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While the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KO mice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from eight families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD., SCOPUS: ar.j, info:eu-repo/semantics/published

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel Na(V)1.3. Pathogenic Na(V)1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (Na(V)1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.

Summary Background Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. Methods We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. Findings We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7–3·2, p=9·1 × 10 −8 ; familial non-acquired focal epilepsy 3·6, 2·7–4·9, p=1·1 × 10 −17 ). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10 −8 ) that were lower than expected from a random sampling of genes. Interpretation We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. Funding National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de nova mutations, including de novo mutations in DNM1 in five individuals and de nova mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de nova mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 x 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de nova mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

Clinical description Action myoclonus – renal failure (AMRF) syndrome typically comprises a continuum of two major (and ultimately fatal) manifestations: progressive myoclonic epilepsy (PME) and renal failure; however, in some instances, the kidneys are not involved. Neurologic manifestations can appear before, simultaneously, or after the renal manifestations. Disease manifestations are usually evident in the late teens or early twenties. In the rare instances in which renal manifestations precede neurologic findings, onset is usually in late childhood / early adolescence but can range to the fifth or sixth decade. Neurologic manifestations begin with tremor at rest (which is exacerbated by fine motor activities) and progress to involuntary, action-activated myoclonic jerks that involve bulbar, proximal, and distal limb muscles; involuntary spontaneous myoclonic jerks; and generalized clonic-tonic-clonic seizures. Sensorimotor peripheral neuropathy and sensorineural hearing loss can also be observed. Renal manifestations include proteinuria that can progress to nephrotic syndrome and end-stage renal disease. Diagnosis/testing The diagnosis of AMRF syndrome is suspected in a previously healthy teenager or young adult with the characteristic neurologic and/or renal manifestations. The diagnosis is confirmed in individuals with biallelic (homozygous or compound heterozygous) loss-of-function pathogenic variants in SCARB2. Management Treatment of manifestations: Symptomatic pharmacologic and psychosocial support is the mainstay of care for the neurologic manifestations. Response to treatment is variable and may worsen over time, necessitating rehabilitative management. Renal insufficiency requires dialysis but response to treatment is poor, and renal transplantation is often necessary. Prevention of secondary complications: Standard measures for prevention of aspiration pneumonia and sudden unexpected death in epilepsy should be followed. Surveillance: Lifelong follow up should include regular monitoring of antiepileptic drug treatment and renal function (including urinary protein excretion, creatinine clearance, and estimated glomerular filtration rate) and periodic assessment of hearing and peripheral nerves. Agents/circumstances to avoid: Diphenylhydantoin, carbamazepine, oxcarbazepine, and possibly lamotrigine increase myoclonus and should be avoided in any individual with PME. Pregnancy management: Because some antiepileptic drugs can lead to an increased risk of malformations, growth retardation, or neurodevelopmental disabilities in exposed fetuses, standard measures for prevention of fetopathy should be followed. Genetic counseling AMRF syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible if the SCARB2 pathogenic variants in the family have been identified.

