Advances in the treatment of fragile X syndrome

Abstract

The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties, including primary ovarian insufficiency, neuropathy and the fragile X-associated tremor/ataxia syndrome, in some older premutation carriers. Therefore, multigenerational family involvement is commonly encountered when a proband is identified with a FMR1 mutation. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition. Trials of metabotropic glutamate receptor 5 antagonists are beginning with individuals with fragile X syndrome. Targeted treatments, medical and behavioral interventions, genetic counseling, and family supports are reviewed here.

FIGURE 1

Depiction of transcription and translation of the FMR1 gene in normal individuals, individuals with the premutation, and individuals with the full mutation. The molecular pathogenesis is different in the premutation diseases, compared with the full mutation that leads to FXS. FMR1 mRNA expression levels are increased with the premutation and decreased or absent with the full mutation. FMRP levels are absent or decreased with the full mutation and normal or close to normal with the premutation.

FIGURE 2

Photograph and pedigree of a family in which the premutation and the full mutation have affected 4 generations. All family members included in the pedigree are in the photograph except one of the twin brothers with FXS. POI indicates primary ovarian insufficiency; nl, normal; pre, premutation; SAB, spontaneous abortion.

FIGURE 3

Pathways in the cortex and hippocampus thought to be involved in the mGluR mechanism of mental retardation in FXS and expected effects of lithium, 2-methyl-6-(phenylethynyl)pyridine (MPEP)/mGluR blockers, and CX516/ampakines. In the normal state, mGluR activation by glutamate (glu) results in activation of dendritic translation through the phospholipase C (PLC) cascade. FMRP levels increase with translational activation, and FMRP then inhibits translation, acting as the negative feedback or “brake” on the translational mechanism. When FMRP is missing in FXS, mGluR-mediated translation lacks the negative feedback balance normally provided by FMRP and is activated excessively and constitutively, leading to excessive synthesis of specific synaptic proteins, internalization of AMPA receptors, and other synaptic changes that result in excessive long-term depression and persistently weak and immature synapses. Treatment with 2-methyl-6-(phenylethynyl)pyridine or other mGluR5 negative modulators would block excessive mGluR-mediated translation directly. Lithium, which blocks inositol phosphate (IP) turnover, thus depleting phospholipase C substrate and blocking phospholipase C-mediated signal transduction, also inhibits glycogen synthase kinase 3β (GSK3β) activity, thus downregulating translation of FMRP target proteins, and would be expected to block in part excessively activated mGluR-mediated translation in FXS. In either case, the system would then move toward the normal level of translational activity, resulting in normalization of synaptic activity and maturation. Treatment with CX516 or other ampakines would be expected to increase AMPA activity directly, as well as redistributing AMPA receptors to the synaptic membrane through activation of BDNF. PKC indicates protein kinase C.