Autism spectrum disorder and cognitive profile in children with Dravet syndrome: Delineation of a specific phenotype

Ouss, Lisa; Leunen, Dorothée; Khallou-Laschet, Jamila; Chémaly, Nicole; Barcia, Giulia; Losito, Emma; Aouidad, Aveline; Barrault, Zoe; Desguerre, Isabelle; Breuillard, Delphine; Nabbout, Rima

doi:10.1002/epi4.12281

Cited by 42 publications

(33 citation statements)

References 39 publications

(149 reference statements)

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“…Two studies assessed ASD in children with DS using standardized tools: the first with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV) and International Classification of Diseases, Tenth Revision (ICD‐10) criteria, the Childhood Autism Rating Scale diagnosis tool and the Autism Behavior Checklist, and the second with gold standard tools (Autism Diagnosis Interview Revised, ie, ADI‐R or Autism Diagnosis Observation Scale 2, ie, ADOS‐2) . Both studies confirmed the occurrence of ASD in 24%‐40% of children.…”

Section: Autism Spectrum Disordermentioning

confidence: 95%

“…ASD features have been reported in patients with DS, but were defined as “autistic traits” often without using standardized tools. Depending on the type of assessment, rates of “autistic traits” vary from 8.3% to 61% . Most studies have reported lack of verbal communication, with 10%‐79% of patients showing social problems, such as poor peer relationships, withdrawn behavior, lack of emotional reciprocity, difficulty negotiating social rules, and excessive familiarity .…”

Section: Autism Spectrum Disordermentioning

confidence: 99%

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SCN1A‐related phenotypes: Epilepsy and beyond

2019

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SCN1A, encoding the alpha 1 subunit of the sodium channel, is associated with several epilepsy syndromes and a range of other diseases. SCN1A represents the archetypal channelopathy associated with a wide phenotypic spectrum of epilepsies ranging from genetic epilepsy with febrile seizures plus (GEFS+), to developmental and epileptic encephalopathies (DEEs). SCN1A disorders also result in other diseases such as hemiplegic migraine and autism spectrum disorder (ASD). Dravet syndrome (DS) is the prototypic DEE with an early onset of febrile status epilepticus, hemiclonic or generalized tonic‐clonic seizures, and later onset of additional seizure types. Electroencephalography (EEG) and magnetic resonance imaging (MRI) are normal at onset. Development is normal in the first year of life but plateaus rapidly, with most patients ultimately having intellectual disability. Epilepsy is drug‐resistant and necessitates polytherapy. Most pathogenic variants occur de novo in the affected child, but they are inherited from mosaic affected or unaffected parents in rare cases. The molecular finding of haploinsufficiency is consistent with a loss‐of‐function defect in cells and animal models. Although seizures are the most commonly reported symptom in DS, many additional issues critically affect patients’ cognitive and behavioral functioning. Hemiplegic migraine (HM) is a rare form of migraine with aura, characterized by the emergence of hemiparesis as part of the aura phase. All SCN1A mutations reported in sporadic/familial HM3 are missense mutations. Most of the experimental results show that they cause a gain of function of NaV1.1 as opposed to the loss of function of the epileptogenic NaV1.1 mutations. SCN1A and SCN2A pathogenic variants have been identified in genetic studies of cohorts of patients with ASD. In addition, ASD features are often reported in patients with Dravet syndrome and other DEEs.

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Section: Autism Spectrum Disordermentioning

confidence: 95%

Section: Autism Spectrum Disordermentioning

confidence: 99%

SCN1A‐related phenotypes: Epilepsy and beyond

2019

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“…Moreover, others suggested that developmental delay in Dravet may be independent of the epilepsy, and caused directly by the underlying SCN1A mutation (Nabbout et al, 2013;Ouss et al, 2019). To examine the relationship between Dravet epilepsy and Dravet associated comorbidities, and identify the onset of Dravet comorbidities, we performed behavioral tests in WT and DS mice.…”

