Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome

Abstract

Fragile X syndrome, the most common heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X (FMR1) gene owing to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, so-called premutation expansions (55-200 repeats) can cause a family of neurodevelopmental phenotypes (attention deficit hyperactivity disorder, autism spectrum disorder, seizure disorder) and neurodegenerative (fragile X-associated tremor/ataxia syndrome [FXTAS]) phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Results of basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the range of clinical manifestations. Advances of knowledge on both mechanistic and clinical fronts are driving new approaches to targeted treatment, but two important necessities are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in view of its differing presentations and associated features.

Figure 1

(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).

Figure 1

(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).

Figure 1

(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).