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. 1999 Jun;64(6):1594–1603. doi: 10.1086/302406

Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation.

P Giunti 1, G Stevanin 1, P F Worth 1, G David 1, A Brice 1, N W Wood 1
PMCID: PMC1377902  PMID: 10330346

Abstract

The SCA7 mutation has been found in 54 patients and 7 at-risk subjects from 17 families who have autosomal dominant cerebellar ataxia (ADCA) II with progressive pigmentary maculopathy. In one isolated case, haplotype reconstruction through three generations confirmed a de novo mutation owing to paternal meiotic instability. Different disease-associated haplotypes segregated among the SCA7-positive kindreds, which indicated a multiple origin of the mutation. One family with the clinical phenotype of ADCA type II did not have the CAG expansion that indicated locus heterogeneity. The distribution of the repeat size in 944 independent normal chromosomes from controls, unaffected at-risk subjects, and one affected individual fell into two ranges. The majority of the alleles were in the first range of 7-19 CAG repeats. A second range could be identified with 28-35 repeats, and we provide evidence that these repeats represent intermediate alleles that are prone to further expansion. The repeat size of the pathological allele, the widest reported for all CAG-repeat disorders, ranged from 37 to approximately 220. The repeat size showed significant negative correlation with both age at onset and age at death. Analysis of the clinical features in the patients with SCA7 confirmed that the most frequently associated features are pigmentary maculopathy, pyramidal tract involvement, and slow saccades. The subjects with <49 repeats tended to have a less complicated neurological phenotype and a longer disease duration, whereas the converse applied to subjects with >/=49 repeats. The degree of instability during meiotic transmission was greater than in all other CAG-repeat disorders and was particularly striking in paternal transmission, in which a median increase in repeat size of 6 and an interquartile range of 12 were observed, versus a median increase of 3 and interquartile range of 3.5 in maternal transmission.

