Title: Influence of age at seizure onset on the acquisition of neurodevelopmental skills in an SCN8A cohort
AbstractObjective
To characterize a cohort of patients withSCN8A‐related epilepsy and to perform analyses to identify correlations involving the acquisition of neurodevelopmental skills.
Methods
We analyzed patient data (n = 91) submitted to an online registry tailored to characteristics of children withSCN8Avariants. Participants provided information on the history of their child's seizures, medications, comorbidities, and developmental skills based on the DenverIIitems. Spearman rank tests were utilized to test for correlations among a variety of aspects of seizures, medications, and neurodevelopmental progression.
Results
The 91 participants carried 71 missense variants (41 newly reported) and three truncating variants. Ages at seizure onset ranged from birth to >12 months of age (mean ± SD = 5 months 21 days ± 7 months 14 days). Multiple seizure types with multimodal onset times and developmental delay were observed as general features of this cohort. We found a positive correlation between a developmental score based upon percentage of acquired skills and the age at seizure onset, current seizure freedom, and initial febrile seizures. Analyses of cohort subgroups revealed clear distinctions between patients who had a single reported variant inSCN8Aand those with an additional variant reported in a gene other thanSCN8A, as well as between patients with different patterns of regression before and at seizure onset.
Significance
This is the first study of anSCN8A patient cohort of this size and for which correlations between age at seizure onset and neurodevelopment were investigated. Our correlation studies suggest that variants of uncertain significance should be considered in assessing children withSCN8A‐related disorders. This study substantially improves the characterization of this patient population and our understanding of the neurodevelopmental effects associated with seizures forSCN8A patients, and provides a clinical context at initial presentation that may be prognostic for developmental outcome.
Identification of patient‐specific epileptogenic networks is critical to designing successful treatment strategies. Multiple noninvasive methods have been used to characterize epileptogenic networks. However, these methods lack the spatiotemporal resolution to allow precise localization of epileptiform activity. We used intracranial recordings, at much higher spatiotemporal resolution, across a cohort of patients with mesial temporal lobe epilepsy (MTLE) to delineate features common to their epileptogenic networks. We used interictal rather than seizure data because interictal spikes occur more frequently, providing us greater power for analyzing variances in the network.
Methods
Intracranial recordings from 10 medically refractoryMTLEpatients were analyzed. In each patient, hour‐long recordings were selected for having frequent interictal discharges and no ictal events. For all possible pairs of electrodes, conditional probability of the occurrence of interictal spikes within a 150‐millisecond bin was computed. These probabilities were used to construct a weighted graph between all electrodes, and the node degree was estimated. To assess the relationship of the highly connected regions in this network to the clinically identified seizure network, logistic regression was used to model the regions that were surgically resected using weighted node degree and number of spikes in each channel as factors. Lastly, the conditional spike probability was normalized and averaged across patients to visualize theMTLEnetwork at group level.
Results
We generated the first graph of connectivity across a cohort ofMTLEpatients using interictal activity. The most consistent connections were hippocampus to amygdala, anterior fusiform cortex to hippocampus, and parahippocampal gyrus projections to amygdala. Additionally, the weighted node degree and number of spikes modeled the brain regions identified as seizure networks by clinicians.
Significance
Apart from identifying interictal measures that can model patient‐specific epileptogenic networks, we also produce a group map of network connectivity from a cohort ofMTLEpatients.
Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution ofCNVs to epilepsies from sizeable populations are not available.
Methods
We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array basedCNVdata. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features.CNVclassification was conducted using a systematic filtering workflow adapted to epilepsy.
Results
Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomalCNVclassified as pathogenic; 19 individuals (1.7%) carried at least one autosomalCNVclassified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenicCNV. We identifiedCNVs covering recently reported (HNRNPU)or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenicCNVcarriers to those of noncarriers of pathogenicCNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenicCNVs (odds ratio = 4.09, confidence interval = 2.51‐6.68;P = 2.34 × 10−9). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency ofCNVs.
