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Polymicrogyria (PMG) is a heterogeneous brain malformation that may result from prenatal vascular disruption or infection, or from numerous genetic causes that still remain difficult to identify. We identified three unrelated patients with polymicrogyria and duplications of chromosome 2p, defined the smallest region of overlap, and performed gene pathway analysis using Cytoscape. The smallest region of overlap in all three children involved 2p16.1-p16.3. All three children have bilateral perisylvian polymicrogyria (BPP), intrauterine and postnatal growth deficiency, similar dysmorphic features, and poor feeding. Two of the three children had documented intellectual disability. Gene pathway analysis suggested a number of developmentally relevant genes and gene clusters that were over-represented in the critical region. We narrowed a rare locus for polymicrogyria to a region of 2p16.1-p16.3 that contains 33-34 genes, 23 of which are expressed in cerebral cortex during human fetal development. Using pathway analysis, we showed that several of the duplicated genes contribute to neurodevelopmental pathways including morphogen, cytokine, hormonal and growth factor signaling, regulation of cell cycle progression, cell morphogenesis, axonal guidance, and neuronal migration. These findings strengthen the evidence for a novel locus associated with polymicrogyria on 2p16.1-p16.3, and comprise the first step in defining the underlying genetic etiology.

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

We identified seven families associatingNEUROD2pathogenic mutations with ASD and intellectual disability. To get insight into the pathophysiological mechanisms, we analyzed cortical development inNeurod2KO mice. Cortical projection neurons (CPNs) over-migrated during embryogenesis, inducing abnormal thickness and laminar positioning of cortical layers. At juvenile ages, dendritic spine turnover and intrinsic excitability were increased in L5 CPNs. Differentially expressed genes inNeurod2KO mice were enriched for voltage-gated ion channels, and the human orthologs of these genes were strongly associated with ASD. Furthermore, adultNeurod2KO mice exhibited core ASD-like behavioral abnormalities. Finally, by generatingNeurod2conditional mutant mice we demonstrate that forebrain excitatory neuron-specificNeurod2deletion recapitulates cellular and behavioral ASD phenotypes found in full KO mice. Our findings demonstrate crucial roles forNeurod2in cortical development and function, whose alterations likely account for ASD and related symptoms in the newly definedNEUROD2mutation syndrome.

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.

BACKGROUND Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated. METHODS Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, = 200x) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing. RESULTS Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria. CONCLUSIONS Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.)

Objective: To describe a potential association between comorbid autoimmune disease and Rasmussen encephalitis (RE) and discuss potential insights into underlying RE pathogenesis. Methods: We report a case series of 4 patients with RE in whom a comorbid autoimmune disease was subsequently diagnosed and review the literature on possible common susceptibility factors. Results: In 4 patients who presented with typical clinical features of RE, a comorbid autoimmune disease was subsequently diagnosed: Hashimoto thyroiditis, ulcerative colitis, Crohn disease, and systemic lupus erythematosus. We discuss the possible common predisposing factors. Conclusions: The association of RE, a rare entity, with a comorbid autoimmune disease raises the possibility of shared mechanisms of susceptibility, including common immunogenetic and/or environmental risk factors.

Dominant mutations in TUBB2B have been reported in patients with polymicrogyria. We further explore the phenotype associated with mutations in TUBB2B. Twenty patients with polymicrogyria (five unilateral) were tested for mutations in TUBB2B by Sanger sequencing. We identified two novel de novo mutations, c.743C>T (p.Ala248Val) and c.1139G>T (p.Arg380Leu) in exon 4 of TUBB2B in three unrelated families. Brain magnetic resonance images showed polymicrogyria involving predominantly the perisylvian regions. In addition, there was a dysmorphic appearance of the basal ganglia, thin corpus callosum, enlargement of the ventricles, thinning of the white matter and hypoplasia of pons and cerebellar vermis. This combination of associated features was absent in all 17 patients with polymicrogyria in whom no mutation was identified. This report underlines that the association of polymicrogyria with thin or absent corpus callosum, dysmorphic basal ganglia, brainstem and vermis hypoplasia is highly likely to result from mutations in TUBB2B and provides further insight in how mutations in TUBB2B affect protein function.

Background Joubert syndrome (JBTS) is a predominantly autosomal recessive disorder characterised by a distinctive midhindbrain malformation, oculomotor apraxia, breathing abnormalities and developmental delay. JBTS is genetically heterogeneous, involving genes required for formation and function of non-motile cilia. Here we investigate the genetic basis of JBTS in 12 French–Canadian (FC) individuals. Methods and results Exome sequencing in all subjects showed that six of them carried rare compound heterozygous mutations in CC2D2A or C5ORF42 , known JBTS genes. In addition, three individuals (two families) were compound heterozygous for the same rare mutations in TMEM231 (c.12T>A[p.Tyr4*]; c.625G>A[p.Asp209Asn]). All three subjects showed a severe neurological phenotype and variable presence of polydactyly, retinopathy and renal cysts. These mutations were not detected among 385 FC controls. TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. siRNA knockdown of TMEM231 was also shown to affect barrier integrity, resulting in a reduction of cilia formation and ciliary localisation of signalling receptors. Conclusions Our data suggest that mutations in TMEM231 cause JBTS, reinforcing the relationship between this condition and the disruption of the barrier at the ciliary transition zone.

