Abstract
The spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominantly inherited progressive ataxia diseases. Up to now, almost 30 different gene loci have been found. In 14 of them, the underlying mutations have been identified. The more common SCAs, SCA1, 2, 3 and 6 are due to translated CAG repeat expansions that code for an elongated polyglutamine tract within the respective proteins. These diseases belong to a larger group of polyglutamine disorders that also includes Huntington’s disease. Epidemiological studies conducted in different European regions found prevalence rates of SCAs ranging from 0.9 to 3.0:100,000. In all SCAs, ataxia is the prominent symptom. However, the majority have a complex phenotype in which ataxia is accompanied by varying non-ataxia symptoms. In all ataxia patients with proven or suspected autosomal dominant mode of inheritance, the available molecular genetic tests for SCA mutations should be performed. Depending on the geographical origin of the family, these tests will lead to positive diagnostic results in at least half of the families.
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Schöls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: Clinical features, genetics, and pathogenesis. Lancet Neurol. 2004;3:291–304.
Gatchel JR, Zoghbi HY. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 2005;6:743–55.
Duenas AM, Goold R, Giunti P. Molecular pathogenesis of spinocerebellar ataxias. Brain. 2006;129:1357–70.
Koeppen AH. The pathogenesis of spinocerebellar ataxia. Cerebellum. 2005;4:62–73.
Estrada R, Galarraga J, Orozco G, Nodarse A, Auburger G. Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies. Acta Neuropathol (Berl). 1999;97:306–10.
Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997;19:333–44.
Schmidt T, Lindenberg KS, Krebs A, Schols L, Laccone F, Herms J, et al. Protein surveillance machinery in brains with spinocerebellar ataxia type 3: Redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol. 2002;51:302–10.
Silva MC, Coutinho P, Pinheiro CD, Neves JM, Serrano P. Hereditary ataxias and spastic paraplegias: Methodological aspects of a prevalence study in Portugal. J Clin Epidemiol. 1997;50:1377–84.
van de Warrenburg BP, Sinke RJ, Verschuuren-Bemelmans CC, Scheffer H, Brunt ER, Ippel PF, et al. Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis. Neurology. 2002;58:702–08.
Schöls L, Krüger R, Amoiridis G, Przuntek H, Epplen JT, Riess O. Spinocerebellar ataxia type 6: Genotype and phenotype in German kindreds. J Neurol Neurosurg Psychiatry. 1998;64:67–73.
Moseley ML, Benzow KA, Schut LJ, Bird TD, Gomez CM, Barkhaus PE, et al. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology. 1998;51:1666–71.
Harding AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families including descendants of ‘the Drew family of Walworth’. Brain. 1982;105:1–28.
Dubourg O, Dürr A, Cancel G, Stevanin G, Chneiweiss H, Penet C, et al. Analysis of the SCA1 CAG repeat in a large number of families with dominant ataxia: Clinical and molecular correlations. Ann Neurol. 1995;37:176–80.
Bürk K, Abele M, Fetter M, Dichgans J, Skalej M, Laccone F, et al. Autosomal dominant cerebellar ataxia type I – Clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain. 1996;119:1497–505.
Schöls L, Amoiridis G, Büttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: Phenotypic differences in genetically defined subtypes? Ann Neurol. 1997;42:924–32.
Schöls L, Gispert S, Vorgerd M, Vieira-Saecker MM, Blanke P, Auburger G, et al. Spinocerebellar ataxia type 2 – Genotype and phenotype in German kindreds. Arch Neurol. 1997;54:1073–80.
Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, et al. Correlation between CAG repeat length and clinical features in Machado-Joseph disease. Am J Hum Genet. 1995;57:54–61.
Geschwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst SM. Spinocerebellar ataxia type 6 – Frequency of the mutation and genotype-phenotype correlations. Neurology. 1997;49:1247–51.
Enevoldson TP, Sanders MD, Harding AE. Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy. A clinical and genetic study of eight families. Brain. 1994;117:445–60.
Klockgether T, Lüdtke R, Kramer B, Abele M, Bürk K, Schöls L, et al. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain. 1998;121(Pt 4):589–600.
Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nature Genet. 1996;14:269–76.
Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet. 1994;8:221–8.
Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the a1A-voltage-dependent calcium channel. Nature Genet. 1997;15:62–9.
Filla A, De Michele G, Campanella G, Perretti A, Santoro L, Serlenga L, et al. Autosomal dominant cerebellar ataxia type I. Clinical and molecular study in 36 Italian families including a comparison between SCA1 and SCA2 phenotypes. J Neurolog Sci. 1996;142:140–7.
Giunti P, Stevanin G, Worth PF, David G, Brice A, Wood NW. Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation. Am J Hum Genet. 1999;64:1594–603.
Riess O, Schöls L, Bottger H, Nolte D, Vieira Saecker AM, Schimming C, et al. SCA6 is caused by moderate CAG expansion in the alpha1A-voltage-dependent calcium channel gene. Hum Mol Genet. 1997;6:1289–93.
Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet. 1994;6:9–13.
Hsiao K, Baker HF, Crow TJ, Poulter M, Owen F, Terwilliger JD, et al. Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome. Nature. 1989;338:342–5.
Matsumura R, Futamura N, Fujimoto Y, Yanagimoto S, Horikawa H, Suzumura A, et al. Spinocerebellar ataxia type 6 – Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology. 1997;49:1238–43.
Abele M, Burk K, Schols L, Schwartz S, Besenthal I, Dichgans J, et al. The aetiology of sporadic adult-onset ataxia. Brain. 2002;125:961–8.
Schöls L, Szymanski S, Peters S, Przuntek H, Epplen JT, Hardt C, et al. Genetic background of apparently idiopathic sporadic cerebellar ataxia. Hum Genet. 2000;107:132–7.
Pujana MA, Corral J, Gratacos M, Combarros O, Berciano J, Genis D, et al. Spinocerebellar ataxias in Spanish patients’ Genetic analysis of familial and sporadic cases. The Ataxia Study Group. Hum Genet. 1999;104:516–22.
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Klockgether, T. The clinical diagnosis of autosomal dominant spinocerebellar ataxias. Cerebellum 7, 101–105 (2008). https://doi.org/10.1007/s12311-008-0023-2
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DOI: https://doi.org/10.1007/s12311-008-0023-2