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PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

OBJECTIVE: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. METHODS: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. RESULTS: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. SIGNIFICANCE: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.

PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP.METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay.RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants.CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

Ionic calcium (Ca2+) is a key messenger in signal transduction and its mitochondrial uptake plays an important role in cell physiology. This uptake is mediated by the mitochondrial Ca2+uniporter (MCU), which is regulated by EMRE (essential MCU regulator) encoded by theSMDT1(single-pass membrane protein with aspartate rich tail 1) gene. This work presents the genetic, clinical and cellular characterization of two patients harbouringSMDT1variants and presenting with muscle problems. Analysis of patient fibroblasts and complementation experiments provide evidence that these variants lead to absence of EMRE protein, induce MCU subcomplex formation and impair mitochondrial Ca2+uptake. However, the activity of the oxidative phosphorylation enzymes, mitochondrial morphology and membrane potential, as well as routine/ATP-linked respiration were not affected. We hypothesize that the muscle-related symptoms in the patients withSMDT1variants result from aberrant mitochondrial Ca2+uptake.

A 7-month-old boy was referred with developmental delay and axial hypotonia (video 1). Screening for inborn errors of metabolism was negative and single nucleotide polymorphism array was normal (46,XY). Myotonic dystrophy (type 1) and spinal muscular atrophy were excluded. Whole exome sequencing yielded biallelic mutations in the tyrosine hydroxylase gene (c.698 G>A, p.Arg233His and c.1211C>T, p.Thr404Met). Subsequent CSF analysis revealed a significantly lowered homovanillic acid/5-hydroxyindoleacetic acid ratio, confirming tyrosine hydroxylase deficiency.1 Treatment with monotherapy levodopa resulted in profoundly improved motor development (video 1). After several weeks of treatment, the patient developed levodopa-induced dyskinesias (video 1),2 insomnia, and hyperactive behavior. All symptoms ameliorated with levodopa reduction.

Diagnostic Exome Sequencing in 100 Consecutive Patients With Both Epilepsy and Intellectual Disability Snoeijen-Schouwenaars FM, van Ool JS, Verhoeven JS, et al. Epilepsia. 2019;60(1):155-164. doi:10.1111/epi.14618. Epub December 7, 2018. PMID: 30525188.Objective:Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole-exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy.Methods:One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. Whole-exome sequencing analysis was performed in 2 steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. Results: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 (40%) of 25 patients with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future.Significance:This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield. Diagnostic Yield of Genetic Tests in Epilepsy: A Meta-Analysis and Cost-Effectiveness Study Sánchez Fernández I, Loddenkemper T, Gaínza-Lein M, Sheidley BR, Poduri A. Neurology. 2019. Epub ahead of print. pii: 10.1212/WNL.0000000000006850. doi:10.1212/WNL.0000000000006850. PMID: 30610098 Objective:To compare the cost-effectiveness of genetic testing strategies in patients with epilepsy of unknown etiology.Methods:This meta-analysis and cost-effectiveness study compared strategies involving 3 genetic tests: chromosomal microarray (CMA), epilepsy panel (EP) with deletion/duplication testing, and whole-exome sequencing (WES) in a cost-effectiveness model, using “no genetic testing”“ as a point of comparison.Results:Twenty studies provided information on the diagnostic yield of CMA (8 studies), EP (9 studies), and WES (6 studies). The diagnostic yield was highest for WES: 0.45 (95% confidence interval [CI]: 0.33-0.57; 0.32 [95% CI: 0.22-0.44] adjusting for potential publication bias), followed by EP: 0.23 (95% CI: 0.18-0.29) and CMA: 0.08 (95% CI: 0.06-0.12). The most cost-effective test was WES with an incremental cost-effectiveness ratio (ICER) of US$15 000/diagnosis. However, after adjusting for potential publication bias, the most cost-effective test was EP (ICER: US$15 848/diagnosis) followed by WES (ICER: US$34 500/diagnosis). Among combination strategies, the most cost-effective strategy was WES, then if nondiagnostic, EP, then if nondiagnostic, CMA (ICER: US$15 336/diagnosis); although adjusting for potential publication bias, the most cost-effective strategy was EP ± CMA ± WES (ICER: US$18 385/diagnosis). Although the cost-effectiveness of individual tests and testing strategies overlapped, CMA was consistently less cost-effective than WES and EP.Conclusion:Whole-exome sequencing and EP are the most cost-effective genetic tests for epilepsy. Our analyses support for a broad population of patients with unexplained epilepsy, starting with these tests. Although less expensive, CMA has lower yield, and its use as the first-tier test is thus not supported from a cost-effectiveness perspective.

