Brain morphometry of Dravet Syndrome

Pérez, Alejandro; García-Pentón, Lorna; Canales-Rodríguez, Erick Jorge; Lerma-Usabiaga, Garikoitz; Iturria-Medina, Yasser; Román, Francisco J.; Davidson, Doug; Alemán‐Gómez, Yasser; Acha, Joana; Carreiras, Manuel

doi:10.1016/j.eplepsyres.2014.06.006

Cited by 13 publications

(20 citation statements)

References 57 publications

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“…In the whole-brain analysis, we found significantly smaller total brain volume, total cortical GM volume, subcortical GM volume, total cortical WM volume and cerebellar WM volume in the patient group compared to the control group. These volume changes are consistent with previous studies, suggesting non-specific neuroimaging findings, such as atrophic change on cerebral and cerebellar area (Brunklaus et al, 2012, Guerrini et al, 2011, Striano et al, 2007) and brain morphometry analysis in patients with Dravet syndrome (Perez et al, 2014). Although the potential mechanism responsible for the volume change is uncertain, functional changes in GABAergic inhibitory interneurons, which are important in normal brain development, can alter the neural network formation (Flores and Mendez, 2014).…”

Section: Discussionsupporting

confidence: 92%

“…The higher incidence of learning difficulties, language delays, motor impairment and behavior disorders in patient with SCN1A mutation-related epilepsy (Dravet, 2011, Wolff et al, 2006) can be explained by the reduced size of these areas, which in turn may cause the malfunction of these structures. Conversely, previous brain morphometric analysis in patients with Dravet syndrome revealed no difference in local GM volume (Perez et al, 2014). This discrepancy could be explained differences in the tools used for analysis and/or characteristics of the enrolled patients, such as the inclusion of younger patient groups irrespective of disease severity.…”

Section: Discussionmentioning

confidence: 65%

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Large-scale structural alteration of brain in epileptic children with SCN1A mutation

Lee

Yum

Kim

et al. 2017

NeuroImage: Clinical

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ObjectiveMutations in SCN1A gene encoding the alpha 1 subunit of the voltage gated sodium channel are associated with several epilepsy syndromes including genetic epilepsy with febrile seizures plus (GEFS +) and severe myoclonic epilepsy of infancy (SMEI). However, in most patients with SCN1A mutation, brain imaging has reported normal or non-specific findings including cerebral or cerebellar atrophy. The aim of this study was to investigate differences in brain morphometry in epileptic children with SCN1A mutation compared to healthy control subjects.MethodsWe obtained cortical morphology (thickness, and surface area) and brain volume (global, subcortical, and regional) measurements using FreeSurfer (version 5.3.0, https://surfer.nmr.mgh.harvard.edu) and compared measurements of children with epilepsy and SCN1A gene mutation (n = 21) with those of age and gender matched healthy controls (n = 42).ResultsCompared to the healthy control group, children with epilepsy and SCN1A gene mutation exhibited smaller total brain, total gray matter and white matter, cerebellar white matter, and subcortical volumes, as well as mean surface area and mean cortical thickness. A regional analysis revealed significantly reduced gray matter volume in the patient group in the bilateral inferior parietal, left lateral orbitofrontal, left precentral, right postcentral, right isthmus cingulate, right middle temporal area with smaller surface area and white matter volume in some of these areas. However, the regional cortical thickness was not significantly different in two groups.SignificanceThis study showed large-scale developmental brain changes in patients with epilepsy and SCN1A gene mutation, which may be associated with the core symptoms of the patients. Further longitudinal MRI studies with larger cohorts are required to confirm the effect of SCN1A gene mutation on structural brain development.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 65%

Large-scale structural alteration of brain in epileptic children with SCN1A mutation

Lee

Yum

Kim

et al. 2017

NeuroImage: Clinical

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“…In addition, a study using brain MRI in a large group of GE patients 35 foundsignificantcortical atrophy, suggesting possible neuronal loss. A brain morphometry study in Dravet syndrome patients indicated global volume reductions of gray and white matter as well as a correlation between the intracranial volume reduction and increased age 36 . The lack of clear clinical evidence of an association of mutations in GE and neurodegeneration may be because epileptic encephalopathies occur in only a small subset of epilepsy patients and thus the relationship may possibly have been unrecognized.…”

Section: Discussionmentioning

confidence: 99%

The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration

et al. 2015

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Genetic epilepsy and neurodegenerative diseases are two common neurological disorders conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies with impaired development and often death respond poorly to anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported that multiple GABAA receptor epilepsy mutations caused protein misfolding and abnormal receptor trafficking. Here we establish in a novel model of a severe human genetic epileptic encephalopathy, the Gabrg2+/Q390X knock-in mouse, that in addition to impairing inhibitory neurotransmission, mutant GABAA receptor γ2(Q390X) subunits accumulated and aggregated intracellularly, activated caspase 3 and caused widespread, age-dependent neurodegeneration. These novel findings suggest that the fundamental protein metabolism and cellular consequences of the epilepsy-associated mutant γ2(Q390X) ion channel subunit are not fundamentally different from those associated with neurodegeneration. The study has far-reaching significance for identification of conserved pathological cascades and mechanism-based therapies that overlap genetic epilepsies and neurodegenerative diseases.

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“…In another study, 35 of 18 children with Dravet syndrome who had MR imaging after 3 years of age, 7 had hippocampal sclerosis or loss of grey–white definition in the temporal lobe. In a study 36 comparing nine patients with Dravet syndrome and SCN1A mutations and nine controls without seizures, globally reduced grey and white matter volumes were seen in individuals with Dravet syndrome.…”

Section: Neuroimaging In Dravet Syndromementioning

confidence: 99%

Dravet Syndrome: Diagnosis and Long-Term Course

Connolly

2016

Can. J. Neurol. Sci.

102

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Dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality. The typical presentation is characterized by hemiclonic or generalized clonic seizures triggered by fever during the first year of life, followed by myoclonic, absence, focal and generalized tonic-clonic seizures. Non-convulsive status epilepticus and epileptic encephalopathy are common. Development is normal in the first year of life, but most individuals eventually suffer from intellectual impairment. Dravet syndrome is associated with mutations in the sodium channel alpha1 subunit gene (SCN1A) in 70-80% of individuals. SCN1A mutation results in inhibition of the GABAergic inhibitory interneurons, leading to excessive neuronal excitation. The "interneuron hypothesis" is the current most accepted pathophysiological mechanism of Dravet syndrome. The mortality rate is increased significantly in Dravet syndrome. Ataxia, a characteristic crouched gait and Parkinson's symptoms may develop in some individuals. It is likely that Dravet syndrome is underdiagnosed in adults with treatment-resistant epilepsy. Early diagnosis is important to avoid anti-seizure medications that exacerbate seizures.

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Brain morphometry of Dravet Syndrome

Cited by 13 publications

References 57 publications

Large-scale structural alteration of brain in epileptic children with SCN1A mutation

Large-scale structural alteration of brain in epileptic children with SCN1A mutation

The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration

Dravet Syndrome: Diagnosis and Long-Term Course

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