Genetics of the Autosomal Dominant Spinocerebellar Ataxias

Abstract

The spinocerebellar ataxias (SCAs) are a clinically, genetically and neuropathologically heterogeneous group of neurological disorders defined by variable degrees of cerebellar ataxia often accompanied by additional cerebellar and noncerebellar symptoms that, in many cases, defy differentiation based on clinical characterisation alone. The clinical symptoms are triggered by neurodegeneration of the cerebellum and its rely connections. Currently, there are 43 different genes associated with the autosomal dominant SCAs identified. Genetic studies refine the clinical diagnosis, provide molecular testing of at risk, a/presymptomatic, prenatal or preimplantation and facilitate genetic counselling in 27 SCA subtypes. Recent scientific advances are shedding light into the altered molecular pathways involved and the mechanisms by which the mutant gene products underlie neurodegeneration. This knowledge should be translated into effectively developing selective therapeutic strategies. The scope of this chapter is to provide an updated summary of the genetic aspects of the autosomal dominant SCAs.

Key Concepts:

  • Ataxia, a term that derives from the Greek, is a neurological disorder characterised by loss of control of voluntary body movements.

  • Spinocerebellar ataxias, also known as SCAs, are a highly heterogeneous group of neurodegenerative diseases caused by cerebellar atrophy triggered by predominant loss of Purkinje cells in the cerebellum.

  • The term ‘spinocerebellar ataxias’ is commonly used for those inherited progressive, congenital or episodic ataxias presenting an autosomal dominant inheritance.

  • Mutations presenting incomplete penetrance in at least 43 genes are responsible for ataxia in the autosomal dominant SCAs.

  • CAG repeat expansions encoding for polyglutamines in the gene products currently underlie neurodegeneration in seven spinocerebellar ataxia subtypes.

  • Anticipation is a genetic phenomenon whereby the clinical symptoms become apparent at an earlier age as it is passed on to the next generation. This is associated with the germline transmission of an unstable expanded CAG‐triplet repeat.

Keywords: spinocerebellar ataxias; cerebellum; neurodegeneration; movement disorders; Purkinje cells; polyglutamine expansions; molecular diagnosis; genetic counselling; ataxia scales

Figure 1.

Ideogram generated with the human genome browser at UCSC (Kent et al., ) showing the chromosomal locations of all 43 SCA genes identified up to date.

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Corral‐Juan, Marc, Corral, Jordi, San Nicolás, Héctor, Volpini, Victor, and Matilla‐Dueñas, Antoni(Oct 2011) Genetics of the Autosomal Dominant Spinocerebellar Ataxias. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006076]