Lovastatin Treatment of a Patient with a <i>De Novo SYNGAP1</i> Protein Truncating Variant

Cook, Edwin H.; Masaki, Jayson T.; Guter, Stephen J.; Najjar, Fedra

doi:10.1089/cap.2018.0159

Cited by 6 publications

(5 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies reported that the LTP in adult Syngap1 +/mice were restored to the WT levels but did not rescue various behavioural deficits in Syngap1 +/mice (19,(22)(23)(24)(25). Encouraged by the LTP restoration upon the treatment of the p300 KAT activator, we asked if p300/CBP KAT activation by CSP-TTK21 rescued behavioural deficits observed in Syngap1 +/mice.…”

Section: Syngap1 +/Mice Behaviour?mentioning

confidence: 88%

“…Furthermore, the restoration of Syngap1 through genetic means following the critical period of neuronal maturation has been observed to reinstate synaptic function, specifically long-term potentiation (LTP). However, it has not been successful in addressing the associated behavioral deficits (19,(22)(23)(24)(25). This indicates that the main obstacle lies in the reestablishment of neuronal network connections, which become significantly more resistant to alterations after the critical period of development.…”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20][21][22][23][24][25] mg/kg of CSP-TTK21 was administered orally post whisker trimming at PND30, PND36, and PND42. The animals were sacrificed at PND51 and transferred into Golgi-Cox staining solution (Fig 4.A).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Epigenetic Modulation to perturb theSYNGAP1Intellectual Disability (ID) that ameliorates synaptic and behavioural deficits

Singh,

Joshi,

Reddy

et al. 2024

Preprint

View full text Add to dashboard Cite

Sporadic heterozygous mutations inSYNGAP1affects social and emotional behaviour that are often observed in intellectual disability (ID) and autism spectrum disorder (ASD). Although neurophysiological deficits have been extensively studied, the epigenetic landscape ofSYNGAP1mutation-mediated intellectual disability is unexplored. Here, we have surprisingly found that the p300/CBP specific acetylation marks of histones are significantly repressed in the adolescent hippocampus ofSyngap1+/-mouse. To establish the causal relationship ofSyngap1+/-phenotype and the altered histone acetylation signature we have treated 2-4 months oldSyngap1+/-mouse with glucose-derived carbon nanosphere (CSP) conjugated potent small molecule activator (TTK21) of p300/CBP lysine acetyltransferase (CSP-TTK21). The enhancement of the p300/CBP specific acetylation marks of histones by CSP-TTK21 restored deficits in spine density, synaptic function, and social preferences ofSyngap1+/-mouse that is very closely comparable to wild type littermates. The hippocampal RNA-Seq analysis of the treated mice revealed that the expression of many critical genes related to the ID/ASD reversed due to the treatment of the specific small molecule activator. This study could be the first demonstration of the reversal of autistic behaviour and neural wiring upon the modulation of altered epigenetic modification (s).

show abstract

Section: Syngap1 +/Mice Behaviour?mentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic Modulation to perturb theSYNGAP1Intellectual Disability (ID) that ameliorates synaptic and behavioural deficits

Singh,

Joshi,

Reddy

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“… 9 , 13 , 14 Other behavioral issues, such as aggression, temper tantrums, and obsessive behaviors, align with previous reports in both children and adults. 11 , 14 - 16 …”

Section: Discussionmentioning

confidence: 99%

Adult Phenotype of SYNGAP1 -DEE

Rong,

Benke,

Zulfiqar Ali

et al. 2023

Neurol Genet

View full text Add to dashboard Cite

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.

show abstract

Lovastatin Treatment of a Patient with a De Novo SYNGAP1 Protein Truncating Variant

Cited by 6 publications

References 8 publications

Epigenetic Modulation to perturb theSYNGAP1Intellectual Disability (ID) that ameliorates synaptic and behavioural deficits

Epigenetic Modulation to perturb theSYNGAP1Intellectual Disability (ID) that ameliorates synaptic and behavioural deficits

SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity

Adult Phenotype of SYNGAP1 -DEE

Contact Info

Product

Resources

About