Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome  Randi Hagerman, MD, Dr Paul Hagerman, MD  The Lancet Neurology  Volume 12, Issue 8, Pages 786-798 (August 2013) DOI: 10.1016/S1474-4422(13)70125-X Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 1 Schematic diagram of the sequestration model for RNA toxicity in the fragile X premutation disorders, including fragile X-associated tremor/ataxia syndrome 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 or sequestration of those proteins leads to a functional insufficiency for their normal function(s). Reduced FMRP concentrations might contribute to the premutation phenotypes for the larger premutation alleles. The Lancet Neurology 2013 12, 786-798DOI: (10.1016/S1474-4422(13)70125-X) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 2 Stylised neuron with single synapse represented, showing cellular dysregulation in fragile X-associated tremor/ataxia syndrome 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. N=nucleus. M=mitochondria. ER=endoplasmic reticulum. The Lancet Neurology 2013 12, 786-798DOI: (10.1016/S1474-4422(13)70125-X) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 3 Schematic representation of the progression of CNS dysfunction Dysfunction primarily driven by the premutation CGG-repeat expansion, but also modulated by second-gene effects and various environmental exposures (eg, untreated hypertension or hypothyroidism, smoking or use of other agents that promote oxidative damage, major illness or, anecdotally, surgery requiring general anaesthesia). FXTAS=fragile X-associated tremor/ataxia syndrome. The Lancet Neurology 2013 12, 786-798DOI: (10.1016/S1474-4422(13)70125-X) Copyright © 2013 Elsevier Ltd Terms and Conditions