Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-848d4c4894-2xdlg Total loading time: 0 Render date: 2024-06-22T15:17:47.737Z Has data issue: false hasContentIssue false

47 - Autosomal dominant cerebellar ataxia

from Part VIII - Cerebellar degenerations

Published online by Cambridge University Press:  04 August 2010

M. Flint Beal ,
Anthony E. Lang  and
Albert C. Ludolph
By
Henry L. Paulson
M. Flint Beal
Affiliation:
Cornell University, New York
Anthony E. Lang
Affiliation:
University of Toronto
Albert C. Ludolph
Affiliation:
Universität Ulm, Germany
Henry L. Paulson
Affiliation:
Department of Neurology, University of Iowa Hospitals and Clinics, IA, USA
Get access

Summary

This review discusses clinical and genetic features of dominantly inherited ataxia. In addition, potential pathogenic mechanisms are discussed with a special focus on the polyglutamine disorders, since most is known about this group of diseases.

Classification of ADCA

Most adult onset hereditary ataxias are dominantly inherited. Harding (1993) clinically divided autosomal dominant cerebellar ataxia (ADCA) into four types, I through IV. Type I ADCA represents cerebellar disease accompanied by brainstem signs. ADCA type II is similar to type I but also includes retinopathy. ADCA type III represents later onset, “pure” cerebellar disease and ADCA type IV represents episodic ataxia.

A newer, favored classification for ADCA reflects the growing number of identified genetic loci, each of which is designated a specific spinocerebellar ataxia or SCA (Table 47.1). As SCAs are mapped to loci, they are assigned numbers – SCA1, SCA2 and so forth, currently up to 21 at the time of this writing. Most SCAs fall within Harding's ADCA type I classification. There is considerable clinical overlap among the ADCA type I group, even within families. In contrast, the sole genetic cause of ADCA type II appears to be SCA7, the only dominant ataxia routinely accompanied by retinal degeneration. Most patients with SCA6 (and several rarer SCAs for which the gene defects have not been identified) manifest as a pure cerebellar syndrome and thus fall within ADCA III. Finally, ADCA type IV currently consists of two genetically identified forms of episodic ataxia (EA), EA-1 and EA-2, caused by mutations in a potassium and calcium channel respectively.

Type
Chapter
Information
Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics
 , pp. 709 - 718
Publisher: Cambridge University Press
Print publication year: 2005

