Fragile X syndrome and epilepsy

Qiu, Lifeng; Yan-hong, Hao; Qing-zhang, LI; Xiong, Zhi‐Qi

doi:10.1007/s12264-008-1221-0

Cited by 16 publications

(12 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Osmolytes control the ion gradient across membranes, and modifications of their levels may facilitate neuronal discharge and epileptiform activity (Liu et al 2008), as described in the Fmr1-deficient mouse (Qiu et al 2008). …”

Section: Altered Osmolyte and Secondary Messengers Balancementioning

confidence: 99%

A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model

Davidovic¹,

Navratil²,

Bonaccorso³

et al. 2011

Genome Res.

104

126

View full text Add to dashboard Cite

Fragile X syndrome (FXS) is the first cause of inherited intellectual disability, due to the silencing of the X-linked Fragile X Mental Retardation 1 gene encoding the RNA-binding protein FMRP. While extensive studies have focused on the cellular and molecular basis of FXS, neither human Fragile X patients nor the mouse model of FXS-the Fmr1-null mouse-have been profiled systematically at the metabolic and neurochemical level to provide a complementary perspective on the current, yet scattered, knowledge of FXS. Using proton high-resolution magic angle spinning nuclear magnetic resonance ( 1 H HR-MAS NMR)-based metabolic profiling, we have identified a metabolic signature and biomarkers associated with FXS in various brain regions of Fmr1-deficient mice. Our study highlights for the first time that Fmr1 gene inactivation has profound, albeit coordinated consequences in brain metabolism leading to alterations in: (1) neurotransmitter levels, (2) osmoregulation, (3) energy metabolism, and (4) oxidative stress response. To functionally connect Fmr1-deficiency to its metabolic biomarkers, we derived a functional interaction network based on the existing knowledge (literature and databases) and show that the FXS metabolic response is initiated by distinct mRNA targets and proteins interacting with FMRP, and then relayed by numerous regulatory proteins. This novel ''integrated metabolome and interactome mapping'' (iMIM) approach advantageously unifies novel metabolic findings with previously unrelated knowledge and highlights the contribution of novel cellular pathways to the pathophysiology of FXS. These metabolomic and integrative systems biology strategies will contribute to the development of potential drug targets and novel therapeutic interventions, which will eventually benefit FXS patients.[Supplemental material is available for this article.]Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability (ID) and the most commonly identified genetic cause of autism (Chelly et al. 2006;Gecz et al. 2009). FXS affects 1 in 4000 males and 1 in 7000 females world-wide (Hagerman 2008) and is caused by the silencing of the X-linked Fragile X Mental Retardation 1 (FMR1) gene positioned in Xq27.3. In FXS patients, a dynamic mutation increasing abnormally the number of CGG repeats in the first exon of the FMR1 gene leads to their hypermethylation and the subsequent absence of its gene product, FMRP (Penagarikano et al. 2007). Although a monogenic disorder, FXS is a disease of complex etiology accompanied by behavioral (hyperactivity, autism), neurological (susceptibility to epileptic seizures), as well as physical abnormalities (macroorchidism, elongated face, hyperextensible finger joints) (Penagarikano et al. 2007). A mouse model of FXS knock-out (KO) for the murine homolog of FMR1, has been generated, exhibiting learning and behavioral abnormalities that recapitulate the human phenotype (The Dutch-Belgian Fragile X Consortium 1994). The absence of FMRP induces abnormal extra dendritic spines...

show abstract

Section: Altered Osmolyte and Secondary Messengers Balancementioning

confidence: 99%

A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model

Davidovic¹,

Navratil²,

Bonaccorso³

et al. 2011

Genome Res.

104

126

View full text Add to dashboard Cite

show abstract

“…Clinical FXS symptoms include delayed and depressed developmental trajectories (Bailey et al, 2001a,b; Hall et al, 2008), short-term working memory deficits (Munir et al, 2000; Cornish et al, 2001; Kwon et al, 2001; Lanfranchi et al, 2009), disordered sleep (Gould et al, 2000; Miano et al, 2008), seizures (Kluger et al, 1996; Musumeci et al, 1999; Singh et al, 1999; Sabaratnam et al, 2001; Berry-Kravis, 2002; Di Bonaventura et al, 2006; Qiu et al, 2008), elevated anxiety (Tsiouris and Brown, 2004), and attention-deficit hyperactivity disorder (Hatton et al, 2002; Sullivan et al, 2006). Significantly, 30% of FXS patients are also diagnosed with autism (Figure 1) (Kau et al, 2004; Hagerman, 2008b; Harris et al, 2008).…”

Section: Fragile X Syndromementioning

confidence: 99%

Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models

Gatto

Broadie

2010

Front. Syn. Neurosci.

148

133

View full text Add to dashboard Cite

Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. The affected genes often encode synaptic components directly, but also include regulators that secondarily mediate the synthesis or assembly of synaptic proteins. The prime example is Fragile X syndrome (FXS), the leading heritable cause of both intellectual disability and autism spectrum disorders. FXS results from loss of mRNA-binding FMRP, which regulates synaptic transcript trafficking, stability and translation in activity-dependent synaptogenesis and plasticity mechanisms. Genetic models of FXS exhibit striking excitatory and inhibitory synapse imbalance, associated with impaired cognitive and social interaction behaviors. Downstream of translation control, a number of specific synaptic proteins regulate excitatory versus inhibitory synaptogenesis, independently or combinatorially, and loss of these proteins is also linked to disrupted neurodevelopment. The current effort is to define the cascade of events linking transcription, translation and the role of specific synaptic proteins in the maintenance of excitatory versus inhibitory synapses during neural circuit formation. This focus includes mechanisms that fine-tune excitation and inhibition during the refinement of functional synaptic circuits, and later modulate this balance throughout life. The use of powerful new genetic models has begun to shed light on the mechanistic bases of excitation/inhibition imbalance for a range of neurodevelopmental disease states.

show abstract

“…While the GABA A receptor has been proposed as a potential target for the treatment of FXS (D'Hulst & Kooy 2007; Heulens et al . 2010), it has been suggested that agonists may have no effects on the genesis of spontaneous seizures (Qiu et al . 2008).…”

Section: Aetiological Mechanisms Underlying Epilepsy and Intellectualmentioning

confidence: 99%

Epilepsy in four genetically determined syndromes of intellectual disability

Leung

Ring

2011

J intellect Disabil Res

View full text Add to dashboard Cite

The annotation highlights research describing disturbances in excitatory and inhibitory neurotransmitter systems, neuronal ion channel and glial functions that provide possible explanations for the co-occurrence of seizures within several ID syndromes, in some cases suggesting possible avenues for research into novel therapeutic targets. Phenotypic overlaps between syndromes may also relate to roles for the implicated genes in different disturbances in linked biochemical pathways.

show abstract

Fragile X syndrome and epilepsy

Cited by 16 publications

References 56 publications

A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model

A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model

Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models

Epilepsy in four genetically determined syndromes of intellectual disability

Contact Info

Product

Resources

About