Repeat expansion disorders

Repeat expansion disorders are complex, primarily neurological, conditions deriving from repetition of nucleotide stretches. These disorders exhibit a wide range of clinical manifestations, many characterized by the presence of ataxia or lack of coordination. The most common of these entail an expansion of trinucleotide repeats in coding regions of certain genes resulting in a pathologic polyglutamine-expanded protein. Other mechanisms include peptides generated from noncanonical translation, repeat expansions in noncoding regions, which perturb gene expression, or the generation of toxic RNA intermediates. A multitude of factors, including repeat length, genomic location, and disruption of endogenous gene function are thought to drive pathology from the subcellular level to the clinical patient phenotypes. In this chapter, we attempt to unravel this complexity, beginning with the pathophysiological ramifications of repeat expansion disorders at the nucleotide level and working our way to anatomic consequences and patient-level presentations. We comment on therapeutic efforts of the past and provide some perspective on novel genetic treatments and clinical trial redesign that pave the way for the future.