Significance
The use of a specifically adapted workflow enabled identification of pathogenic autosomalCNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenicCNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm includingCNVdetection. Collaborative large‐scaleCNVreanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.
Riddle, Malini; Mezias, Erica; Foley, Duncan; LeSauter, Joseph; Silver, Rae; Foxe, ed., John(
, European Journal of Neuroscience)
Abstract
The hypothalamic suprachiasmatic nucleus (SCN), locus of the master circadian clock, bears many neuronal types. At the cellular–molecular level, the clock is comprised of feedback loops involving ‘clock’ genes includingPeriod1andPeriod2,and their protein products,PERIOD1 andPERIOD2 (PER1/2). In the canonical model of circadian oscillation, thePER1/2 proteins oscillate together. While their rhythmic expression in theSCNas a whole has been described, the possibility of regional differences remains unknown. To explore these clock proteins in distinctSCNregions, we assessed their expression through the rostro‐caudal extent of theSCNin sagittal sections. We developed an automated method for tracking three fluorophores in digital images of sections triply labeled forPER1,PER2, and gastrin‐releasing peptide (used to locate the core). In theSCNas a whole, neurons expressing high levels ofPER2 were concentrated in the rostral, rostrodorsal, and caudal portions of the nucleus, and those expressing high levels ofPER1 lay in a broad central area. Within these overall patterns, adjacent cells differed in expression levels of the two proteins. The results demonstrate spatially distinct localization of highPER1 vs.PER2 expression, raising the possibility that their distribution is functionally significant in encoding and communicating temporal information. The findings provoke the question of whether there are fundamental differences inPER1/2 levels amongSCNneurons and/or whether topographical differences in protein expression are a product ofSCNnetwork organization rather than intrinsic differences among neurons.
Mahendra, Ankit; Yang, Xingyu; Abnouf, Shaza; Adolacion, Jay R. T.; Park, Daechan; Soomro, Sanam; Roszik, Jason; Coarfa, Cristian; Romain, Gabrielle; Wanzeck, Keith; et al(
, Arthritis & Rheumatology)
Objective
To obtain the comprehensive transcriptome profile of human citrulline‐specific B cells from patients with rheumatoid arthritis (RA).
Methods
Citrulline‐ and hemagglutinin‐specific B cells were sorted by flow cytometry using peptide–streptavidin conjugates from the peripheral blood ofRApatients and healthy individuals. The transcriptome profile of the sorted cells was obtained byRNA‐sequencing, and expression of key protein molecules was evaluated by aptamer‐basedSOMAscan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays.
Results
Citrulline‐specific B cells, in comparison to citrulline‐negative B cells, from patients withRAdifferentially expressed the interleukin‐15 receptor α (IL‐15Rα) gene as well as genes related to protein citrullination and cyclicAMPsignaling. In analyses of an independent cohort of cyclic citrullinated peptide–seropositiveRApatients, the expression ofIL‐15Rα protein was enriched in citrulline‐specific B cells from the patients’ peripheral blood, and surprisingly, all B cells fromRApatients were capable of producing the epidermal growth factor ligand amphiregulin (AREG). Production ofAREGdirectly led to increased migration and proliferation of fibroblast‐like synoviocytes, and, in combination with anti–citrullinated protein antibodies, led to the increased differentiation of osteoclasts.
Conclusion
To the best of our knowledge, this is the first study to document the whole transcriptome profile of autoreactive B cells in any autoimmune disease. These data identify several genes and pathways that may be targeted by repurposing severalUSFood and Drug Administration–approved drugs, and could serve as the foundation for the comparative assessment of B cell profiles in other autoimmune diseases.
Kim, Myeongseop; Alapan, Yunus; Adhikari, Anima; Little, Jane A.; Gurkan, Umut A.(
, Microcirculation)
AbstractObjectives
The advancement of microfluidic technology has facilitated the simulation of physiological conditions of the microcirculation, such as oxygen tension, fluid flow, and shear stress in these devices. Here, we present a micro‐gas exchanger integrated with microfluidics to studyRBCadhesion under hypoxic flow conditions mimicking postcapillary venules.