Interstitial deletions of 6q are associated with variable phenotypes, including growth retardation, dysmorphic features, upper limb malformations, and Prader-Willi (PW)-like features. Only a minority of cases in the literature have been characterized with high resolution techniques, making genotype-phenotype correlations difficult. We report 12 individuals with overlapping, 200-kb to 16.4-Mb interstitial deletions within 6q15q22.33 characterized by microarray-based comparative genomic hybridization to better correlate deletion regions with specific phenotypes. Four individuals have a PW-like phenotype, though only two have deletion of SIM1, the candidate gene for this feature. Therefore, other genes on 6q may contribute to this phenotype including multiple genes on 6q16 and our newly proposed candidate, the transcription cofactor gene VGLL2 on 6q22.2. Two individuals present with movement disorders as a major feature, and ataxia is present in a third. The 4.1-Mb 6q22.1q22.2 critical region for movement disorders includes the cerebellar-expressed candidate gene GOPC. Observed brain malformations include thick corpus callosum in two subjects, cerebellar vermal hypoplasia in two subjects, and cerebellar atrophy in one subject. Seven subjects' deletions overlap a ~250-kb cluster of four genes on 6q22.1 including MARCKS, HDAC2, and HS3ST5, which are involved in neural development. Two subjects have only this gene cluster deleted, and one deletion was apparently de novo, suggesting at least one of these genes plays an important role in development. Although the phenotypes associated with 6q deletions can vary, using overlapping deletions to delineate critical regions improves genotype-phenotype correlation for interstitial 6q deletions.

We report on nine unrelated children fitting a diagnosis of Carey-Fineman-Ziter syndrome (CFZS). All children presented with Mobius sequence, Pierre Robin complex (6/9) or micrognathia, and hypotonia. Some had primary hypoventilation, delayed development, and acral anomalies. The neuropathological investigations performed in two patients showed a combination of dysplastic lesions (neuronal heterotopias) and encephaloclastic changes consisting of small foci of necrosis with microcalcifications. The mother of a third child had severe trauma during her 2nd month of pregnancy. Based on a review of the literature on MS and CFZS, we suggest designating as "Robin-Mobius phenotype" a distinct clinical variant of MS with extensive brainstem involvement, Robin complex, hypotonia without specific muscle disorder, clubfeet and variable acral anomalies. This condition appears to bear a higher risk of mental handicap and perhaps a higher recurrence risk than "common" MS. Neuropathology and neuroimaging are suggestive, at least in some cases, of a vascular disruption, which could be exogenous, or secondary to a genetic predisposition. Etiologic heterogeneity seems likely and, in that respect, the original CFZS family could represent a private syndrome fitting on the "Robin-Mobius" spectrum. Despite the existence of two familial reports, recurrence risk is probably much lower than 25%, although exact figures cannot be extracted from the available literature.

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.

Neuro-Behcet’s syndrome was investigated with CT scan and magnetic resonance imaging (MRI) with a follow-up of 8.5 months, showing correlation with the patient’s clinical state and reversibility of bo

We report on nine unrelated children fitting a diagnosis of Carey-Fineman-Ziter syndrome (CFZS). All children presented with Möbius sequence, Pierre Robin complex (6/9) or micrognathia, and hypotonia. Some had primary hypoventilation, delayed development, and acral anomalies. The neuropathological investigations performed in two patients showed a combination of dysplastic lesions (neuronal heterotopias) and encephaloclastic changes consisting of small foci of necrosis with microcalcifications. The mother of a third child had severe trauma during her 2nd month of pregnancy. Based on a review of the literature on MS and CFZS, we suggest designating as "Robin-Möbius phenotype" a distinct clinical variant of MS with extensive brainstem involvement, Robin complex, hypotonia without specific muscle disorder, clubfeet and variable acral anomalies. This condition appears to bear a higher risk of mental handicap and perhaps a higher recurrence risk than "common" MS. Neuropathology and neuroimaging are suggestive, at least in some cases, of a vascular disruption, which could be exogenous, or secondary to a genetic predisposition. Etiologic heterogeneity seems likely and, in that respect, the original CFZS family could represent a private syndrome fitting on the "Robin-Möbius" spectrum. Despite the existence of two familial reports, recurrence risk is probably much lower than 25%, although exact figures cannot be extracted from the available literature.

