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In data was presented at the 2015 American Epilepsy Society Annual Meeting, Candace Myers, PhD, of the University of Washington, and colleagues have shown that targeted high throughput resequencing of genes in which a de novo mutation was previously been identified can help expand the phenotypic spectrum associated with these genes.
They sought to expand on their previous study where they identified 329 de novo mutations in 305 genes when 264 trios (affected child and unaffected parents).
For their current study the researchers performed targeted capture and high-throughput resequencing of 27 genes in which a de novo mutation was identified in one or more proband with Infantile Spasms (IS) or Lennox-Gastaut syndrome (LGS) in our prior study. 537 patients with diverse Epileptic Encephalopathy phenotypes were screened.
They were able to confirm the role of at least 7 additional genes in the genetic etiology of EE and expand the phenotypic spectrum associated with these genes beyond IS and LGS in which they were first discovered.
Among the genes identified there were recurrent and novel mutations in ALG13, CACNA1A, DNM1, GABRB3, GNAO1, IQSEC2, and SLC1A2 highlighting the importance of these genes in Epileptic Encephalopathies. Interestingly, 44% of the pathogenic variants identified in this study were recurrent mutations.
In addition they also identified a parent with a mosaic germline mutation in the case of two independent families with multiple affected individuals. GABRB3 accounted for the majority of pathogenic variants (n=6/537), accounting for ~1% of our cohort.
Citation: Myers C, McMahon J, Schneider A, et al. Abstract 1.315. Gene discovery in epileptic encephalopathies through targeted resequencing of candidate genes. Presented at: American Epilepsy Society Annual Meeting. Dec 4-8; Philadelphia.
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According to research presented at the 2015 American Epilepsy Society annual meeting in Philadelphia, dysfunction of brain circuits in pediatric patients with focal epilepsy results from a significant reduction in Circadian Locomotor Output Cycles Kaput (Clock) expression.
The researchers including Judy Liu MD PhD and her colleagues at the Children’s National Medical Center in Washington studied patients with focal epilepsy enrolled under their epilepsy surgery program. They used high-resolution 3t magnetic resonance imaging to determine epileptogenic foci and collected samples directly from the operating room for transcriptome analysis performed by microarray using Illumina® Gene Expression Bead Chip Array technology.
Studies in mice were also conducted for histological and gene expression analyses, whole cell patch-clamp electrophysiology, and pentylenetetrazole (ptz) seizure induction.
They found that compared with normal brain tissue the epileptogenic tissue showed a significant reduction of Circadian Locomotor Output Cycles Kaput (Clock) expression in 20 out of the 25 patients. Patients with decreased Clock included those with focal cortical dysplasias, tuberous sclerosis complex, Sturge-Weber syndrome, and Rasmussen's encephalitis.
The protein encoded by the Clock gene plays a central role in the regulation of circadian rhythms. Polymorphisms in this gene may be associated with behavioral changes, obesity, and metabolic syndrome. Two transcripts encoding the same protein have been found for this gene.
Deletion of the circadian clock in excitatory neurons in mice was associated with loss of spines in the apical dendrite and primary branches, a phenotype also seen in epileptogenic tissue of human pyramidal neurons.
These results point towards the key role of circadian genes in the pathogenesis of focal epilepsy in children and provide a link between the sleep-wake cycle and seizure threshold.
In addition it opens up the prospects of the circadian pathway being a promising target for therapeutic intervention.
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Research presented at the 2015 American Epilepsy Society Annual Meeting in Philadelphia shows that early detection of cognitive difficulties using a brief computerized cognitive screening may help improve delays in intervention. Cognitive problems and behavioural problems in epilepsy are frequent.
Cognitive difficulties in children with epilepsy affect different domains, including memory, language, and executive function that occur during critical periods of development. However screening tools currently available do not adequately identify these children, resulting in a delay in intervention.
In their study Megan E. Bone, of the University of Pittsburgh School of Medicine, and colleagues evaluated the feasibility of the brief CNS Vital Signs (CNSVS) computerized cognitive battery for the detection of comorbidities in children with new-onset epilepsy.
They studied 33 patients (17 male; 26 generalized epilepsy, 7 focal epilepsy) aged 8-17 years with new-onset epilepsy and no previous antiepileptic drug treatment. Patients completed the CNSVS, which is completed in approximately 30 minutes, and parents completed the Strength and Difficulties Questionnaire, at two subsequent intervals (2-12 months = T2, 12-18 months= T3) during routine clinical appointments. Baseline scores were compared to subsequent scores using the Reliable Change Index (RCI).
All participants completed at least one follow up testing (mean follow-up time = 5.5 mo.), and 16 completed a third testing (mean total follow-up time = 14.5 mo.). Between baseline and first follow-up, 85% of patients had clinically significant changes in one of more cognitive domains including memory, psychomotor speed, reaction time, complex attention, and cognitive flexibility.
There was no apparent relationship between change in cognitive performance and seizure medication, epilepsy type, and seizure control. Composite memory, cognitive flexibility, reaction time, and complex attention showed the most change at both follow-up intervals, while no significant changes were observed for psychomotor speed.
