Publisher Summary This chapter discusses the fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). Fragile X syndrome, the leading heritable form of mental retardation and FXTAS, a newly discovered neurodegenerative disorder are both caused by CGG repeat expansions in the fragile X mental retardation 1 (FMR1) gene; however, the two disorders involve separate groups of individuals, and occur by entirely different molecular mechanisms. Although fragile X syndrome is caused by silencing of the FMRl gene for large (> 200 CGG repeats; full mutation) expansions, FXTAS appears to be caused by increased transcriptional activity of smaller (55 to 200 CGG repeats; premutation) expansion. Furthermore, FXTAS is likely to be one of the few genetic disorders that are caused by a “toxic” gain-of-function of the FMRl mRNA. There is a moderate to severe loss of brain volume with FXTAS, in contrast to the overall increase in brain volume observed in fragile X syndrome. A protocol has recently been developed for the isolation of microgram quantities of purified inclusions from postmortem human brain tissue of FXTAS cases using automated sorting of immunofluorescence-tagged inclusions.