General Overview: Genetic Instability and Hereditary Neurological DiseasesSubstantial progress has been made in the past 20 years in our understanding of the pathophysiology, genetics, and biochemistry of approximately 20 neurological diseases associated with simple sequence amplification (1, 2). These data serve as the overarching subject of this minireview series. Dynamic mutations involving the role of DNA hairpin loops or slipped strand conformations with differing relative stabilities of repeating tri-, tetra-, or pentanucleotide tracts are involved in these expansions and deletions (reviewed in Refs. 1 and 3-6). The diseases, including fragile X syndrome, myotonic dystrophy, Huntington disease, and Friedreich ataxia, are reviewed elsewhere (1), along with their inheritance patterns, chromosomal localizations, protein products, and loci of the repeat sequences. In type 2 diseases, for example, the repeat expansions are massive (thousands of repeats), whereas in type 1 diseases, the TRS 2 are in coding regions and elicit a modest expansion of a polyamino acid tract (usually glutamine, but alanine in some diseases) (1, 2). The clinical observation of anticipation, the decrease in age of onset, and the increase in severity with progression through a family pedigree are observed with most, but not all, of these diseases. Usually, a more severe neurological syndrome is observed in patients with longer repeat tracts. Substantial work over the past decade has demonstrated that the expansions and deletions are mediated by DNA replication, repair, and recombination, probably acting in concert (reviewed in Refs. 1 and 3-7). The slippage of the repeating DNA complementary strands to form non-B DNA structures, such as hairpin loops or slipped strand conformations, with differing relative stabilities is an important component in the mechanism (1, 3-7).In general, the genetic instabilities in the simple repeating sequences are found within the TRS, not in the flanking regions, for the majority of these neurological disorders (1, 2). However, a large number of articles (Ͼ30) have described a variety of classical mutations, such as deletions, found in the DNA of fragile X syndrome patients in the vicinity of the CGG⅐CCG repeats. This behavior seems to be more frequent for the fragile X syndrome than for other hereditary neurological diseases (8).To focus on the molecular mechanisms of the mutagenic spectra found in deletions related to fragile X syndrome, I shall not consider other folate-sensitive fragile sites (1, 2, 8) that also have CGG⅐CCG expansions.