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Selected References

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  1. Benomar A., Le Guern E., Dürr A., Ouhabi H., Stevanin G., Yahyaoui M., Chkili T., Agid Y., Brice A. Autosomal-dominant cerebellar ataxia with retinal degeneration (ADCA type II) is genetically different from ADCA type I. Ann Neurol. 1994 Apr;35(4):439–444. doi: 10.1002/ana.410350411. [DOI] [PubMed] [Google Scholar]
  2. Bürk K., Stevanin G., Didierjean O., Cancel G., Trottier Y., Skalej M., Abele M., Brice A., Dichgans J., Klockgether T. Clinical and genetic analysis of three German kindreds with autosomal dominant cerebellar ataxia type I linked to the SCA2 locus. J Neurol. 1997 Apr;244(4):256–261. doi: 10.1007/s004150050081. [DOI] [PubMed] [Google Scholar]
  3. David G., Abbas N., Stevanin G., Dürr A., Yvert G., Cancel G., Weber C., Imbert G., Saudou F., Antoniou E. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet. 1997 Sep;17(1):65–70. doi: 10.1038/ng0997-65. [DOI] [PubMed] [Google Scholar]
  4. David G., Dürr A., Stevanin G., Cancel G., Abbas N., Benomar A., Belal S., Lebre A. S., Abada-Bendib M., Grid D. Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7). Hum Mol Genet. 1998 Feb;7(2):165–170. doi: 10.1093/hmg/7.2.165. [DOI] [PubMed] [Google Scholar]
  5. David G., Giunti P., Abbas N., Coullin P., Stevanin G., Horta W., Gemmill R., Weissenbach J., Wood N., Cunha S. The gene for autosomal dominant cerebellar ataxia type II is located in a 5-cM region in 3p12-p13: genetic and physical mapping of the SCA7 locus. Am J Hum Genet. 1996 Dec;59(6):1328–1336. [PMC free article] [PubMed] [Google Scholar]
  6. Del-Favero J., Krols L., Michalik A., Theuns J., Löfgren A., Goossens D., Wehnert A., Van den Bossche D., Van Zand K., Backhovens H. Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) caused by CAG triplet repeat expansion. Hum Mol Genet. 1998 Feb;7(2):177–186. doi: 10.1093/hmg/7.2.177. [DOI] [PubMed] [Google Scholar]
  7. Enevoldson T. P., Sanders M. D., Harding A. E. Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy. A clinical and genetic study of eight families. Brain. 1994 Jun;117(Pt 3):445–460. doi: 10.1093/brain/117.3.445. [DOI] [PubMed] [Google Scholar]
  8. Flanigan K., Gardner K., Alderson K., Galster B., Otterud B., Leppert M. F., Kaplan C., Ptácek L. J. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet. 1996 Aug;59(2):392–399. [PMC free article] [PubMed] [Google Scholar]
  9. Giunti P., Sabbadini G., Sweeney M. G., Davis M. B., Veneziano L., Mantuano E., Federico A., Plasmati R., Frontali M., Wood N. W. The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates. Brain. 1998 Mar;121(Pt 3):459–467. doi: 10.1093/brain/121.3.459. [DOI] [PubMed] [Google Scholar]
  10. Gouw L. G., Kaplan C. D., Haines J. H., Digre K. B., Rutledge S. L., Matilla A., Leppert M., Zoghbi H. Y., Ptácek L. J. Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nat Genet. 1995 May;10(1):89–93. doi: 10.1038/ng0595-89. [DOI] [PubMed] [Google Scholar]
  11. Gouw L. G., Kaplan C. D., Haines J. H., Digre K. B., Rutledge S. L., Matilla A., Leppert M., Zoghbi H. Y., Ptácek L. J. Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nat Genet. 1995 May;10(1):89–93. doi: 10.1038/ng0595-89. [DOI] [PubMed] [Google Scholar]
  12. Harding A. E. Clinical features and classification of inherited ataxias. Adv Neurol. 1993;61:1–14. [PubMed] [Google Scholar]
  13. Harding A. E. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the 'the Drew family of Walworth'. Brain. 1982 Mar;105(Pt 1):1–28. doi: 10.1093/brain/105.1.1. [DOI] [PubMed] [Google Scholar]
  14. Holmberg M., Johansson J., Forsgren L., Heijbel J., Sandgren O., Holmgren G. Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1. Hum Mol Genet. 1995 Aug;4(8):1441–1445. doi: 10.1093/hmg/4.8.1441. [DOI] [PubMed] [Google Scholar]
  15. Ikeuchi T., Igarashi S., Takiyama Y., Onodera O., Oyake M., Takano H., Koide R., Tanaka H., Tsuji S. Non-Mendelian transmission in dentatorubral-pallidoluysian atrophy and Machado-Joseph disease: the mutant allele is preferentially transmitted in male meiosis. Am J Hum Genet. 1996 Apr;58(4):730–733. [PMC free article] [PubMed] [Google Scholar]
  16. Imbert G., Saudou F., Yvert G., Devys D., Trottier Y., Garnier J. M., Weber C., Mandel J. L., Cancel G., Abbas N. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet. 1996 Nov;14(3):285–291. doi: 10.1038/ng1196-285. [DOI] [PubMed] [Google Scholar]
