Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials

Braat, Sien; Kooy, R. Frank

doi:10.1016/j.neuropharm.2014.06.028

Cited by 70 publications

(41 citation statements)

References 45 publications

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“…Finally, in a subsequent study the researchers used expression analysis for the GABA-A receptor subunits and reported increased levels of α2 subunit mRNA levels, which could possibly explain the lack of mature response to GABA signaling [115]. This latter finding is in line with previous results on the disruption of the GABA signaling pathway in mouse models and patients [100,116,117,118,119,120], hence confirming the authenticity of this model system. …”

Section: Neurological Pathology In Fxs Neurons Derived From Hpscsupporting

confidence: 77%

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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Section: Neurological Pathology In Fxs Neurons Derived From Hpscsupporting

confidence: 77%

Modeling Fragile X Syndrome Using Human Pluripotent Stem Cells

Mor‐Shaked

Eiges

2016

Genes

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“…In two studies [67,68], 3% of sporadic and 10-13% of familial POI patients carried FRAXA premutations; in a more extensive follow-up, Murray et al [69] found the permutation in 0.7% of 2,000 women with early menopause and in 2% of women with POI (an odds ratio for POI of 5.4 compared with 0.4% in controls). FMR1 has a primary effect in the brain [70], but is also implicated in the DNA damage response [71], and could thereby have a determinative effect on chromosome dynamics and oocyte stability. A similar POI phenotype is seen in FRAXE, associated with CGG triplet expansion in FMR2, in Xq28 [72].…”

Section: X-autosomal Translocations and Chromosomal Changesmentioning

confidence: 99%

Dynamics of the Ovarian Reserve and Impact of Genetic and Epidemiological Factors on Age of Menopause1

Pelosi

Simonsick

Forabosco³

et al. 2015

Biology of Reproduction

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The narrow standard age range of menopause, ∼50 yr, belies the complex balance of forces that govern the underlying formation and progressive loss of ovarian follicles (the "ovarian reserve" whose size determines the age of menopause). We show here the first quantitative graph of follicle numbers, distinguished from oocyte counts, across the reproductive lifespan, and review the current state of information about genetic and epidemiological risk factors in relation to possible preservation of reproductive capacity. In addition to structural X-chromosome changes, several genes involved in the process of follicle formation and/or maintenance are implicated in Mendelian inherited primary ovarian insufficiency (POI), with menopause before age 40. Furthermore, variants in a largely distinct cohort of reported genes-notably involved in pathways relevant to atresia, including DNA repair and cell death-have shown smaller but additive effects on the variation in timing of menopause in the normal range, early menopause (age <45), and POI. Epidemiological factors show effect sizes comparable to those of genetic factors, with smoking accounting for about 5% of the risk of early menopause, equivalent to the summed effect of the top 17 genetic variants. The identified genetic and epidemiological factors underline the importance of early detection of reproductive problems to enhance possible interventions.

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“…Kazdoba et al [98] showed that ganaxolone, a synthetic analog of allopregnanolone, can improve social and repetitive behaviors in an ASD mouse model. Braat and Kooy [99] suggested that ganaxolone is a potential candidate for treatment of fragile X syndrome which is a frequently inherited cause of syndromic autism [100]. Ligsay et al [101] conducted a randomized, doubleblind placebo-controlled trial of ganaxolone in fragile X syndrome and reported no significant improvement in the overall population investigated, but suggested that this drug might be beneficial in treatment of fragile X syndrome children displaying high anxiety or reduced cognitive abilities.…”

Section: Reviewmentioning

confidence: 99%

Neuroactive Steroids and Related Steroids in Autism Spectrum Disorders

Zheng¹,

Wang²,

Li³

et al. 2018

Neuropsychiatry

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Neuroactive steroids (rapidly acting steroids that act as allosteric modulators of neurotransmitter receptors such as the ɣ-aminobutyric acid A (GABA A ) receptor and the NMDA glutamate receptor) are involved in brain development and have been proposed to be important in the etiology and/or pharmacotherapy of a number of psychiatric and neurologic disorders, but there is limited information available on their association with autism spectrum disorders (ASD). This paper reviews the possible involvement of neuroactive steroids (NASs) and some related steroids, including testosterone, androstenedione and estradiol steroids in the etiology of ASD. NASs include progesterone, pregnanolone, pregnenolone, pregnenolone sulfate, allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Studies on the levels of NASs and related steroids in blood, urine, saliva, and amniotic fluid in ASD are also reviewed. The results on plasma levels of NASs in ASD reported in the literature are generally inconclusive, probably because of differences among studies in terms of experimental design and factors such as age, gender, number of subjects, and medication being taken and differences in time of day at which samples are taken and storage conditions of samples. Future studies on levels of NASs in ASD should include careful consideration of the factors mentioned above, the possible advantages of saliva sampling and the use of assay procedures that provide simultaneous analysis of levels of a large number of these steroids.

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Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials

Cited by 70 publications

References 45 publications

Modeling Fragile X Syndrome Using Human Pluripotent Stem Cells

Modeling Fragile X Syndrome Using Human Pluripotent Stem Cells

Dynamics of the Ovarian Reserve and Impact of Genetic and Epidemiological Factors on Age of Menopause1

Neuroactive Steroids and Related Steroids in Autism Spectrum Disorders

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