The neurology and corresponding genetics of fragile X disorders: insights into the genetics of neurodegeneration

Abstract

There have been significant advances in understanding how the fragile X gene (FMR1) can lead to distinct neurological syndromes. Clinical features of two disorders – fragile X syndrome and fragile X-associated tremor ataxia syndrome (FXTAS) – are highlighted in this article. These two disorders – one a neurodevelopmental disorder, the other a neurodegenerative disorder – are caused by a single expanded CGG repeat sequence within the FMR1 gene. Minor differences in repeat length result in the markedly different phenotypes. Understanding the action of FMR1 in FXTAS and fragile X syndrome has yielded significant insights into the genetics of neurodegeneration. Moreover, the genetic model in FXTAS is similar to several other neurologic genetic disorders, suggesting there are common pathways shared by many phenotypically diverse progressive neurodegenerative disorders. Finally, it is possible that targeted therapies for disorders such as FXTAS may also be effective in other neurodegenerative disorders that share similar mechanisms of pathogenesis.