The first international conference on SYNGAP1-related brain disorders: a stakeholder meeting of families, researchers, clinicians, and regulators

Weldon, Monica; Kılınç, Murat; Holder, J. Lloyd; Rumbaugh, Gavin

doi:10.1186/s11689-018-9225-1

Cited by 43 publications

(52 citation statements)

References 42 publications

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“…Recently described as causative of developmental and epileptic encephalopathy, reports of patients with SYNGAP1 mutations are rapidly increasing 10–12 . More than 120 patients are reported, 98% had intellectual disability (122/124), 91% seizures (113/124), and 55% ASD (68/124).…”

Section: Discussionmentioning

confidence: 99%

Add‐on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy

et al. 2020

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Mutations in SYNGAP1 are associated with developmental delay, epilepsy, and autism spectrum disorder (ASD). Epilepsy is often drug‐resistant in this syndrome with frequent drop attacks. In a prospective study of add‐on cannabidiol (CBD), we identified three patients with SYNGAP1 mutations: two boys and one girl. Seizure onset was at 3.5, 8, and 18 months (M), respectively, with numerous atypical absences per day associated with eyelid myoclonia (2/3 patients), upper limb myoclonic jerks (2/3 patients), and drop attacks (all patients). Seizures were resistant to at least 5 antiepileptic drugs (AEDs). After CBD introduction, two patients were responders since M2 and achieve a seizure reduction of 90% and 80%, respectively, at M9 with disappearance of drop attacks. EEGs showed an improvement regarding background activity and interictal anomalies. The last patient showed a late response at M7 of treatment with an 80% decrease in seizure frequency. Caregiver in all three evaluated as much improved the status of their children. Treatment was well‐tolerated in all, and no major adverse events (AEs) were reported. CBD showed efficacy in patients with drug‐resistant epilepsy due to SYNGAP1 mutations. Other patients with rare genetic developmental and epileptic encephalopathies with drug‐resistant epilepsies might benefit from CBD.

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Section: Discussionmentioning

confidence: 99%

Add‐on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy

et al. 2020

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“…While there are no known SYNGAP1 patient variants found in any of the final few exons of the gene that give rise to the major C-terminal isoforms , our results imply that restoring function or expression of SynGAP-a1 could be therapeutically beneficial. Nearly all SYNGAP1-related NDD cases are thought to be caused by genetic haploinsufficiency (Weldon et al, 2018), or reduced SynGAP protein expression within brain cells. Therefore, SYNGAP1 neurodevelopmental disorders are an attractive target for emerging therapies to restore gene function in patients.…”

Section: Discussionmentioning

confidence: 99%

Splicing of the SynGAP Carboxyl-Terminus Enables Isoform-Specific Tuning of NMDA Receptor Signaling Linked to Cognitive Function

Kılınç

Creson

Rojas

et al. 2020

Preprint

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SynGAP-a1 is a splice variant of the neurodevelopmental disorder risk gene, SYNGAP1/Syngap1. a1 encodes the C-terminal PDZ binding motif (PBM) that promotes liquidliquid phase separation, a candidate process for postsynaptic density organization within excitatory synapses. However, it remains unknown how the endogenous SynGAP PBM regulates synapse properties and related cognitive functions. We found that a major PBM function in mice is to limit the mobility of SynGAP-a1 in response to NMDA receptor activation. Genetic disruption of the PBM increased SynGAP-a1 mobility to levels consistent with other non-PBM-containing Cterminal isoforms. This resulted in a lowering of the threshold for NMDA receptor-dependent signaling required for plasticity, leading to aberrant strengthening of excitatory synapses in spontaneously active neurons. PBM-deficient animals also exhibited a lower seizure threshold, disrupted LTP, and impaired cognition. Thus, the PBM enables isoform-specific SynGAP gating of NMDA receptor function, a mechanism linking synaptic signaling dynamics to network excitability and cognition.

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“…Hets both express electrographic and behavioral seizures [21,26,30]. Seizures in many MRD5 patients are medically refractory.…”

Section: Mrd5 Patients and Syngap1mentioning

confidence: 99%

Re-expression of SynGAP Protein in Adulthood Improves Translatable Measures of Brain Function and Behavior in a Model of Neurodevelopmental Disorders

Rojas

Hwaun

et al. 2018

Preprint

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Background: Neurodevelopmental disorder (NDD) risk genes have pleiotropic biological functions, such as control over both developmental and non-developmental processes that influence disease-related phenotypes. Currently, it remains unclear how developmental versus non-developmental processes influence the duration and/or effectiveness of permissive treatment windows for NDDs. SYNGAP1 haploinsufficiency causes an NDD defined by autistic traits, cognitive impairment, and epilepsy. Syngap1 heterozygosity in mice disrupts a developmental critical period, and, consistent with this, certain behavioral abnormalities are resistant to gene therapy initiated in adulthood. However, the Syngap1 endophenotype is extensive and this protein has diverse cell biological functions. Therefore, SynGAP pleiotropy may influence the permissive treatment window for previously untested disease-relevant phenotypes.Methods: A whole-body gene restoration technique was used to determine how restoration of SynGAP protein in adult heterozygous mice impacted previously untested phenotypes, such as memory, seizure susceptibility, systems-level cortical hyperexcitability, and hippocampal oscillations linked to mnemonic processes.Results: Adult restoration of SynGAP protein in haploinsufficient mice reversed long-term contextual memory deficits and behavioral measures of seizure susceptibility. Moreover, SynGAP re-expression in adult mice eliminated brain state-dependent, patient-linked paroxysmal interictal spiking and increased the amplitude of hippocampal theta oscillations.Conclusions: SynGAP protein in the mature brain dynamically regulates neural circuit function and influences disease-relevant phenotypes. The impact of these findings is that treatments targeting certain debilitating aspects of SYNGAP1-related disorders may be effective throughout life. Moreover, the efficacy of experimental treatments for SYNGAP1 patients may be quantifiable through changes in species-conserved, state-dependent pathological electroencephalogram signals.

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The first international conference on SYNGAP1-related brain disorders: a stakeholder meeting of families, researchers, clinicians, and regulators

Cited by 43 publications

References 42 publications

Add‐on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy

Add‐on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy

Splicing of the SynGAP Carboxyl-Terminus Enables Isoform-Specific Tuning of NMDA Receptor Signaling Linked to Cognitive Function

Re-expression of SynGAP Protein in Adulthood Improves Translatable Measures of Brain Function and Behavior in a Model of Neurodevelopmental Disorders

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