Section: Behavioral Deficits In Ds Mice During the Febrile Worseningmentioning

confidence: 99%

“…Based on these observations, it was suggested that the severe frequent seizures contribute to cognitive decline and the other Dravet-associated comorbidities (Ben-Ari and Holmes, 2006;Cetica et al, 2017). Other clinical studies, however, have suggested that developmental delay is epilepsyindependent, indicating that cognitive deficits cannot be prevented, even with adequate seizure control (Brunklaus and Zuberi, 2014;Nabbout et al, 2013;Ouss et al, 2019).…”

Section: Behavioral Alterations In Ds Mice During the Febrile Stagementioning

confidence: 99%

“…Conversely, several prospective clinical studies identified early developmental alterations, demonstrating deficits in visuomotor function before the onset of spontaneous seizures (Battaglia et al, 2016;Chieffo et al, 2011;Guzzetta, 2011), as well as delayed mastery of independent sitting (Verheyen et al, 2019), indicating early development is not completely normal. Furthermore, other studies have shown dissociation between the severity of epilepsy and cognitive abilities (Nabbout et al, 2013;Ouss et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Early EEG and behavioral alterations in Dravet mice

Fadila

Quinn

Maia

et al. 2020

Preprint

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Dravet Syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins around the age of six months, with a febrile stage, characterized by febrile seizures with otherwise normal development. By the end of the first year of life, the disease progresses to the worsening stage, featuring recurrent intractable seizures and the appearance of additional comorbidities, including global developmental delay, cognitive deficits, hyperactivity and motor problems. Later, in early school years, Dravet reaches the stabilization stage, in which seizure burden decreases, while Dravet-associated comorbidities persist. Dravet syndrome mouse models (DS) faithfully recapitulate the three stages of the human syndrome. Here, we performed power spectral analyses of background EEG activity in DS and their wild-type (WT) littermates, demonstrating disease stagerelated alterations. Specifically, while the febrile stage activity resembled that of WT mice, we observed a marked reduction in total power during the worsening stage and a smaller reduction during the stabilization stage. Moreover, low EEG power at the worsening stage correlated with increased risk for premature death, suggesting that such measurements can potentially be used as a marker for Dravet severity. With normal development at the febrile stage and the presentation of developmental delay at the worsening stage, the contribution of recurrent seizures to the emergence of Dravet-associated comorbidities is still debated.Thus, we further characterized the behavior of WT and DS mice during the different stages of Dravet. At the febrile stage, despite their normal background EEG patterns, DS mice already demonstrated motor impairment and hyperactivity in the open field, that persisted to the worsening and stabilization stages. Conversely, clear evidence for deficits in working memory emerged later in life, during the worsening stage. These results indicate that despite the mild epilepsy at the febrile stage, DS development is already altered, suggesting that the pathophysiological mechanisms governing the appearance of some Dravet behavioral comorbidities may be independent of the epileptic phenotype. Highlights • Reduction in background EEG power in Dravet• Low EEG power correlates with the risk of premature death• Motor deficits and hyperactivity are evident as early as the febrile stage • Cognitive deficits and detection of increased anxiety begin at the worsening stage 10 min, and were selected from throughout the entire recording. Spikes were detected using LabChart 8 software (ADInstruments, Sydney, Australia). The threshold was set to 7 standard divisions, and their maximal allowed duration was set to 250 ms. Early motor activityWT and DS mice were tested from P8 to P11. Mice were individually placed in the middle of a 13 cm wide circle and the latency to cross the drawn borders of the circle was measured. The test was repeated three times and averaged. If the mouse was unable to cross the border of the circle within 1 min, the test was terminated. ...

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Neuropsychological Comorbidities in Pediatric Epilepsy

Emerton

Morgan

2022

Handbook of Pediatric Epilepsy

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Autism spectrum disorder and cognitive profile in children with Dravet syndrome: Delineation of a specific phenotype

Cited by 42 publications

References 39 publications

SCN1A‐related phenotypes: Epilepsy and beyond

SCN1A‐related phenotypes: Epilepsy and beyond

Early EEG and behavioral alterations in Dravet mice

Neuropsychological Comorbidities in Pediatric Epilepsy

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