Positive Short-Term Effect of Low-Dose Rosuvastatin in a Patient with SYNGAP1-Associated Epilepsy

Kluger, Gerhard; Stülpnagel-Steinbeis, Celina von; Arnold, Stephan; Eschermann, Kirsten; Hartlieb, Till

doi:10.1055/s-0039-1681066

Cited by 9 publications

(7 citation statements)

References 7 publications

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“…SYNGAP1- related intellectual disability has been classified as a RASopathy resulting from loss of function of the SYNGAP1 gene ( 32 ). Several therapeutic strategies to ameliorate aberrant biochemical signaling downstream of Ras as a result of SYNGAP1 haploinsufficiency have been tested ( 33 , 34 ). However, the efficacy of this treatment approach remains inconclusive.…”

Section: Discussionmentioning

confidence: 99%

SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity

Araki,

Rajkovich,

Gerber

et al. 2024

Science

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SynGAP is an abundant synaptic GTPase-activating protein (GAP) critical for synaptic plasticity, learning, memory, and cognition. Mutations in SYNGAP1 in humans result in intellectual disability, autistic-like behaviors, and epilepsy. Heterozygous Syngap1 -knockout mice display deficits in synaptic plasticity, learning, and memory and exhibit seizures. It is unclear whether SynGAP imparts structural properties at synapses independently of its GAP activity. Here, we report that inactivating mutations within the GAP domain do not inhibit synaptic plasticity or cause behavioral deficits. Instead, SynGAP modulates synaptic strength by physically competing with the AMPA-receptor-TARP excitatory receptor complex in the formation of molecular condensates with synaptic scaffolding proteins. These results have major implications for developing therapeutic treatments for SYNGAP1 -related neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 99%

SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity

Araki,

Rajkovich,

Gerber

et al. 2024

Science

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“…While case reports suggest potential efficacy of various medications including statins ( 52 ), more research is needed, and currently, there is no standard-of-care disease-modifying treatment for SRID ( 25 ). In preclinical literature, interventions including lovastatin treatment in hippocampal slices ( 53 ) and acute perampanel treatment ( 53 ) have been explored. However, studies showing definitive phenotypic rescue in Syngap1 +/− mice with pharmacologic treatment are lacking.…”

Section: Discussionmentioning

confidence: 99%

Mouse models of SYNGAP1 -related intellectual disability

Araki,

Gerber,

Rajkovich

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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SYNGAP1 is a Ras-GTPase-activating protein highly enriched at excitatory synapses in the brain. De novo loss-of-function mutations in SYNGAP1 are a major cause of genetically defined neurodevelopmental disorders (NDDs). These mutations are highly penetrant and cause SYNGAP1 -related intellectual disability (SRID), an NDD characterized by cognitive impairment, social deficits, early-onset seizures, and sleep disturbances. Studies in rodent neurons have shown that Syngap1 regulates developing excitatory synapse structure and function, and heterozygous Syngap1 knockout mice have deficits in synaptic plasticity, learning, and memory and have seizures. However, how specific SYNGAP1 mutations found in humans lead to disease has not been investigated in vivo. To explore this, we utilized the CRISPR-Cas9 system to generate knock-in mouse models with two distinct known causal variants of SRID: one with a frameshift mutation leading to a premature stop codon, SYNGAP1; L813RfsX22, and a second with a single-nucleotide mutation in an intron that creates a cryptic splice acceptor site leading to premature stop codon, SYNGAP1; c.3583-9G>A . While reduction in Syngap1 mRNA varies from 30 to 50% depending on the specific mutation, both models show ~50% reduction in Syngap1 protein, have deficits in synaptic plasticity, and recapitulate key features of SRID including hyperactivity and impaired working memory. These data suggest that half the amount of SYNGAP1 protein is key to the pathogenesis of SRID. These results provide a resource to study SRID and establish a framework for the development of therapeutic strategies for this disorder.

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“…Similarly, one adult in the literature discontinued levetiracetam at age 13 years due to behavioral issues. 12 Given the caregiver burden associated with neurobehavioural challenges in patients with DEEs, considerations for behavioral changes when selecting an ASM may be worthwhile. 30 , 31 …”

Section: Discussionmentioning

confidence: 99%

Adult Phenotype of SYNGAP1 -DEE

Rong,

Benke,

Zulfiqar Ali

et al. 2023

Neurol Genet

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Background and ObjectivesSYNGAP1variants are associated with rare developmental and epileptic encephalopathies (DEEs). AlthoughSYNGAP1-related childhood phenotypes are well characterized, the adult phenotype remains ill-defined. We sought to investigate phenotypes and outcomes in adults withSYNGAP1variants and epilepsy.MethodsPatients 18 years or older with DEE carrying likely pathogenic and pathogenic (LP/P)SYNGAP1variants were recruited through physicians' practices and patient organization groups. We used standardized questionnaires to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder and adaptive skills of patients. We also assessed caregiver burden.ResultsFourteen unrelated adult patients (median: 21 years, range: 18–65 years) withSYNGAP1-DEE were identified, 11 with novel and 3 with known LP/PSYNGAP1de novo variants. One patient with a partial exon 3 deletion had greater daily living skills and social skills than others with single-nucleotide variants. Ten of 14 (71%) patients had drug-resistant seizures, treated with a median of 2 antiseizure medications. All patients (100%) had abnormal pain processing. Sleep disturbances, social communication disorders, and aggressive/self-injurious behaviors were each reported in 86% of patients. Only half of adults could walk with minimal or no assistance. Toileting was normal in 29%, and 71% had constipation. No adult patients could read or understand verbal material at a sixth-grade level or higher. Aggressive/self-injurious behaviors were leading cause of caregiver burden. The oldest patient was aged 65 years; although nonambulant, she had walked independently when younger.DiscussionSeventy-one percent of patients withSYNGAP1-DEEs continue to have seizures when adults. Nonseizure comorbidities, especially aggression and self-injurious behaviors, are major management challenges in adults withSYNGAP1-DEE. Only 50% of adults can ambulate with minimal or no assistance. Almost all adult patients depend on caregivers for many activities of daily living. Prompt diagnostic genetic testing of adults with DEE can inform clinical care and guide outcomes of precision therapies.

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Positive Short-Term Effect of Low-Dose Rosuvastatin in a Patient with SYNGAP1-Associated Epilepsy

Cited by 9 publications

References 7 publications

SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity

SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity

Mouse models of SYNGAP1 -related intellectual disability

Adult Phenotype of SYNGAP1 -DEE

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