  17. Jodice C., Mantuano E., Veneziano L., Trettel F., Sabbadini G., Calandriello L., Francia A., Spadaro M., Pierelli F., Salvi F. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum Mol Genet. 1997 Oct;6(11):1973–1978. doi: 10.1093/hmg/6.11.1973. [DOI] [PubMed] [Google Scholar]
  18. Johansson J., Forsgren L., Sandgren O., Brice A., Holmgren G., Holmberg M. Expanded CAG repeats in Swedish spinocerebellar ataxia type 7 (SCA7) patients: effect of CAG repeat length on the clinical manifestation. Hum Mol Genet. 1998 Feb;7(2):171–176. doi: 10.1093/hmg/7.2.171. [DOI] [PubMed] [Google Scholar]
  19. Jöbsis G. J., Weber J. W., Barth P. G., Keizers H., Baas F., van Schooneveld M. J., van Hilten J. J., Troost D., Geesink H. H., Bolhuis P. A. Autosomal dominant cerebellar ataxia with retinal degeneration (ADCA II): clinical and neuropathological findings in two pedigrees and genetic linkage to 3p12-p21.1. J Neurol Neurosurg Psychiatry. 1997 Apr;62(4):367–371. doi: 10.1136/jnnp.62.4.367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kawaguchi Y., Okamoto T., Taniwaki M., Aizawa M., Inoue M., Katayama S., Kawakami H., Nakamura S., Nishimura M., Akiguchi I. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994 Nov;8(3):221–228. doi: 10.1038/ng1194-221. [DOI] [PubMed] [Google Scholar]
  21. Krols L., Martin J. J., David G., Van Regemorter N., Benomar A., Löfgren A., Stevanin G., Dürr A., Brice A., Van Broeckhoven C. Refinement of the locus for autosomal dominant cerebellar ataxia type II to chromosome 3p21.1-14.1. Hum Genet. 1997 Feb;99(2):225–232. doi: 10.1007/s004390050344. [DOI] [PubMed] [Google Scholar]
  22. Orr H. T., Chung M. Y., Banfi S., Kwiatkowski T. J., Jr, Servadio A., Beaudet A. L., McCall A. E., Duvick L. A., Ranum L. P., Zoghbi H. Y. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993 Jul;4(3):221–226. doi: 10.1038/ng0793-221. [DOI] [PubMed] [Google Scholar]
  23. Pulst S. M., Nechiporuk A., Nechiporuk T., Gispert S., Chen X. N., Lopes-Cendes I., Pearlman S., Starkman S., Orozco-Diaz G., Lunkes A. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996 Nov;14(3):269–276. doi: 10.1038/ng1196-269. [DOI] [PubMed] [Google Scholar]
  24. Ranum L. P., Schut L. J., Lundgren J. K., Orr H. T., Livingston D. M. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nat Genet. 1994 Nov;8(3):280–284. doi: 10.1038/ng1194-280. [DOI] [PubMed] [Google Scholar]
  25. Rubinsztein D. C., Leggo J., Coles R., Almqvist E., Biancalana V., Cassiman J. J., Chotai K., Connarty M., Crauford D., Curtis A. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet. 1996 Jul;59(1):16–22. [PMC free article] [PubMed] [Google Scholar]
  26. Sanpei K., Takano H., Igarashi S., Sato T., Oyake M., Sasaki H., Wakisaka A., Tashiro K., Ishida Y., Ikeuchi T. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996 Nov;14(3):277–284. doi: 10.1038/ng1196-277. [DOI] [PubMed] [Google Scholar]
  27. Sathasivam K., Amaechi I., Mangiarini L., Bates G. Identification of an HD patient with a (CAG)180 repeat expansion and the propagation of highly expanded CAG repeats in lambda phage. Hum Genet. 1997 May;99(5):692–695. doi: 10.1007/s004390050432. [DOI] [PubMed] [Google Scholar]
  28. Schöls L., Gispert S., Vorgerd M., Menezes Vieira-Saecker A. M., Blanke P., Auburger G., Amoiridis G., Meves S., Epplen J. T., Przuntek H. Spinocerebellar ataxia type 2. Genotype and phenotype in German kindreds. Arch Neurol. 1997 Sep;54(9):1073–1080. doi: 10.1001/archneur.1997.00550210011007. [DOI] [PubMed] [Google Scholar]
  29. Stevanin G., Giunti P., Belal G. D., Dürr A., Ruberg M., Wood N., Brice A. De novo expansion of intermediate alleles in spinocerebellar ataxia 7. Hum Mol Genet. 1998 Oct;7(11):1809–1813. doi: 10.1093/hmg/7.11.1809. [DOI] [PubMed] [Google Scholar]
  30. Takiyama Y., Sakoe K., Soutome M., Namekawa M., Ogawa T., Nakano I., Igarashi S., Oyake M., Tanaka H., Tsuji S. Single sperm analysis of the CAG repeats in the gene for Machado-Joseph disease (MJD1): evidence for non-Mendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on the intergenerational instability. Hum Mol Genet. 1997 Jul;6(7):1063–1068. doi: 10.1093/hmg/6.7.1063. [DOI] [PubMed] [Google Scholar]
  31. Zhuchenko O., Bailey J., Bonnen P., Ashizawa T., Stockton D. W., Amos C., Dobyns W. B., Subramony S. H., Zoghbi H. Y., Lee C. C. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997 Jan;15(1):62–69. doi: 10.1038/ng0197-62. [DOI] [PubMed] [Google Scholar]

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