In patients who improved or declined, change occurred at the first follow-up and remained stable thereafter. Parental concerns did not necessarily align with CNSVS score changes.
Citation: Bone ME, Triplett R, Rubin P, Asato MR. Abstract 1.293. Brief computerized screening detects cognitive changes in children with epilepsy. Presented at: American Epilepsy Society Annual Meeting; Dec 4-8, 2015; Philadelphia.
CNS Vital Signs (CNSVS) computerized cognitive battery
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Although novel treatment strategies based on the gene therapy approach for epilepsy has been encouraging, there is still a gap in demonstrating a proof-of-concept in a clinically relevant animal model and study design.
In a study published in Neurobiology of Disease on Dec 1, 2015 researchers from Lund University in Sweden and colleagues at University of Copenhagen Denmark delivered genes for a signal substance "neuropeptide Y" and its receptor into the brain of test animals with post intrahippocampal kainate-induced status epilepticus (SE) model of chronic epilepsy, and succeeded in considerably reducing the number of epileptic seizures among the animals. The test has been designed to as far as possible mimic a future situation involving treatment of human patients.
Neuropeptide Y (NPY), which is widely expressed in the brain, is involved in various brain functions, including regulation of neuronal excitability and seizures.
The intrahippocampal kainate model resembles the disease development of human chronic mesial temporal lobe epilepsy (mTLE) in that spontaneous seizures originate in the sclerotic hippocampus, only a part of the animals develops chronic epilepsy, animals show largely variable seizure frequency and tends to progressively increase over time.
Despite significant hippocampal degeneration caused by the kainate injection, the use of MRI allowed targeting the recombinant adeno-associated viral (rAAV) vectors encoding NPY and Y2 receptor genes to the remaining dorsal and ventral hippocampal areas ipsilateral to the kainate injection.
The study results have so far been positive.Continuous video-EEG monitoring demonstrated not only prevention of the progressive increase in seizure frequency in rAAV-NPY/Y2 treated animals as compared to the controls, and for 80 % of the animals the number of seizures was reduced by almost half.
This translationally designed study in a clinically relevant model of epilepsy suggests that simultaneous overexpression of NPY and Y2 receptors unilaterally in the seizure focus is a relevant and promising approach that can be further validated in more extensive preclinical studies.
Gene therapy treatments could initially be carried out on patients who have already been selected for surgical procedures. In the long term, however, gene therapy will be of the greatest benefit to those patients who cannot be operated on.
There are patients with severe epilepsy whose epileptic focus is so badly placed that an operation is out of question since it can impair e.g. speech or movement. These patients can therefore never undergo a surgical procedure, but could be helped by gene therapy in the future.
Citation: Translational approach for gene therapy in epilepsy: Model system and unilateral overexpression of neuropeptide Y and Y2 receptors, Ledri LN, Melin E, Christiansen SH, Gøtzsche CR, Cifra A, Woldbye DP, Kokaia M, Neurobiology of Disease , doi: 10.1016/j.nbd.2015.11.014, published online 1 December 2015.
Cover image: Translational pre-clinical design of the study. A schematic overview of plausible interventions for epilepsy treatment using viral vector-based gene therapy for epilepsy patients. The pre-clinical study in rats has been designed based on a clinical perspective for possible future clinical trials in patients with intractable temporal lobe epilepsy and that are candidates for surgical resection of the epileptic focus.
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In a study, published Dec. 4, 2015 in the journal Science, investigators from the Bench to Bassinet Program’s Pediatric Cardiac Genomics Consortium used exome sequencing to genetically evaluate 1,213 family trios composed of a child with congenital heart disease and the mother and father. Through this technique, which examines only the protein-coding regions of DNA, they found that children with moderate-to-severe congenital heart disease had a substantial number of "de novo" gene mutations. De novo mutations occur within egg, sperm, and fertilized cells, but are not part of the genetic makeup of the mother or father.
Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain.
These mutations accounted for 20% of patients with Congenital heart disease (CHD), neurodevelopmental disabilities (NDDs), and extracardiac congenital anomalies (CAs) but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.
These findings have implications for basic research and clinical medicine. Further analyses of these mutated genes, would help uncover new pathways that are critical for the development of the heart, brain, and other organs.
If the relationship between the de novo mutations and neurodevelopmental abnormalities in children continues to hold, clinical genetic tests could be created for newborns with moderate-to- severe congenital heart abnormalities. The patients found to carry the gene mutations could then be targeted for greater surveillance and early interventions that might address and limit developmental delays and improve their outcomes.
Congenital heart disease in which there are structural defects in the heart is the most common type of birth defect in the United States, and one of the leading causes of infant death. Nearly 40,000 children are born with congenital heart disease each year, and experts estimate that approximately 1 to 2 million adults and 800,000 children in the U.S. currently live with the disease.Surgery is often performed early in life to repair heart defects,but once children reach school age, many exhibit various attention deficits, including attention deficit hyperactivity disorder, and other neurobehavioral problems.
Citation:
Bench to Bassinet Program’s Pediatric Cardiac Genomics Consortium
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