Repetitive DNA sequences are abundant in the human genome, scattered throughout the regions between genes and, in some cases, within genes. They take the form of minisatellites (repeat sequences ranging in length from tens to hundreds of nucleotides) and microsatellites (repeat sequences consisting of one to several nucleotides in length) and have an intrinsic genetic instability that results in frequent length changes (Charlesworth et al., 1994; Tautz & Schlotterer, 1994). Thus, mini- and microsatellites are highly polymorphic between individuals, a feature which has led to their extensive use in genetic research as markers in positional cloning of genes and also in forensic medicine for DNA-based identification, socalled ‘DNA fingerprinting’. While the normal role of these sequences, if any, remains unclear, repeat sequences have gained a great deal of attention over the past decade because of their emerging role in human disease. In particular, expansions of repetitive sequences within genes are increasingly found to underlie hereditary neurological diseases. In this chapter we discuss mechanisms that have been proposed to generate repeat expansion, the relationship between repeat length and disease manifestations, and present a classification scheme for organizing trinucleotide expansion diseases. Finally, we discuss the clinical features, genetics, pathology and molecular pathogenesis of 16 currently recognized trinucleotide expansion diseases.
Neurologists have long recognized the clinical phenomenon of anticipation, the tendency of certain inherited neurological diseases to appear earlier in successive generations, often with more severe clinical manifestations. This phenomenon, which was described as early as 1918 in myotonic dystrophy (Fleischer, 1918) and subsequently observed in other neurodegenerative diseases, was at odds with the classical Mendelian genetic principle that mutations are stably passed on to offspring. Thus, for many years the phenomenon of anticipation was attributed to ascertainment bias. Then, in 1991, spinobulbar muscular atrophy and the fragile X syndrome were found to result from expanded trinucleotide repeats in their respective genes. Furthermore, these expanded repeats were found to be unstable, frequently becoming longer in successive generations. Since longer repeat expansions are generally associated with earlier disease onset and more severe disease, this provided a molecular basis for anticipation. Since then, this dynamic form of genetic mutation has been found to underlie an increasing number of inherited neurological diseases, most of which exhibit anticipation.