Background It is well known that patients with temporal lobe epilepsy may present with generalized seizures, and the temporal localization depends on further investigation. We present a family with five individuals in three generations where the clinical pattern consisted largely of generalized seizures, but who were then shown to have epilepsy due to an LGI1 mutation. We wish to discuss the clinical and EEG findings in these patients, and to compare these with families with autosomal dominant partial epilepsy with auditory features (ADPEAF) or familial lateral temporal lobe epilepsy (FLTLE) reported in the literature. Family report The proband is a 46-year-old female college graduate who had normal development and no history of head trauma, central nervous system infection or febrile seizures. She had four nocturnal generalized tonic-clonic seizures (GTCS), all occurred around 5–6 am, the first one at age 19years. Diphenylhydantoin was prescribed and later replaced by carbamazepine CR. She has been seizure free since adequate compliance with treatment. Her first EEG performed at 19 years showed an excess of slow waves at 2–4Hz over both posterior head regions without epileptic activity. Her second EEG at 22years showed spikes and slow spike waves alternating over both temporal regions, mostly during drowsiness, and increased during hyperventilation. During intermittent photic stimulation, a photomyoclonic response appeared. Her 40-year-old sister had her first GTCS at 12years which was generalized from the onset. All but one of her subsequent attacks occurred during sleep. Before the only seizure that occurred while awake, she felt numbness of her whole body and heard a whooshing sound suggestive of neocortical temporal lobe involvement. The third sister is 52years old; she had her first GTCS at 19years. A year prior to this, she had transient symptoms of a tingling sensation associated with a whooshing noise. She later had other generalized attacks preceded by this aura. A diagnosis of neocortical or lateral temporal lobe epilepsy, possibly ADPEAF or FLTLE, was suggested. Although the proband only had nocturnal GTCS, LGI1 sequencing was performed on the basis of the family history. A c.611delC mutation leading to a frameshift and premature termination of the protein was identified. Discussion Generalized nocturnal and diurnal seizures associated with interictal generalized spike-wave activity occurring in a family with ADPEAF is unusual. They may represent secondarily generalized seizures or primary generalized seizures or both. In addition, photosensitivity in the proband is unusual as well. Among the reported patients with LGI1 mutation, there are several who have had GTCS and interictal generalized spike-wave and/or polyspike-wave discharges [Ottman et al., 2004]. This family further illustrates that patients with ADPEAF or FLTLE may present with generalized seizures and generalized spike and wave epileptic discharges. Intensive monitoring and attention to aura with auditory features should lead to accurate diagnosis of this genetically determined epileptic syndrome. This report points to the importance of detailed family history to help orient the diagnosis by genetic testing.

Interest in genetic malformations of the frontal lobe has grown from the recognition that certain brain malformations have a predilection for the frontal lobes or are more severe in the anterior brain. These malformations can be deleterious, as the frontal lobes in humans are particularly large in comparison with those of other species and play an important role in cognitive developmental functions.

PURPOSE: Elucidating the potential contribution of specific autoantibodies (Ab's) to the etiology and/or pathology of some human epilepsies. METHODS: Six epilepsy patients with Rasmussen's encephalitis (RE) and 71 patients with other epilepsies were tested for Ab's to the "B" peptide (amino acids 372-395) of the glutamate/AMPA subtype 3 receptor (GluR3B peptide), double-stranded DNA (dsDNA), and additional autoimmune disease-associated autoantigens, and for the ability of their serum and cerebrospinal-fluid (CSF) to kill neurons. RESULTS: Elevated anti-GluR3B Ab' s were found in serum and CSF of most RE patients, and in serum of 17/71 (24%) patients with other epilepsies. In two RE patients, anti-GluR3B Ab's decreased drastically in CSF following functional-hemispherotomy, in association with seizure cessation and neurological improvement. Serum and CSF of two RE patients, and serum of 12/71 (17%) patients with other epilepsies, contained elevated anti-dsDNA Ab's, the hallmark of systemic-lupus-erythematosus. The sera (but not the CSF) of some RE patients contained also clinically elevated levels of "classical" autoimmune Ab's to glutamic-acid-decarboxylase, cardiolipin, beta2-glycoprotein-I and nuclear-antigens SS-A and RNP-70. Sera and CSF of some RE patients caused substantial death of hippocampal neurons. CONCLUSIONS: Some epilepsy patients harbor Ab's to GluR3 and dsDNA on both sides of the blood-brain barrier, and additional autoimmune Ab's only in serum. Since all these Ab's may be detrimental to the nervous system and/or peripheral organs, we recommend testing for their presence in epilepsy, and silencing their activity in Ab-positive patients., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: cp.j, info:eu-repo/semantics/published