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Baloh, R. W., Yue, Q., Furman, J. M. & Nelson, S. F. (1997). Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann. Neurol., 41(1), 8–16CrossRefGoogle ScholarPubMed
Bonini, N. M. (2002). Chaperoning brain degeneration. Proc. Natl Acad. Sci., USA, 99 (Suppl. 4), 16407–11CrossRefGoogle ScholarPubMed
Brkanac, Z., Bylenok, L., Fernandez, M.et al. (2002a). A new dominant spinocerebellar ataxia linked to chromosome 19q13.4-qter. Arch. Neurol., 59(8), 1291–5CrossRefGoogle Scholar
Brkanac, Z., Fernandez, M., Matsushita, M.et al. (2002b). Autosomal dominant sensory/motor neuropathy with Ataxia (SMNA): Linkage to chromosome 7q22–q32. Am. J. Med. Genet., 114(4), 450–7CrossRefGoogle Scholar
Cancel, G., Durr, A., Didierjean, O.et al. (1997). Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. Hum. Mol. Genet., 6(5), 709–15CrossRefGoogle ScholarPubMed
Chai, Y., Berke, S. S., Cohen, R. E. & Paulson, H. L. (2003). Poly-ubiquitin binding by the polyQ disease protein ataxin-3 links its normal function to protein surveillance pathways. J. Biol. Chem., 279, 3605–11CrossRefGoogle ScholarPubMed
Chan, H. Y., Warrick, J. M., Gray-Board, G. L., Paulson, H. L. & Bonini, N. M. (2000). Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum. Mol. Genet., 22, 9(19), 2811–20CrossRefGoogle Scholar
Chen, D.-H., Brkanac, Z., Verlinde, C. L. M. J.et al. (2003). Missense mutations in the regulatory domain of PKC-gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am. J. Hum. Genet., 72, 839–49CrossRefGoogle ScholarPubMed
Cummings, C. J. & Zoghbi, H. Y. (2000). Trinucleotide repeats: mechanisms and pathophysiology. Annu. Rev. Genom. Hum. Genet., 1, 281–328CrossRefGoogle ScholarPubMed
Damji, K. F., Allingham, R. R., Pollock, S. C.et al. (1996). Periodic vestibulocerebellar ataxia, an autosomal dominant ataxia with defective smooth pursuit, is genetically distinct from other autosomal dominant ataxias. Arch. Neurol., 53, 338–44CrossRefGoogle ScholarPubMed
David, G., Abbas, N., , Stevanin, G., et al. (1997). Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat. Genet., 17, 65–70CrossRefGoogle ScholarPubMed
Day, J. W., Schut, L. J., Moseley, M. L., Durand, A. C. & Ranum, L. P. (2000). Spinocerebellar ataxia type 8. Clinical features in a large family. Neurology, 55, 649–57CrossRefGoogle Scholar
Donaldson, K. M., Li, W., , Ching, K. A., Batalov, S., , Tsai, C. C. & Joazeiro, C. A. (2003). Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates. Proc. Natl Acad. Sci., USA, 100(15), 8892–7CrossRefGoogle ScholarPubMed
Durr, A., Stevanin, G., Cancel, G.et al. (1996). Spinocerebellar ataxia 3 and Machado–Joseph disease: clinical, molecular and neuropathologic features. Ann. Neurol., 39, 490–9CrossRefGoogle Scholar
Geschwind, D. H., Perlman, S., Figueroa, C. P., Yreiman, L. J. & Pulst, S. M. (1997). The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia. Am. J. Hum. Genet., 60, 842–50Google ScholarPubMed
Gomez, C. M., Thompson, R. M., Gammack, J. T.et al. (1997). Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Ann. Neurol., 42, 933–50CrossRefGoogle ScholarPubMed
Grewal, R. P., Achari, M., Matsuura, T.et al. (2002). Clinical features and ATTCT repeat expansion in spinocerebellar ataxia type 10. Arch. Neurol., 59(8), 1285–90CrossRefGoogle ScholarPubMed
Harding, A. E. (1993). Clinical features and classification of inherited ataxias. Adv. Neurol., 61, 1–14Google ScholarPubMed
Herman-Bert, A., Stevanin, G., Netter, J. C.et al. (2000). Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3–q13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation. Am. J. Hum. Genet., 67, 229–35CrossRefGoogle Scholar
Holmberg, M., Duysckaerts, C., Durr, A.et al. (1998). Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum. Mol. Genet., 7, 913–18CrossRefGoogle ScholarPubMed
Holmes, S. E., O'Hearn, E. E., Mclnnis, M. G.et al. (1999). Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12. Nat. Genet., 23, 391–2CrossRefGoogle ScholarPubMed
Hughes, R. E. (2002). Polyglutamine disease: acetyltransferases awry. Curr. Biol., 12(4), R141–3CrossRefGoogle ScholarPubMed
Ikeuchi, T., Takano, H., Koide, R.et al. (1997). Spinocerebellar ataxia type 6: CAG repeat expansion in a1A voltage-dependent calcium channel gene and clinical variations in Japanese population. Ann. Neurol., 42, 879–84CrossRefGoogle Scholar
Imbert, G., Sandon, F., Yvert, G.et al. (1996). Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat. Genet., 14, 285–91CrossRefGoogle ScholarPubMed
Koide, R., Kobayashi, S., Shimohata, T.et al. (1999). A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease?Hum. Molec. Genet., 8, 2047–53CrossRefGoogle ScholarPubMed
Koob, M. D., Moseley, M. L., Schut, L. J.et al. (1999). An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat. Genet., 21, 379–8493CrossRefGoogle Scholar
Maciel, P., Gaspas, C., Stefano, A. L.et al. (1995). Correlation between CAG repeat length and clinical features in Machado–Joseph disease. Am. J. Hum. Genet., 57, 54–61Google ScholarPubMed
Matilla, T., McCall, A., Subramony, S. H. & Zoghbi, H. Y. (1995). Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado–Joseph disease. Ann. Neurol., 38, 68–72CrossRefGoogle ScholarPubMed
Matsuura, T., Yamagata, T. & Burgess, D. L. (2000). Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia 10. Nat. Genet., 26(2), 191–4CrossRefGoogle Scholar
