Repeat instability has been associated with more than 20 diverse neurological disorders, including neurodegenerative and neuromuscular disease (Gatchel and Zoghbi 2005; Pearson et al. 2005; Orr and Zoghbi 2007). Repeat expansions as a cause of disease was initially described in 1991 when specific unstable trinucleotide repeats were associated with fragile X syndrome (see Box 7.8) (Verkerk et al. 1991), and spinal and bulbar muscular atrophy (see Box 7.12) (La Spada et al. 1991). Expansions of trinucleotide repeats are responsible for the majority of disorders caused by unstable repeats. Other repeat lengths are also associated with disease, notably tetranucleotide repeats, for example CCTG repeats and dystrophia myotonica type 2 (see Box 7.15) (Liquori et al. 2001), and pentanucleotide repeats, for example ATTCT repeats and spinocerebellar ataxia type 10 (Fig. 7.8) (Matsuura et al. 2000). Instability or mutation of longer repeat lengths have also been found to cause disease, notably involving minisatellite DNA, as seen in progressive myoclonic epilepsy (see Box 7.4), and in satellite DNA where reduced numbers of a 3.3 kb repeat at 4q35 are associated with facioscapulohumeral dystrophy (see Box 7.2).
The study of the molecular basis of these 'unstable repeat' diseases has been of particular interest as the disease associated repeat mutations are dynamic, changing between generations and within individuals dependent on the specific tissues involved (Pearson et al. 2005; Orr and Zoghbi 2007). These were remarkable findings: that disease-causing mutations were not necessarily transmitted stably from parents to children and that the variation in disease phenotype could be related to the size of the repeat expansion. In most of these diseases, disease severity and age of onset is associated with increasing numbers of repeats, and the likelihood of repeat expansion increases with longer lengths of repeats. Across successive generations, as repeat expansion occurs, the disease severity in affected individuals is seen to increase with an earlier age of
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