SYNGAP1 Mutation in Focal and Generalized Epilepsy: A Literature Overview and A Case Report with Special Aspects of the EEG

Stülpnagel, Celina von; Funke, Claudia; Haberl, C.; Hörtnagel, Konstanze; Jüngling, J.; Weber, Yvonne G.; Staudt, Martin; Kluger, Gerhard

doi:10.1055/s-0035-1554098

Cited by 30 publications

(12 citation statements)

References 14 publications

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“…The SYNGAP1 gene has emerged as a high-risk locus for neuropsychiatric disorders that cross diagnostic barriers (Hoischen et al, 2014; Zhu et al, 2014). Indeed, causal rare variants are found in enriched populations with ID (Deciphering Developmental Disorders, 2015, 2017; Hamdan et al, 2009; Rauch et al, 2012), ASD (Hamdan et al, 2011; O'Roak et al, 2014), severe epilepsy (Carvill et al, 2013; von Stulpnagel et al, 2015) and schizophrenia (Purcell et al, 2014). Severe de novo variants in SYNGAP1 resulting in haploinsufficiency lead to a defined phenotype characterized by ID with epilepsy [termed Mental Retardation- Type 5(MRD5); OMIM#603384] that may explain up to 1% of ID cases (Berryer et al, 2013; Deciphering Developmental Disorders, 2015, 2017).…”

Section: Syngap1 Gene Function Is Important In Health and Diseasementioning

confidence: 99%

Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders

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Creson

Rojas

et al. 2018

Molecular and Cellular Neuroscience

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SYNGAP1 loss-of-function variants are causally associated with intellectual disability, severe epilepsy, autism spectrum disorder and schizophrenia. While there are hundreds of genetic risk factors for neurodevelopmental disorders (NDDs), this gene is somewhat unique because of the frequency and penetrance of loss-of-function variants found in patients combined with the range of brain disorders associated with SYNGAP1 pathogenicity. These clinical findings indicate that SYNGAP1 regulates fundamental neurodevelopmental processes that are necessary for brain development. Here, we describe four phenotypic domains that are controlled by Syngap1 expression across vertebrate species. Two domains, the maturation of cognitive functions and maintenance of excitatory-inhibitory balance, are defined exclusively through a review of the current literature. Two additional domains are defined by integrating the current literature with new data indicating that SYNGAP1/Syngap1 regulates innate survival behaviors and brain structure. These four phenotypic domains are commonly disrupted in NDDs, suggesting that a deeper understanding of developmental Syngap1 functions will be generalizable to other NDDs of known or unknown etiology. Therefore, we discuss the known molecular and cellular functions of Syngap1 and consider how these functions may contribute to the emergence of disease-relevant phenotypes. Finally, we identify major unexplored areas of Syngap1 neurobiology and discuss how a deeper understanding of this gene may uncover general principles of NDD pathobiology.

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Section: Syngap1 Gene Function Is Important In Health and Diseasementioning

confidence: 99%

Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders

Kılınç

Creson

Rojas

et al. 2018

Molecular and Cellular Neuroscience

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“…MRD5 patients suffer from cognitive impairments, such as absent or poor language acquisition, and very low non-verbal IQ 19, 20 . SYNGAP1 is also a risk factor for epileptic encephalopathies 21, 22 and most MRD5 patients have comorbid epilepsy 18-20 . Currently, the impact of SYNGAP1/ Syngap1 pathogenicity on sensory functions is unknown, but is necessary for a deeper understanding of the complex phenotypes observed in this genetically-defined NDD.…”

Section: Introductionmentioning

confidence: 99%

SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits

et al. 2018

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In addition to cognitive impairments, neurodevelopmental disorders (NDDs) often result in sensory processing deficits. However, the biological mechanisms that underlie impaired sensory processing associated with NDDs are generally understudied and poorly understood. We found that SYNGAP1 haploinsufficiency in humans, which causes a sporadic neurodevelopmental disorder defined by cognitive impairment, autistic features, and epilepsy, also leads to deficits in tactile-related sensory processing. In vivo neurophysiological analysis in Syngap1 mouse models revealed that upper-lamina neurons in somatosensory cortex (SSC) weakly encode information related to touch. This was caused by reduced synaptic connectivity and impaired intrinsic excitability within upper-lamina SSC neurons. These results were unexpected given that Syngap1 heterozygosity is known to cause circuit hyperexcitability in brain areas more directly linked to cognitive functions. Thus, Syngap1 heterozygosity causes a range of circuit-specific pathologies, including reduced activity within cortical neurons required for touch processing, which may contribute to sensory phenotypes observed in patients.

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“…SYNGAP1 is a recently discovered NDD gene (Hoischen et al, 2014; Zhu et al, 2014; Hamdan et al, 2009), causally-linked to a range of sporadic disorders, including ID (Deciphering Developmental Disorders Study, 2015; Deciphering Developmental Disorders Study, 2017; Hamdan et al, 2009; Rauch et al, 2012), ASD (Kyle Satterstrom et al, 2018; O'Roak et al, 2014; Hamdan et al, 2011), severe epilepsy (Vlaskamp et al, 2019; Carvill et al, 2013; von Stülpnagel et al, 2015) and schizophrenia (Purcell et al, 2014). De novo nonsense variants in SYNGAP1 resulting in haploinsufficiency lead to a relatively frequent genetically-defined form of ID with epilepsy (termed MRD5; OMIM#603384).…”

Section: Introductionmentioning

confidence: 99%

Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior

Creson

Rojas

Hwaun

et al. 2019

eLife

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It remains unclear to what extent neurodevelopmental disorder (NDD) risk genes retain functions into adulthood and how they may influence disease phenotypes. SYNGAP1 haploinsufficiency causes a severe NDD defined by autistic traits, cognitive impairment, and epilepsy. To determine if this gene retains therapeutically-relevant biological functions into adulthood, we performed a gene restoration technique in a mouse model for SYNGAP1 haploinsufficiency. Adult restoration of SynGAP protein improved behavioral and electrophysiological measures of memory and seizure. This included the elimination of interictal events that worsened during sleep. These events may be a biomarker for generalized cortical dysfunction in SYNGAP1 disorders because they also worsened during sleep in the human patient population. We conclude that SynGAP protein retains biological functions throughout adulthood and that non-developmental functions may contribute to disease phenotypes. Thus, treatments that target debilitating aspects of severe NDDs, such as medically-refractory seizures and cognitive impairment, may be effective in adult patients.

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SYNGAP1 Mutation in Focal and Generalized Epilepsy: A Literature Overview and A Case Report with Special Aspects of the EEG

Cited by 30 publications

References 14 publications

Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders

Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders

SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits

Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior

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