Matsuura, T., , Ranum, L. P., Volpini, V., et al. (2002). Spinocerebellar ataxia type 10 is rare in populations other than Mexicans. Neurology, 58(6), 983–4CrossRefGoogle Scholar
Miller, V. M., Xia, H., Marrs, G. L.et al. (2003). Allele specific silencing of dominant disease genes. Proc. Natl Acad. Sci., USA, 100(12), 7195–200CrossRefGoogle ScholarPubMed
Miyoshi, Y., Yamada, T., Tanimura, M.et al. (2001). A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1–24.1. Neurology, 57(1), 96–100CrossRefGoogle ScholarPubMed
Moseley, M. L., Schut, L. J., Bird, T. D.et al. (2000). SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance. Nat. Genet., 26(2), 191–4Google Scholar
Moseley, M. L., Weatherspoon, M., Rasmussen, L., Day, J. W. & Ranum, L. P. W. (2002). SCA8 BAC transgenic mice have a progressive and lethal neurological phenotype demonstrating pathogenicity of the CTG expansion. Am. Soc. Hum. Genet. Abstract.Google Scholar
Muchowski, P. J. (2002). Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones?Neuron, 35(1), 9–12CrossRefGoogle ScholarPubMed
Nagaoka, U.Takashima, M., Ishikawa, K.et al. (2000). A gene on SCA4 locus causes dominantly inherited pure cerebellar ataxia. Neurology, 54(10), 1971–5CrossRefGoogle ScholarPubMed
Nakamura, K., Jeong, S.-Y., Uchihara, T.et al. (2001). SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum. Molec. Genet., 10, 1441–8CrossRefGoogle ScholarPubMed
Orr, H. T., Chung, M. Y., Banfi, S.et al. (1993). Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat. Genet., 4, 221–6CrossRefGoogle ScholarPubMed
Piedras-Renteria, E. S., Watase, K., Harata, N.et al. (2001). Increased expression of alpha 1A Ca2+ channel currents arising from expanded trinucleotide repeats in spinocerebellar ataxia type 6. J. Neurosci., 21, 9185–93CrossRefGoogle ScholarPubMed
Pulst, S- M., Nechiporuk, A., Nechiporuk, T.et al. (1996). Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat. Genet., 14, 269–76CrossRefGoogle ScholarPubMed
Ranum, L. P., Chung, M. Y., Banfi, S.et al. (1994). Molecular and clinical correlations in spinocerebellar ataxia type 1: evidence for familial effects on the age of onset. Am. J. Hum. Genet., 55, 244–52Google Scholar
Sanpei, K., Takano, H., Igarashi, S.et al. (1996). Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat. Genet., 14, 277–84CrossRefGoogle ScholarPubMed
Schols, L., Vieira-Saecker, A. M., Schols, S., Przuntek, H., Epplen, J. T., Riess, D. & Schols, L. (1995). Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients. Hum. Mol. Genet., 4, 1001–5CrossRefGoogle ScholarPubMed
Schols, L., , Gispert, S., Vorgerd, M.et al. (1997). Spinocerebellar ataxia type 2. Genotype and phenotype in German kindreds. Arch. Neurol., 54(9), 1073–80CrossRefGoogle Scholar
Shan, D. E., Soong, B. W., Sun, C. M., Lee, S. J., Liao, K. K. & Liu, R. S. (2001). Spinocerebellar ataxia type 2 presenting as familial levodopa-responsive parkinsonism. Ann. Neurol., 50(6), 812–15CrossRefGoogle ScholarPubMed
Sherman, M. Y. & Goldberg, A. L. (2001). Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron, 29(1), 15–32CrossRefGoogle ScholarPubMed
Sobrido, M. J., Cholfin, J. A., Perlman, S., Pulst, S. M. & Geschwind, D. H. (2001). SCA8 repeat expansions in ataxia: a controversial association. Neurology, 57(7), 1310–12CrossRefGoogle ScholarPubMed
Srivastava, A. K., Choudhry, S., Gopinath, M. S.et al. (2001). Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12. Ann. Neurol., 50(6), 796–800CrossRefGoogle ScholarPubMed
Steckley, J. L., Ebers, G. C., Cader, M. Z. & McLachlan, R. S. (2001). An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus. Neurology, 57, 1499–502CrossRefGoogle ScholarPubMed
Storey, E., Gardner, R. J., Knight, M. A.et al. (2001). A new autosomal dominant pure cerebellar ataxia. Neurology, 57, 1913–15CrossRefGoogle ScholarPubMed
Taylor, J. P., Hardy, J., & Fischbeck, K. H. (2002). Toxic proteins in neurodegenerative disease. Science, 296(5575), 1991–5CrossRefGoogle ScholarPubMed
Alfen, N., Sinke, R. J., Zwarts, M. J.et al. (2001). Intermediate CAG repeat lengths (53,54) for MJD/SCA3 are associated with an abnormal phenotype. Ann. Neurol., 49(6), 805–7CrossRefGoogle ScholarPubMed
Verbeek, D. S., Schelhaas, J. H., Ippel, E. F., Beemer, F. A., Pearson, P. L. & Sinke, R. J. (2002). Identification of a novel SCA locus (SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21–q21. Hum. Genet., 111, 388–93CrossRefGoogle Scholar
Vuillaume, I., Devos, D., Schraen-Maschke, S. et al. (2002). A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3–p15.1. Ann. Neurol. 2002 (on line)
Xia, H., Mao, Q., Paulson, H. L. & Davidson, B. L. (2002). siRNA-mediated gene silencing in vitro and in vivo. Nat. Biotechnol., 20(10), 1006–10CrossRefGoogle ScholarPubMed
Yabe, I., Sasaki, H., Kikuchi, S.et al. (2002). Late onset ataxia phenotype in dentatorubro-pallidoluysian atrophy (DRPLA). J. Neurol., 249, 432–6CrossRefGoogle Scholar
Yamashita, I., Sasaki, H., Yabe, I.et al. (2000). A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cm interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter. Ann. Neurol. 48(2), 156–633.0.CO;2-9>CrossRefGoogle ScholarPubMed
Zoghbi, H. Y. & Orr, H. T. (2000). Glutamine repeats and neurodegeneration. Ann. Rev. Neurosci., 23, 217–47, 52–3CrossRefGoogle ScholarPubMed
Zhuchenko, O., Bailey, J., Bonnen, P.et al. (1997). Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat. Genet., 15(1), 62–9CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×