Rationale Unverricht–Lundborg disease (ULD) (EPM1) is an autosomal recessive neurodegenerative disease with progressive myoclonus epilepsy (PME). The onset is usually between 6 and 15years of age with myoclonus and generalized tonic-clonic seizures, variable severity and course, and variable degrees of cognitive deterioration. With good antiepileptic management, the patients can now survive into their 50's and 60's. The gene for this disorder was identified in 1996 as cystatin B ( CSTB ), a cysteine protease inhibitor. The most common mutation is a dodecamer repeat, although rare point mutations have also been described. Objective To present an extended phenotype of ULD (EPM1). Methods The proband who carried a diagnosis of juvenile myoclonus epilepsy (JME) presented with her partner for preconceptional genetic counseling. Since she had a distant family history of Unverricht–Lundborg disease on the maternal side, carrier screening for the CSTB gene was carried out for both, employing detection of the dodecamer repeat expansion and sequencing of the CSTB gene to rule out point mutations. Results This 30-year-old female had a single generalized tonic-clonic seizure during sleep at the age of 11years, and onset of myoclonic jerks on awakening at around the same time, which were well-controlled by valproic acid. She carries a clinical diagnosis of JME. She was born prematurely after 25weeks' gestation weighing 750 grams. Developmental milestones were normal, and she was on the honor roll at school in grade X. She works as a high school teacher for behaviourally challenged children. Both paternal grandparents were of Irish origin; both maternal grandparents were French–Canadian, from the Gaspe peninsula of Quebec. Four siblings of the maternal grandmother were diagnosed clinically with ULD and were known to us; the three affected sisters died in their 20's and 30's, and the affected brother died at age 65. A third degree cousin of the mother had epilepsy and died at 18years of age. A paternal uncle had a single generalized tonic-clonic seizure at the age of 7years. A distant cousin of the paternal great grandmother was also said to have PME. CSTB testing revealed that our patient was a compound heterozygote for two mutations: an expansion of the dodecamer repeat and a splice site c.67–1G>C mutation in intron 1, predicting a deletion of the downstream exon 2 with in-frame deletion of 34 aminoacids (p.delV23_K56). This is the second most common mutation underlying EPM1, and the most common point mutation. The husband has no potential EPM1-causing sequence alterations. Conclusion Although ULD is often confused with JME in the early stages of the disease, it is rare to find patients with ULD at age 30 who are as well controlled and high-functioning as this patient. Furthermore, other compound heterozygotes with the same combination of mutations have had more severe phenotypes with progressive deterioration. The reason for the milder phenotype in this individual remains unexplained, and may be due to modifying genes and/or gene–environment interactions.

Objective: To study patients with Rasmussen encephalitis (RE) and associated autoimmune disorders (AID). Background RE is a rare chronic inflammatory disease characterized by intractable focal epilepsy, often epilepsia partialis continua, progressing to hemiparesis, cognitive impairment, and unilateral cerebral atrophy. The etiology of RE remains unknown. We have previously reported the occurrence of two rare AID, Behcet9s disease and RE, in a father and son respectively. Design/Methods: Review of medical records of four individuals with a dual diagnosis of RE and other AID. Results: The diagnosis of RE in all four patients was based on previously reported criteria, and was pathologically confirmed in patients 2, 3 and 4. In family 1, a patient with RE onset at 2 years developed Hashimoto9s thyroiditis at 15 years; he also had a brother with Type 1 (autoimmune) diabetes mellitus. In family 2, the patient had RE onset at 3 years, and developed ulcerative colitis at 10 years. In family 3, the patient had RE at the age of 6 years, and developed Crohn9s disease at age 14. In family 4, the patient had RE onset at 14 years and onset of systemic lupus erythematosus at 31 years. In these four families, the second AID appeared several years after the onset of RE, with a mean interval of 11 years (median 10 years). Conclusions: We suggest that the incidence of a second AID in RE patients may be higher than by chance; however, the true frequency and relative risk are unknown. Our observations suggest that there may be a common predisposing factor for the development of autoimmune responses in these patients. Further study of the long term evolution of RE patients, as well as detailed family histories, and use of newer molecular techniques such as CGH microarray and whole exome sequencing, are warranted to clarify this. Disclosure: Dr. Amrom has nothing to disclose.