Abnormal Nerve Conduction Features in Fragile X Premutation Carriers

Abstract

Fragile X–associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative syndrome that occurs in approximately 38% of carriers of premutation expansions (55-200 CGG repeats; noncoding) of the fragile X mental retardation 1 gene (FMR1)^1-4 who have been ascertained through families with fragile X syndrome probands. Premutation CGG repeat expansions are associated with a 2- to 8-fold elevation in FMR1 messenger RNA (mRNA) levels,^5,6 resulting in mRNA gain-of-function toxic effects and formation of intranuclear inclusions in neurons and astrocytes of carriers with FXTAS.^7-9 Analysis of the FXTAS-associated inclusions has identified several of the constituent proteins, including lamin A/C and other neurofilaments, myelin basic protein, αB-crystallin, and hnRNPA2.⁹ There is evidence of active dysregulation of lamin A/C in neural cells after transfection with the premutation-sized CGG repeats.