Pharmacotherapy for Fragile X Syndrome: Progress to Date

Davenport, Matthew H.; Schaefer, Tori L.; Friedmann, Katherine J.; Fitzpatrick, Sarah E.; Erickson, Craig A.

doi:10.1007/s40265-016-0542-y

Cited by 34 publications

(29 citation statements)

References 149 publications

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“…In Fmr1 knockout (KO) mice, the glutamatergic receptors signalling and/or localization is enhanced. New studies that try to reduce excitatory neurotransmission by antagonism of group I metabotropic glutamate receptors (mGluRs), particularly mGluR5, are still underway [93]. By now, studies conducted on Fmr1 KO mice demonstrated that the reduction of mGluR5 levels can normalize protein synthesis, dendritic spines, and some behaviour [94].…”

Section: Discussionmentioning

confidence: 99%

Fragile X syndrome: a review of clinical and molecular diagnoses

et al. 2017

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BackgroundFragile X Syndrome (FXS) is the second cause of intellectual disability after Down syndrome and the most prevalent cause of intellectual disability in males, affecting 1:5000–7000 men and 1:4000–6000 women. It is caused by an alteration of the FMR1 gene, which maps at the Xq27.3 band: more than 99% of individuals have a CGG expansion (>200 triplets) in the 5′ UTR of the gene, and FMR1 mutations and duplication/deletion are responsible for the remaining (<1%) molecular diagnoses of FXS. The aim of this review was to gather the current clinical and molecular knowledge about FXS to provide clinicians with a tool to guide the initial assessment and follow-up of FXS and to offer to laboratory workers and researchers an update about the current diagnostic procedures.DiscussionFXS is a well-known condition; however, most of the studies thus far have focused on neuropsychiatric features. Unfortunately, some of the available studies have limitations, such as the paucity of patients enrolled or bias due to the collection of the data in a single-country population, which may be not representative of the average global FXS population. In recent years, insight into the adult presentation of the disease has progressively increased. Pharmacological treatment of FXS is essentially symptom based, but the growing understanding of the molecular and biological mechanisms of the disease are paving the way to targeted therapy, which may reverse the effects of FMRP deficiency and be a real cure for the disease itself, not just its symptoms.ConclusionsThe clinical spectrum of FXS is wide, presenting not only as an isolated intellectual disability but as a multi-systemic condition, involving predominantly the central nervous system but potentially affecting any apparatus. Given the relative high frequency of the condition and its complex clinical management, FXS appears to have an important economic and social burden.

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Section: Discussionmentioning

confidence: 99%

Fragile X syndrome: a review of clinical and molecular diagnoses

et al. 2017

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“…In fact, the existence of rare unmethylated full mutation individuals [122], suggests that pharmacologically restoring FMR1 transcription may be possible. …”

Section: Therapeutic Strategies In Fxsmentioning

confidence: 99%

Modeling Fragile X Syndrome Using Human Pluripotent Stem Cells

Mor‐Shaked

Eiges

2016

Genes

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Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from a loss-of-function mutation by a CGG repeat expansion at the 5′ untranslated region of the X-linked fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeats beyond 200 copies results in protein deficiency by leading to aberrant methylation of the FMR1 promoter and the switch from active to repressive histone modifications. Additionally, the CGGs become increasingly unstable, resulting in high degree of variation in expansion size between and within tissues of affected individuals. It is still unclear how the FMR1 protein (FMRP) deficiency leads to disease pathology in neurons. Nor do we know the mechanisms by which the CGG expansion results in aberrant DNA methylation, or becomes unstable in somatic cells of patients, at least in part due to the lack of appropriate animal or cellular models. This review summarizes the current contribution of pluripotent stem cells, mutant human embryonic stem cells, and patient-derived induced pluripotent stem cells to disease modeling of FXS for basic and applied research, including the development of new therapeutic approaches.

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“…Studies report that drugs used to treat excessive glutamate and insufficient γ-aminobutyric acid (GABA), signaling pathways affected by FMRP, are under different stages of development in FXS [15]. Thus, it is interesting to know whether the imbalance between excitatory and inhibitory circuitry is caused by a lack of astrocytic FMRP.…”

Section: Introductionmentioning

confidence: 99%

Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

Wang

Zhou

et al. 2016

Genes

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Fragile X syndrome (FXS) is a form of inherited mental retardation that results from the absence of the fragile X mental retardation protein (FMRP), the product of the Fmr1 gene. Numerous studies have shown that FMRP expression in astrocytes is important in the development of FXS. Although astrocytes affect neuronal dendrite development in Fmr1 knockout (KO) mice, the factors released by astrocytes are still unclear. We cultured wild type (WT) cortical neurons in astrocyte-conditioned medium (ACM) from WT or Fmr1 KO mice. Immunocytochemistry and Western blotting were performed to detect the dendritic growth of both WT and KO neurons. We determined glutamate and γ-aminobutyric acid (GABA) levels using high-performance liquid chromatography (HPLC). The total neuronal dendritic length was reduced when cultured in the Fmr1 KO ACM. This neurotoxicity was triggered by an imbalanced release of glutamate and GABA from Fmr1 KO astrocytes. We found increased glutaminase and GABA transaminase (GABA-T) expression and decreased monoamine oxidase B expression in Fmr1 KO astrocytes. The elevated levels of glutamate contributed to oxidative stress in the cultured neurons. Vigabatrin (VGB), a GABA-T inhibitor, reversed the changes caused by glutamate and GABA release in Fmr1 KO astrocytes and the abnormal behaviors in Fmr1 KO mice. Our results indicate that the imbalance in the astrocytic glutamate and GABA release may be involved in the neuropathology and the underlying symptoms of FXS, and provides a therapeutic target for treatment.

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Pharmacotherapy for Fragile X Syndrome: Progress to Date

Cited by 34 publications

References 149 publications

Fragile X syndrome: a review of clinical and molecular diagnoses

Fragile X syndrome: a review of clinical and molecular diagnoses

Modeling Fragile X Syndrome Using Human Pluripotent Stem Cells

Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

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