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. Author manuscript; available in PMC: 2014 Feb 12.

Published in final edited form as: Lancet Neurol. 2013 Aug;12(8):786–798. doi: 10.1016/S1474-4422(13)70125-X

(A) Schematic of the sequestration model for RNA toxicity in the fragile X premutation disorders, including FXTAS. One or more RNA-binding proteins bind to the CGG-repeat RNA in a length-dependent fashion, such that little binding occurs in the normal CGG-repeat range. Excess binding/sequestration of those proteins leads to a functional insufficiency for their normal function(s). Reduced FMR1 levels may contribute to the premutation phenotypes for the larger premutation alleles. (B) Stylized neuron with single synapse represented. CGG-repeat expansion leads to downstream effects that include reduced mitochondrial function, altered calcium regulation, and increased, synchronous firing of neurons in mouse hippocampal neuronal networks. (C) Schematic representation of the progression of CNS dysfunction, primarily driven by the premutation CGG-repeat expansion, but also modulated by second-gene effects, and various environmental exposures (e.g., untreated hypertension or hypothyroidism, smoking and/or use of other agents that promote oxidative damage, major illness or – anecdotally – surgery requiring general anesthesia).

(A) Schematic of the sequestration model for RNA toxicity in the fragile X premutation disorders, including FXTAS. One or more RNA-binding proteins bind to the CGG-repeat RNA in a length-dependent fashion, such that little binding occurs in the normal CGG-repeat range. Excess binding/sequestration of those proteins leads to a functional insufficiency for their normal function(s). Reduced FMR1 levels may contribute to the premutation phenotypes for the larger premutation alleles. (B) Stylized neuron with single synapse represented. CGG-repeat expansion leads to downstream effects that include reduced mitochondrial function, altered calcium regulation, and increased, synchronous firing of neurons in mouse hippocampal neuronal networks. (C) Schematic representation of the progression of CNS dysfunction, primarily driven by the premutation CGG-repeat expansion, but also modulated by second-gene effects, and various environmental exposures (e.g., untreated hypertension or hypothyroidism, smoking and/or use of other agents that promote oxidative damage, major illness or – anecdotally – surgery requiring general anesthesia).