ObjectiveWe describe a third patient with brain small vessel disease 3 (BSVD3), being the first with a homozygous essential splice site variant in the COLGALT1 gene, with a more severe phenotype than the 2 children reported earlier.MethodsAnalysis of whole exome sequencing (WES) data of the child and parents was performed. We validated the missplicing of the homozygous variant using reverse transcription PCR and Sanger sequencing of the mRNA in a lymphocyte culture.ResultsThe patient presented antenatally with porencephaly on ultrasound and MRI. Postnatally, he showed a severe developmental delay, refractory epilepsy, spastic quadriplegia, and a progressive hydrocephalus. WES revealed a homozygous canonical splice site variant NM_024656.3:c.625-2A>C. PCR and Sanger sequencing of the mRNA demonstrated that 2 cryptic splice sites are activated, causing a frameshift in the major transcript and in-frame deletion in a minor transcript.ConclusionsWe report a third patient with biallelic pathogenic variants in COLGALT1, confirming the role of this gene in autosomal recessive BSVD3.

ObjectiveDe novo missense mutations in the RHOBTB2 gene have been described as causative for developmental and epileptic encephalopathy.MethodsThe clinical phenotype of this disorder includes early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorder. Three RHOBTB2 patients have been described with acute encephalopathy and febrile epileptic status. All showed severe EEG abnormalities during this episode and abnormal MRI with hemisphere swelling or reduced diffusion in various brain regions.ResultsWe describe the episode of acute encephalopathy after head trauma in a 5-year-old RHOBTB2 patient. At admission, Glasgow coma scale score was E4M4V1. EEG was severely abnormal showing a noncontinuous pattern with slow activity without epileptic activity indicating severe encephalopathy. A second EEG on day 8 was still severely slowed and showed focal delta activity frontotemporal in both hemispheres. Gradually, he recovered, and on day 11, he had regained his normal reactivity, behavior, and mood. Two months after discharge, EEG showed further decrease in slow activity and increase in normal electroencephalographic activity. After discharge, parents noted that he showed more hyperkinetic movements compared to before this period of encephalopathy. Follow-up MRI showed an increment of hippocampal atrophy. In addition, we summarize the clinical characteristics of a second RHOBTB2 patient with increase of focal periventricular atrophy and development of hemiparesis after epileptic status.ConclusionsAcute encephalopathy in RHOBTB2 patients can also be triggered by head trauma.

BackgroundRare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described.MethodsClinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation.ResultsClinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1).ConclusionsVariants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.

Objective: To describe the clinical spectrum of benign nocturnal alternating hemiplegia of childhood (BNAHC) including long-term follow-up data of previously published cases and to propose an underlying genetic cause of this disorder. Methods: We studied the medical data of two novel patients, reviewed the literature on BNAHC, and gathered information of the most recent follow-up of published cases regarding the course of episodes, further development, attempted drugs, ancillary investigations, and sequelae. Results: All patients, i.e. two novel cases and twelve patients identified in the literature (13 boys, 1 girl, age at onset four months to three years), experienced episodes of hemiplegia during nocturnal or daytime sleep heralded by inconsolable crying. Possible triggers included stress and sleep deprivation. Eleven of fourteen patients had a family history of migraine or 'intermittent headache' and two sets of siblings are reported. In one case, exome sequencing revealed a heterozygous 16p11.2 deletion involving 33 genes, including the PRRT2 gene. EEG showed ictal and/or interictal contralateral slowing in four patients. Treatment efficacy was generally disappointing. A complete disappearance of attacks appeared in nearly all cases at most recent follow-up. In a remarkably high number of cases (10/14, 71%), hyperactive behaviour was reported during follow-up. Conclusion: We underscore the phenotypic homogeneity including the self-limiting course of BNAHC episodes and suggest the condition be renamed 'benign childhood hemiplegia during sleep' (BCHS). We propose a role for the PRRT2 gene and the resulting neuronal hyperexcitability as one of its possible underpinning mechanisms and discuss the clinical similarities of BCHS with the recognized PRRT2-related disorders. (C) 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Contains fulltext : 218293.pdf (Publisher’s version ) (Closed access) Several de novo variants in the KIF1A gene have been reported to cause a complicated form of hereditary spastic paraplegia. Additional symptoms include cognitive impairment and varying degrees of peripheral neuropathy, epilepsy, decreased visual acuity, and ataxia. We describe four patients (ages 10-18 years), focusing on their mobility and gait characteristics. Two patients were not able to walk without assistance and showed a severe abnormal gait pattern, crouch gait. At examination, severe contractures were found.In addition to describing the different phenotypes with specific attention to gait in our cases, we reviewed known KIF1A mutations and summarized their associated phenotypes.We conclude that mobility and cognition are severely affected in children with spastic paraplegia due to de novo KIF1A mutations. Deterioration in mobility is most likely due to progressive spasticity, muscle weakness, and the secondary development of severe contractures, possibly combined with an additional progressive polyneuropathy. Close follow-up and treatment of these patients are warranted.

Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders. Three of the variants were recurrent. Upon transfection of HEK293 cells, we found that mutant RHOBTB2 was more abundant than the wild-type, most likely because of impaired degradation in the proteasome. Similarly, elevated amounts of the Drosophila ortholog RhoBTB in vivo were associated with seizure susceptibility and severe locomotor defects. Knockdown of RhoBTB in the Drosophila dendritic arborization neurons resulted in a decreased number of dendrites, thus suggesting a role of RhoBTB in dendritic development. We have established missense variants in the BTB-domain-encoding region of RHOBTB2 as causative for a developmental and epileptic encephalopathy and have elucidated the role of atypical Rho GTPase RhoBTB in Drosophila neurological function and possibly dendrite development.

Het Epilepsiefonds en ZonMw hebben recent een subsidie verleend aan een onderzoeksgroep van het Radboudumc, het Maastricht UMC+ en Kempenhaeghe voor het ontwikkelen van een nieuwe techniek die een belangrijke stap kan zijn in de evolutie van een algemene, ziekte-georiënteerde behandeling naar een specifieke, op de patiënt afgestemde behandeling. In deze bijdrage wordt nader ingegaan op de inhoud van het onderzoek.

Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes.Clinical and molecular characterisation was performed on 17 patients withClinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygousVariants in

BACKGROUND AND PURPOSE: The "ears of the lynx" MR imaging sign has been described in case reports of hereditary spastic paraplegia with a thin corpus callosum, mostly associated with mutations in the spatacsin vesicle trafficking associated gene, causing Spastic Paraplegia type 11 (SPG11). This sign corresponds to long T1 and T2 values in the forceps minor of the corpus callosum, which appears hyperintense on FLAIR and hypointense on T1-weighted images. Our purpose was to determine the sensitivity and specificity of the ears of the lynx MR imaging sign for genetic cases compared with common potential mimics.MATERIALS AND METHODS: Four independent raters, blinded to the diagnosis, determined whether the ears of the lynx sign was present in each of a set of 204 single anonymized FLAIR and T1-weighted MR images from 34 patients with causal mutations associated with SPG11 or Spastic Paraplegia type 15 (SPG15). 34 healthy controls, and 34 patients with multiple sclerosis.RESULTS: The interrater reliability for FLAIR images was substantial (Cohen kappa, 0.66-0.77). For these images, the sensitivity of the ears of the lynx sign across raters ranged from 78.8 to 97.0 and the specificity ranged from 90.9 to 100. The accuracy of the sign, measured by area under the receiver operating characteristic curve, ranged from very good (87.1) to excellent (93.9).CONCLUSIONS: The ears of the lynx sign on FLAIR MR imaging is highly specific for the most common genetic subtypes of hereditary spastic paraplegia with a thin corpus callosum. When this sign is present, there is a high likelihood of a genetic mutation, particularly associated with SPG11 or SPG15, even in the absence of a family history.

The clinical presentations of autoimmune encephalitides tend to be a mixture of neuropsychiatric and somatic symptoms. The focus of this chapter concerns these clinical problems: the clinical phenomenology, the prevalence, and the possible pathophysiologies of anti-NMDAR or the other types of autoimmune encephalitis. We also specifically address the psychopharmacologic and nonpsychopharmacologic treatments. Our main questions are: What are the most used and best justified drug treatments? What are the most frequent side effects? And which other treatment options, such as ECT, are available? We discuss the main findings, present limitations, and we conclude by giving recommendations and presenting two algorithms.

A 4-year-old boy with macrocephaly (+3 SD) was evaluated with MRI, which showed a subdural hygroma secondary to rupture of a left temporal arachnoid cyst and triventricular enlargement. Two years later, we repeated imaging to explore the possibility of a third ventriculostomy. There was a flow void across the floor of the third ventricle (figure). By using 3D cardiac-gated dynamic imaging, we demonstrated that a spontaneous ventriculostomy had already occurred (video, [links.lww.com/WNL/B217][1]). Spontaneous third ventriculostomy is rare and can occur in children and adults with chronic hydrocephalus.1 [1]: http://links.lww.com/WNL/B217

Contains fulltext : 167701.pdf (Publisher’s version ) (Open Access) The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