Methods
We simulated a range of physiological conditions and exploredRBCadhesion to endothelial or subendothelial components (FNorLN). Blood samples were injected into microchannels at normoxic or hypoxic physiological flow conditions. Quantitative evaluation ofRBCadhesion was performed on 35 subjects with homozygousSCD.
Results
Significant heterogeneity inRBCadherence response to hypoxia was seen amongSCDpatients.RBCs from a HEA population showed a significantly greater increase in adhesion compared toRBCs from a HNA population, for bothFNandLN.
Conclusions
The approach presented here enabled the control of oxygen tension in blood during microscale flow and the quantification ofRBCadhesion in a cost‐efficient and patient‐specific manner. We identified a unique patient population in whichRBCs showed enhanced adhesion in hypoxia in vitro. Clinical correlates suggest a more severe clinical phenotype in this subgroup.
Encinas, Alejandra C., Moore, Ida, Watkins, Joseph C., and Hammer, Michael F. Influence of age at seizure onset on the acquisition of neurodevelopmental skills in an SCN8A cohort. Epilepsia 60.8 Web. doi:10.1111/epi.16288.
Encinas, Alejandra C., Moore, Ida, Watkins, Joseph C., & Hammer, Michael F. Influence of age at seizure onset on the acquisition of neurodevelopmental skills in an SCN8A cohort. Epilepsia, 60 (8). https://doi.org/10.1111/epi.16288
Encinas, Alejandra C., Moore, Ida, Watkins, Joseph C., and Hammer, Michael F.
"Influence of age at seizure onset on the acquisition of neurodevelopmental skills in an SCN8A cohort". Epilepsia 60 (8). Country unknown/Code not available: Wiley-Blackwell. https://doi.org/10.1111/epi.16288.https://par.nsf.gov/biblio/10371965.
@article{osti_10371965,
place = {Country unknown/Code not available},
title = {Influence of age at seizure onset on the acquisition of neurodevelopmental skills in an SCN8A cohort},
url = {https://par.nsf.gov/biblio/10371965},
DOI = {10.1111/epi.16288},
abstractNote = {Abstract ObjectiveTo characterize a cohort of patients withSCN8A‐related epilepsy and to perform analyses to identify correlations involving the acquisition of neurodevelopmental skills. MethodsWe analyzed patient data (n = 91) submitted to an online registry tailored to characteristics of children withSCN8Avariants. Participants provided information on the history of their child's seizures, medications, comorbidities, and developmental skills based on the DenverIIitems. Spearman rank tests were utilized to test for correlations among a variety of aspects of seizures, medications, and neurodevelopmental progression. ResultsThe 91 participants carried 71 missense variants (41 newly reported) and three truncating variants. Ages at seizure onset ranged from birth to >12 months of age (mean ± SD = 5 months 21 days ± 7 months 14 days). Multiple seizure types with multimodal onset times and developmental delay were observed as general features of this cohort. We found a positive correlation between a developmental score based upon percentage of acquired skills and the age at seizure onset, current seizure freedom, and initial febrile seizures. Analyses of cohort subgroups revealed clear distinctions between patients who had a single reported variant inSCN8Aand those with an additional variant reported in a gene other thanSCN8A, as well as between patients with different patterns of regression before and at seizure onset. SignificanceThis is the first study of anSCN8A patient cohort of this size and for which correlations between age at seizure onset and neurodevelopment were investigated. Our correlation studies suggest that variants of uncertain significance should be considered in assessing children withSCN8A‐related disorders. This study substantially improves the characterization of this patient population and our understanding of the neurodevelopmental effects associated with seizures forSCN8A patients, and provides a clinical context at initial presentation that may be prognostic for developmental outcome.},
journal = {Epilepsia},
volume = {60},
number = {8},
publisher = {Wiley-Blackwell},
author = {Encinas, Alejandra C. and Moore, Ida and Watkins, Joseph C. and Hammer, Michael F.},
}
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