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.

Background Action myoclonus renal failure (AMRF) syndrome is an autosomal recessive form of progressive myoclonus epilepsy with tremor and myoclonus that may be intractable. It was initially described in three French Canadian families. AMRF is caused by mutations in the SCARB2 gene, encoding a lysosomal membrane protein. Disease onset is usually in the late teens or early twenties, and begins with tremor and proteinuria, progressing to action myoclonus, tonic–clonic seizures and renal failure. Methods We describe the clinical and EEG investigations, including EEG with surface EMG electrodes (EEG-sEMG), as well as clinical video recording in three patients with AMRF syndrome associated with a confirmed SCARB2 gene mutation. Results Patients 1 and 2 had onset of action myoclonus at 21 and 22 years, respectively. They had no proteinuria. EEG-sEMG in both patients showed a normal background activity with numerous trains of generalized polyspike and waves at a frequency of 4 Hz, at times associated with jerks. In patient 1 there was photosensitivity at lower stimulation frequencies (2–6 Hz) and one generalized tonic–clonic seizure was recorded at 8 Hz lasting 1 min. Patient 3 presented fine tremor of upper limbs at 14 years, renal failure at 15 years, and action myoclonus at 27 years. He never had tonic–clonic seizures. The EEG-sEMG showed a tremor that had a frequency of 4–5 Hz, there were no myoclonic jerks demonstrated on surface electrodes. All three patients had normal intelligence and the SCARB2 nonsense mutation Q288X. Discussion The early clinical findings in AMRF are fine tremor and proteinuria, followed by action myoclonus, renal failure and occasional generalized tonic–clonic seizures. In some patients, the renal failure may present prior to the neurological symptoms or may not develop. The key EEG findings consist of background activity within the normal range, unlike many PME’s, where it is slow. The other EEG findings are similar to those seen in other PME’s, in particular the photosensitivity at low stimulation frequencies. In the early stages of the disease, JME should be in the differential diagnosis. If the tremor and myoclonus become intractable, and/or the patient develops proteinuria or renal failure, AMRF should be considered.

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.

Objective: To study twenty patients with epilepsy and subcortical band heterotopia without LIS1/DCX mutations. Background Subcortical band heterotopia (SBH), also called double cortex syndrome, is a malformation of cortical development due to deficient neuronal migration. Anterior and posterior SBH are associated with DCX and LIS1 gene mutations, respectively. Design/Methods: Review of our database of adult epilepsy patients with SBH for which no DCX or LIS1 mutation was found; perform karyotype and CGH array in these patients. Results: Twenty-eight patients presenting with various degrees of epilepsy, with or without associated cognitive delay, had an SBH. All were sporadic. They were evaluated with DCX and/or LIS1 sequencing and MLPA analysis. In twenty patients, no DCX or LIS1 mutation was identified. Karyotype and/or array CGH were then carried out in a number of patients. In one woman, the karyotype showed a rearrangement of chromosome 9, suggesting a paracentric inversion of the q13-q22.3 region. Karyotype analysis in both parents was normal, indicating a de novo chromosomal rearrangement in the proband. This patient had a history of infantile spasms, morning myoclonic seizures and pervasive developmental delay. She presented a thick and diffuse SBH. DCX and LIS1 sequencing and deletion/duplication analysis were negative. A CGH microarray (with 135,000 oligonucleotides) was added and did not reveal any deletion or duplication. A higher resolution CGH microarray is planned in order to detect a possible microdeletion/duplication. Conclusions: Genetic evaluation of SBH deserves DCX and/or LIS1 sequencing and deletion/duplication analysis, but does not always reveal the genetic cause of this brain malformation. Karyotype analysis and/or array CGH may still be of interest in these unsolved cases. Careful analysis of other sporadic SBH patients, as well as familial cases, negative for DCX/LIS1 evaluation, is mandatory in order to elucidate their genetic cause and improve genetic counselling. Disclosure: Dr. Andermann has nothing to disclose. Dr. Amrom has nothing to disclose. Dr. D9Agostino has nothing to disclose. Dr. Dubeau has nothing to disclose. Dr. Andermann has nothing to disclose. Dr. Dobyns has nothing to disclose.

We studied a 10-year-old girl with Sydenham's chorea (SC) using positron emission tomography (PET) with fluorodeoxyglucose (FDG). Choreic movements involved the head and the left side of her body. PET showed increased glucose metabolism in the right caudate nucleus and putamen. Three months after complete recovery, striatal glucose metabolism had returned to normal in the caudate nucleus. In the right putamen, glucose metabolism had decreased compared to that in the first study but remained elevated compared to that of normal young adults. We propose that the transient striatal hypermetabolism may have been due to increased afferent inputs to the striatum as a consequence of striatal or subthalamic nucleus dysfunction.