence for association of familial Parkinson's disease with CAG\/CTG repeat expansion. Neurology 1995;45:1760-3.","journal-title":"Neurology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1093\/hmg\/4.10.1957","article-title":"CAG\/CTG repeat expansions and schizophrenia: association with disease in females and with early age-at-onset","volume":"4","author":"Morris, A.G.; Gaitonde, E.; McKenna, P.J.; Mollon, J.D.; Hunt, D.M.","year":"1995","unstructured":"Morris AG, Gaitonde E, McKenna PJ, Mollon JD, Hunt DM. CAG\/CTG repeat expansions and schizophrenia: association with disease in females and with early age-at-onset. Hum Mol Genet 1995;4: 1957-61.","journal-title":"Hum Mol Genet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/ng0895-380","article-title":"Expanded CAG\/CTG repeats in schizophrenia and bipolar disorder","volume":"10","author":"O'Donovan, M.C.; Guy, C.; Craddock, N.","year":"1995","unstructured":"O'Donovan MC, Guy C, Craddock N, et al. Expanded CAG\/CTG repeats in schizophrenia and bipolar disorder. Nat Genet 1995;10:380-1.","journal-title":"Nat Genet"},{"key":"ref_26","first-page":"905","article-title":"Search for unstable DNA in schizophrenia families with evidence for genetic anticipation","volume":"59","author":"Petronis, A.; Bassett, A.S.; Honer, W.G.","year":"1996","unstructured":"Petronis A, Bassett AS, Honer WG, et al. Search for unstable DNA in schizophrenia families with evidence for genetic anticipation. Am J Hum Genet 1996;59:905-1 1.","journal-title":"Am J Hum Genet"},{"key":"ref_27","first-page":"912","article-title":"Expansion of 50 CAG\/CTG\/CTG repeats excluded in schizophrenia by application of a highly efficient approach using repeat expansion detection and a PCR screening set","volume":"59","author":"Bowen, T.; Guy, C.; Speight, G.","year":"1996","unstructured":"Bowen T, Guy C, Speight G, et al. Expansion of 50 CAG\/CTG\/CTG repeats excluded in schizophrenia by application of a highly efficient approach using repeat expansion detection and a PCR screening set. Am _7 Hum Genet 1996;59:912-17.","journal-title":"Am _7 Hum Genet"},{"article-title":"The repeat expansion detection (RED) method throughout the analysis of diseases with CAG\/CTG\/GTC repeat expansion: usefulness and limitations. Hum Mutat","author":"Martorell, L.; Pujana, M.A.; Volpini, V.","key":"ref_28","unstructured":"Martorell L, Pujana MA, Volpini V, et al. The repeat expansion detection (RED) method throughout the analysis of diseases with CAG\/CTG\/GTC repeat expansion: usefulness and limitations. Hum Mutat (in press)."},{"key":"ref_29","first-page":"1","article-title":"Repeat expansion detection using Ampligase' thermostable DNA ligase","volume":"2","author":"Sirugo, G.; Kidd, K.K.","year":"1995","unstructured":"Sirugo G, Kidd KK. Repeat expansion detection using Ampligase' thermostable DNA ligase. Epicentre Forum 1995;2:1-3.","journal-title":"Epicentre Forum"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1093\/hmg\/5.12.1887","article-title":"et al Screening for proteins with polyglutamine expansions in autosomal dominant cerebellar ataxias","volume":"5","author":"Stevanin, G.; Trottier, Y.; Cancel, G.","year":"1996","unstructured":"Stevanin G, Trottier Y, Cancel G, et al Screening for proteins with polyglutamine expansions in autosomal dominant cerebellar ataxias. Hum Mol Genet 1996;5:1887-92.","journal-title":"Hum Mol Genet"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg.35.2.99","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:23:06Z","timestamp":1760721786000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg.35.2.99"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,2]]},"references-count":30,"journal-issue":{"issue":"2","published-online":{"date-parts":[[1998,2,1]]},"published-print":{"date-parts":[[1998,2]]}},"alternative-id":["10.1136\/jmg.35.2.99"],"URL":"https:\/\/doi.org\/10.1136\/jmg.35.2.99","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"type":"print","value":"0022-2593"},{"type":"electronic","value":"1468-6244"}],"subject":[],"published":{"date-parts":[[1998,2]]}}}