Toward fulfilling the promise of molecular medicine in fragile X syndrome

Abstract

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.

Figure 1

The promise of molecular medicine in psychiatric and neurodevelopmental disorders (see sidebar “The Promise of Molecular Medicine in Brain Disorders” for explanation).

Figure 2

Some milestones in defining the pathophysiology of fragile X syndrome (FXS). The current therapeutic efforts in FXS originate from the mixing of two independent lines of research: genetic research on FXS (left timeline, yellow) and basic neurobiology research on mGluR-dependent synaptic plasticity (right timeline, blue). The discovery that mGluR-LTD is exaggerated in Fmr1 knockout (KO) mice (17) led to the mGluR theory of FXS pathophysiology, culminating in the initiation of clinical trials to test the efficacy of mGluR5 antagonists in the treatment of FXS. Numbers in parentheses are reference citations. Fmr1, fragile X mental retardation 1; FMRP, fragile X mental retardation protein; mGluR, metabotropic glutamate receptor; LTD, long-term depression; MPEP, 2-methyl-6-(phenylethynyl)-pyridine.

Figure 3

Prospects for the treatment of a developmental brain disorder. (a) Divergence of brain maturation in normal development versus development in fragile X syndrome (FXS). This continuous divergence results in an accumulated deficit in individuals with FXS that increases with age. (b) Prospects for treatment of this accumulated deficit in FXS. Three scenarios are conceivable with respect to interventions that occur following symptom onset: (i ) The optimistic view assumes that pharmacological intervention after symptom onset results in near-complete reversal of associated phenotypes. (ii ) The pessimistic view is that after an initial window of opportunity, pharmacological approaches can no longer alter the course of the disorder. (iii ) The intermediate (but still hopeful) view suggests that pharmacological intervention can slow or prevent progression of symptoms, although it may not fully correct previously established impairments.