SYNGAP1-related developmental and epileptic encephalopathy: The impact on daily life

Barco, Tommaso Lo; Gaetano, Luciana De; Santangelo, Elisabetta; Bravi, Tonino; Proietti, Jacopo; Cantalupo, Gaetano; Brambilla, Isabella; Darra, Francesca

doi:10.1016/j.yebeh.2021.108500

Cited by 10 publications

(6 citation statements)

References 19 publications

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“…Initially, we established that Syngap1 loss-of-function leads to behavioral hypo- sensitivity when sensing with whiskers, which is expressed across tactile domains, including detection sensitivity, texture discrimination, and object localization (Figure 6A) . These mouse studies are consistent with reports of tactile hyposensitivity and very high pain thresholds in SYNGAP1-DEE patients, including impaired behavioral reactivity in response to external stimuli applied to the body 23,80 . Importantly, similar to the mouse model, this human patient population is defined by heterozygous loss-of-function variants within the SYNGAP1 gene.…”

Section: Discussionsupporting

confidence: 91%

Syngap1Promotes Cognitive Function through Regulation of Cortical Sensorimotor Dynamics

Vaissiere,

Michaelson,

Creson

et al. 2023

Preprint

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SummaryPerception, a cognitive construct, emerges through sensorimotor integration (SMI). The molecular and cellular mechanisms that shape SMI within circuits that promote cognition are poorly understood. Here, we demonstrate that expression of the autism/intellectual disability gene,Syngap1, in mouse cortical excitatory neurons promotes touch sensitivity required to elicit perceptual behaviors. CorticalSyngap1expression enabled touch-induced feedback signals within sensorimotor loops by assembling circuits that support tactile sensitivity. These circuits also encoded correlates of attention that promoted self-generated whisker movements underlying purposeful and sustained object exploration. AsSyngap1deficient animals explored objects with whiskers, relatively weak touch signals were integrated with relatively strong motor signals. This produced a signal-to-noise deficit consistent with impaired tactile sensitivity, reduced tactile exploration, and weak tactile learning. Thus,Syngap1expression in cortex promotes tactile perception by assembling circuits that integrate touch and whisker motor signals. DeficientSyngap1expression likely contributes to cognitive impairment through abnormal top-down SMI.

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Section: Discussionsupporting

confidence: 91%

Syngap1Promotes Cognitive Function through Regulation of Cortical Sensorimotor Dynamics

Vaissiere,

Michaelson,

Creson

et al. 2023

Preprint

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“… 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%

“…We found that all adults in our cohort had below average adaptive skills, at similar levels to pediatric SYNGAP1 patients. 30 While direct comparisons cannot be made due to different assessment tools used in each study, Table 2 presents a brief summary of the daily living abilities of pediatric patients (range: 3.7–17.7 years) as reported by Lo Barco et al and the adults of this study. 30 When compared with the pediatric sample, 25% more adults were able to dress themselves with assistance, pointing toward possible improved daily living abilities across the life course.…”

Section: Discussionmentioning

confidence: 99%

“… 30 While direct comparisons cannot be made due to different assessment tools used in each study, Table 2 presents a brief summary of the daily living abilities of pediatric patients (range: 3.7–17.7 years) as reported by Lo Barco et al and the adults of this study. 30 When compared with the pediatric sample, 25% more adults were able to dress themselves with assistance, pointing toward possible improved daily living abilities across the life course. The proportion of patients able to feed themselves was similar in both pediatric and adult patients (∼60–70%), suggesting that these skills may be preserved into middle age.…”

Section: Discussionmentioning

confidence: 99%

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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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“…• Constipation, reflux, links between GI and aggression, some with G-tube 66 161 162 163 164 165 166 167…”

Section: Introduction To Autism and Gastrointestinal Symptomsmentioning

confidence: 99%

Gastrointestinal Dysfunction in Genetically Defined Neurodevelopmental Disorders

Davidson,

Holingue,

Jimenez-Gomez

et al. 2023

Semin Neurol

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Gastrointestinal symptoms are common in most forms of neurodevelopment disorders (NDDs) such as in autism spectrum disorders (ASD). The current patient-reported outcome measures with validated questionnaires used in the general population of children without NDDS cannot be used in the autistic individuals. We explore here the multifactorial pathophysiology of ASD and the role of genetics and the environment in this disease spectrum and focus instead on possible diagnostics that could provide future objective insight into the connection of the gut-brain-microbiome in this disease entity. We provide our own data from both humans and a zebrafish model of ASD called Phelan-McDermid Syndrome. We hope that this review highlights the gaps in our current knowledge on many of these profound NDDs and that it provides a future framework upon which clinicians and researchers can build and network with other interested multidisciplinary specialties.

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SYNGAP1-related developmental and epileptic encephalopathy: The impact on daily life

Cited by 10 publications

References 19 publications

Syngap1Promotes Cognitive Function through Regulation of Cortical Sensorimotor Dynamics

Syngap1Promotes Cognitive Function through Regulation of Cortical Sensorimotor Dynamics

Adult Phenotype of SYNGAP1 -DEE

Gastrointestinal Dysfunction in Genetically Defined Neurodevelopmental Disorders

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