Morphometry and network-based atrophy patterns in SCN1A-related Dravet syndrome

Abstract

Mutations of the voltage-gated sodium channel SCN1A gene (MIM#182389) are among the most clinically relevant epilepsy-related genetic mutations and present variable phenotypes, from the milder genetic epilepsy with febrile seizures plus to Dravet syndrome, a severe developmental and epileptic encephalopathy. Qualitative neuroimaging studies have identified malformations of cortical development in some patients and mild atrophic changes, partially confirmed by quantitative studies. Precise correlations between MRI findings and clinical variables have not been addressed. We used morphometric methods and network-based models to detect abnormal brain structural patterns in 34 patients with SCN1A-related epilepsy, including 22 with Dravet syndrome. By measuring the morphometric characteristics of the cortical mantle and volume of subcortical structures, we found bilateral atrophic changes in the hippocampus, amygdala, and the temporo-limbic cortex (P-value < 0.05). By correlating atrophic patterns with brain connectivity profiles, we found the region of the hippocampal formation as the epicenter of the structural changes. We also observed that Dravet syndrome was associated with more severe atrophy patterns with respect to the genetic epilepsy with febrile seizures plus phenotype (r = −0.0613, P-value = 0.03), thus suggesting that both the underlying mutation and seizure severity contribute to determine atrophic changes.

Clinical and molecular characterization of patients with YWHAG‐related epilepsy

“…Lack of information does not allow discerning whether MRI was not performed or unrevealing, leaving open the possibility that a systematic analysis in a large cohort, ideally by applying morphometric methods, might reveal a common pattern of abnormality, despite nonspecific qualitative findings. 25,26 Dysmorphisms, described in 69% of previously published patients, were observed in only 25% of those included in this report, and no recognizable recurrent pattern could be identified in this and previous studies. However, mild dysmorphisms in a rare condition are easily underreported, as they may escape recognition if patients are not seen by expert clinical geneticists and are reported via an international collaboration in which each center contributes single or very few observations, making interindividual comparison impossible.…”

“…Variable brain MRI alterations, not suggesting a recurrent pattern of abnormality, were identified in 17% of our patients (4/24, 17%) and in 27% (4/15, 27%) of those previously reported, for whom, however, this information was not available in 38%. Lack of information does not allow discerning whether MRI was not performed or unrevealing, leaving open the possibility that a systematic analysis in a large cohort, ideally by applying morphometric methods, might reveal a common pattern of abnormality, despite nonspecific qualitative findings 25,26 …”

Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19-related developmental and epileptic encephalopathy

“…Studies exploring quantitative sub eld alterations in TLE reported an overall effect of temporal lobe seizures manifesting as bilateral medial hippocampal atrophy, and a more selective effect of hippocampal seizures, leading to disease-proportional CA1 atrophy [50,51]. The hippocampal formation acts as an epicenter of more intense structural changes even in epilepsy syndromes in which no clear indication of seizure genesis in the hippocampus exists, such as SCN1A-related Dravet syndrome [52] and idiopathic generalized epilepsy syndromes [20,53]. In a previous study of PCDH19-related encephalopathy, we demonstrated altered gyri cation in the parahippocampal and entorhinal regions, and diffusion abnormalities in the underlying white matter (Lenge et al, 2020), but no alterations emerged in the hippocampus when it was examined as a whole.…”