Autosomal Dominant Spinocerebellar Ataxias and Episodic Ataxias
Hereditary autosomal dominant spinocerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders consisting of 31 spinocerebellar ataxia syndromes (SCAs), dentatorubral-pallidoluysian atrophy (DRPLA), and 7 episodic ataxia s
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Franco Taroni, Luisa Chiapparini, and Caterina Mariotti
Abstract
Hereditary autosomal dominant spinocerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders consisting of 31 spinocerebellar ataxia syndromes (SCAs), dentatorubral-pallidoluysian atrophy (DRPLA), and 7 episodic ataxia syndromes (EAs). SCAs are characterized by disequilibrium, slowly progressive incoordination (ataxia) of gait and limbs, dysarthria, and/or oculomotor disorder due to cerebellar degeneration in the absence of coexisting diseases. The degenerative process can be limited to the cerebellum (ADCA type III) or may additionally involve the retina (ADCA type II), optic nerve, pontomedullary systems, basal ganglia, cerebral cortex, spinal tracts, or peripheral nerves (ADCA type I and DRPLA). In EAs, the disease presents with recurrent, discrete episodes of ataxia, giddiness, and vertigo with or without interictal abnormalities. Prevalence of ADCAs has been estimated between 0.8 and 3.5:100,000. Onset is usually between ages 30 and 50 years, although early onset in childhood and later onset after the age of 60 years can be observed. Genetic classification includes 31 SCA loci (SCA1-SCA36, numbered in the order of locus or gene description) with 20 genes identified, DRPLA, and 7 EA loci (EA1-7) with 4 genes identified.
F. Taroni (*) Fondazione IRCCS Istituto Neurologico C., Besta Via Celoria, 11–20133 Milano, Italy and Department of Diagnostics and Applied Technology, Unit of Genetics of Neurodegenerative and Metabolic Diseases Istituto Neurologico “Carlo Besta”, Via Celoria 11, I-20133 Milan, Italy e-mail: [email protected] L. Chiapparini Unit of Neuroradiology, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy e-mail: [email protected] C. Mariotti Department of Diagnostics and Applied Technology, Unit of Genetics of Neurodegenerative and Metabolic Disease, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy e-mail: [email protected] M. Manto, D.L. Gruol, J.D. Schmahmann, N. Koibuchi, F. Rossi (eds.), 2193 Handbook of the Cerebellum and Cerebellar Disorders, DOI 10.1007/978-94-007-1333-8_101, # Springer Science+Business Media Dordrecht 2013
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F. Taroni et al.
Twelve ADCAs are caused by dynamic expansions of polyglutamine-encoding CAG repeats (SCA1-3, 6, 7, 17, and DRPLA) or repeats falling outside the coding region (SCA8, 10, 12, 31, and 36). In these conditions, repeat size influences disease progression and severity, while its variability is responsible for variability in age of onset, with larger repeats in early onset cases. Additionally, instability of expanded alleles leads to the phenomenon of anticipation (earlier onset and more severe disease in successive generations). All other ADCAs are caused by conventional mutations in genes with distinct functions. The clinical phenotypes of the most common forms have been firmly established. Genetic testing enables identification of the causative gene in 50–60% of ADCA cases. Despite
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