Deciphering the concepts behind “Epileptic encephalopathy” and “Developmental and epileptic encephalopathy”

Scheffer, Ingrid E.; Liao, Jianxiang

doi:10.1016/j.ejpn.2019.12.023

Cited by 135 publications

(124 citation statements)

References 17 publications

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“…This has been observed previously in other genetic conditions ( Weckhuysen et al , 2012 ; Berecki et al , 2019 ), leading to the assumption that genetic defects themselves are influencing development and cognition, independently from seizure control. This is reflected in the ILAE’s terminology of ‘developmental and epileptic encephalopathies’, though a clear distinction between epileptic and developmental encephalopathy has been advised ( Scheffer et al , 2017 ; Scheffer and Liao, 2020 ). Furthermore, some EEG abnormalities continued to be prominent after achieving seizure freedom.…”

Section: Discussionmentioning

confidence: 99%

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Neuray

Maroofian

Scala

et al. 2020

Brain

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Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1−/− mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy.

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Section: Discussionmentioning

confidence: 99%

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Neuray

Maroofian

Scala

et al. 2020

Brain

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“…Acute seizures alone, without a contributing genetic mutation, can disrupt thalamocortical critical period plasticity and are associated with impaired sensorimotor integration 30 . The phenotypic spectrum of SYNGAP1 DEE may be strongly influenced by the interaction between the aberrant synaptic plasticity caused by SYNGAP1 haploinsufficiency and the concurrent epilepsy 5,29 . Specifically, uncontrolled early-life seizures may compound the neurodevelopmental impairments caused by the lack of functional SYNGAP1.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we found that Syngap1 haploinsufficiency causes spontaneous recurrent seizures early in life (P7-P12). During development, persistent seizures and interictal epileptiform activity worsen developmental regression, cognitive function, and cause behavioral impairments 28,29 . Acute seizures alone, without a contributing genetic mutation, can disrupt thalamocortical critical period plasticity and are associated with impaired sensorimotor integration 30 .…”

Section: Discussionmentioning

confidence: 99%

GABAergic signaling promotes early-life seizures in epileptic SYNGAP1^+/-mice

Sullivan

Kipnis

Ammanuel

et al. 2020

Preprint

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ObjectiveSYNGAP1 encephalopathy is a developmental and epileptic encephalopathy caused by pathogenic loss of function variants. Syngap1-heterozygous (Het+/-) mice demonstrate progressive epilepsy with multiple seizure phenotypes in adulthood. Here, we investigate early-life seizures in Het+/- pups and explore of Syngap1 encephalopathy during development.MethodsPost-natal day 7 (P7) and P12 mice were investigated by tethered video-electroencephalographic (vEEG). The effects of GABAergic drugs phenobarbital (PB) and pentylenetetrazol (PTZ) were investigated at P7 and P12, respectively. 24h tethered vEEG was performed at P24, and telemetric 24h vEEG with 6h sleep deprivation was performed at P35. The effect of perampanel (PMP), an AMPA receptor antagonist, was investigated at P24.ResultsHet+/- mice have spontaneous early-life seizures that lack an overt behavioral phenotype. These subclinical seizures are refractory to PB, but the GABAA receptor (GABAAR) antagonist PTZ significantly reduced seizure frequency suggesting that GABAergic signaling may promote seizure generation in Het+/- pups. At juvenile ages, Het+/- pups recapitulated the early emergence of high gamma (35-50Hz) during NREM and disruption of behavioral-state gamma homeostasis. This biomarker was significantly exacerbated in Het+/- pups after increasing sleep pressure with sleep deprivation.SignificanceSeizures during development have adverse effects on cognitive function. Therefore, an improved understanding of the SYNGAP1 epilepsy during developmental ages is necessary to delineate the deleterious interactions between aberrant synaptic function and recurrent seizures. The development of evidence-based therapies for early-life intervention will benefit from these insights.

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“…Evolution, definitions and use of the terms "developmental'' and "epileptic'' encephalopathy [2][3][4][5][6] The original concept of epileptic encephalopathies (EE) is related to conditions whereby the abundant epileptiform abnormalities and/or high number of epileptic seizures themselves contribute to cognitive regression [7]. In contrast, in conditions where the cognitive development and behavior is impaired independently to the epilepsy onset, and epilepsy is characterized by a high frequency of seizures and abundant epileptiform abnormalities, the term "developmental and epileptic encephalopathy'' (DEE) is more appropriate: this was proposed in the 2017 revision of the classification [2,3].…”

Section: • 41mentioning

confidence: 99%

“…Most patients with DEE have a genetic etiology, whereby the genetic variant is responsible for both cognitive impairment and severe epilepsy: in such cases, even with control of seizures, the cognitive outcome is expected to be poor. The term "developmental encephalopathy'' (DE) is a separate entity to DEE [4]. The term "developmental encephalopathy'' should be used in the setting of a person with developmental delay, or intellectual disability, due to a non-progressive brain state who also has co-existing epilepsy.…”

Section: • 41mentioning

confidence: 99%

Developmental and epileptic encephalopathies: recognition and approaches to care

Raga¹,

Specchio²,

Rheims³

et al. 2021

Epileptic Disorders

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The term "developmental and epileptic encephalopathy'' (DEE) refers to when cognitive functions are influenced by both seizure and interictal epileptiform activity and the neurobiological process behind the epilepsy. Many DEEs are related to gene variants and the onset is typically during early childhood. In this setting, neurocognition, whilst not improved by seizure control, may benefit from some precision therapies. In patients with non-progressive diseases with cognitive impairment and co-existing epilepsy, in whom the epileptiform activity does not affect or has minimal effect on function, the term "developmental encephalopathy'' (DE) can be used. In contrast, for those patients with direct impact on cognition due to epileptic or epileptiform activity, the term "epileptic encephalopathy'' (EE) is preferred, as most can revert to their normal or near normal baseline cognitive state with appropriate intervention. These children need aggressive treatment. Clinicians must tailor care towards individual needs and realistic expectations for each affected person; those with DE are unlikely to gain from aggressive antiseizure medication whilst those with EE will gain. Patients with DEE might benefit from a precision medicine approach in order to reduce the overall burden of epilepsy.

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Deciphering the concepts behind “Epileptic encephalopathy” and “Developmental and epileptic encephalopathy”

Cited by 135 publications

References 17 publications

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

GABAergic signaling promotes early-life seizures in epileptic SYNGAP1^+/-mice

Developmental and epileptic encephalopathies: recognition and approaches to care

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Deciphering the concepts behind “Epileptic encephalopathy” and “Developmental and epileptic encephalopathy”

Cited by 135 publications

References 17 publications

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

GABAergic signaling promotes early-life seizures in epileptic SYNGAP1+/-mice

Developmental and epileptic encephalopathies: recognition and approaches to care

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GABAergic signaling promotes early-life seizures in epileptic SYNGAP1^+/-mice