ObjectivePathogenic variants in SCN1A can give rise to extremely variable disease severities that may be indistinguishable at their first presentation. We aim to find clinical features that can help predict the evolution of seizures into Dravet syndrome and clinical features that predict cognitive outcome in Dravet syndrome. We specifically investigate the role of contraindicated medication (CIM) as a possible modifier of cognitive decline.MethodsA cohort of 164 Dutch participants with SCN1A-related seizures was evaluated. Clinical data were collected from medical records and semistructured telephone interviews. Cognitive function was classified by a child neurologist, neuropsychologist, and clinical geneticist. Several clinical variables, including duration of CIM use in the first 5years of disease, were evaluated in univariate and multivariate analyses.ResultsA longer duration of CIM use in the first 5years after seizure onset was significantly associated with a worse cognitive outcome at time of inclusion, and with lower interpolated intelligence quotient/developmental quotient scores after the first 5years of disease in Dravet syndrome patients. CIM use remained a significant predictor for cognitive outcome in a multivariate regression model, as did age at the first observation of developmental delay and age at first afebrile seizure. Age at first afebrile seizure was the most accurate predictor for evolution of seizures into Dravet syndrome for the complete cohort.SignificanceOur data suggest that a longer CIM use in the first 5years of disease can have negative effects on cognitive outcome in Dravet syndrome. An early diagnosis is essential to avoid these drugs. Furthermore, we identified age at first afebrile seizure as an important predictor for evolution of seizures into Dravet syndrome and for the severity of Dravet syndrome, which can be used to counsel parents of young patients with SCN1A-related seizures.

Objective: Antiglutamate decarboxylase (anti-GAD) antibodies are associated with several neurological manifestations, like epilepsy and movement disorders. However, in daily neurological practice, it remains hard to define when to test for anti-GAD antibodies in patients with neurologic and/or psychiatric symptoms. Therefore, here, we report the patient characteristics of a large retrospective cohort of patients tested for anti-GAD antibodies in clinical practice and compare the characteristics of anti-GAD positive and anti-GAD negative patients.Methods: We blindly assessed relevant clinical symptoms and comorbidities and functional outcome with the modified Rankin Scale (mRS) in a retrospective observational cohort of all patients in which the decision to assess anti-GAD levels had been made based solely on the presence of possible associated neurological and/or psychiatric symptoms (N = 119).Results: Out of 119 patients, 17 (143%) were anti-GAD positive. The anti-GAD positive patients had a median age of 30 years (range: 3-64; 2 children). They all had epilepsy, with 8 (47%) patients reporting cognitive complaints. Psychiatric symptoms were less prevalent in anti-GAD positive patients, only 1 anti-GAD positive patient (6%) versus 34 anti-GAD negative patients (33%) reported psychiatric symptoms (p = 0.021). The most frequent comorbidity of anti-GAD positive patients was diabetes mellitus type 1 (n = 8). Twelve (71%) and 13 (78%) of the anti-GAD positive patients were functionally independent at the time of diagnosis and after one year, respectively (mRS score: 0 to 2). There was no significant difference in functional status at any time during follow-up compared with the anti-GAD negative group.Conclusion: Antiglutamate decarboxylase (anti-GAD) antibodies relate to epilepsy with or without cognitive complaints. However, psychiatric symptoms were almost absent in anti-GAD positive patients, and the presence of anti-GAD antibodies contributed little to the prognosis in our cohort. (C) 2018 Elsevier Inc. All rights reserved.

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation. Electronic supplementary material The online version of this article (doi:10.1007/s13311-015-0372-8) contains supplementary material, which is available to authorized users.

Objective:To study the effect of vaccination-associated seizure onset on disease course and estimate the risk of subsequent seizures after infant pertussis combination and measles, mumps, and rubella (MMR) vaccinations in Dravet syndrome (DS).Methods:We retrospectively analyzed data from hospital medical files, child health clinics, and the vaccination register for children with DS and pathogenic SCN1A mutations. Seizures within 24 hours after infant whole-cell, acellular, or nonpertussis combination vaccination or within 5 to 12 days after MMR vaccination were defined as "vaccination-associated." Risks of vaccination-associated seizures for the different vaccines were analyzed in univariable and in multivariable logistic regression for pertussis combination vaccines and by a self-controlled case series analysis using parental seizure registries for MMR vaccines. Disease courses of children with and without vaccination-associated seizure onset were compared.Results:Children who had DS (n = 77) with and without vaccination-associated seizure onset (21% and 79%, respectively) differed in age at first seizure (median 3.7 vs 6.1 months, p Conclusions:Our results suggest that vaccination-associated earlier seizure onset does not alter disease course in DS, while the risk of subsequent vaccination-associated seizures is probably vaccine-specific.

Glucose transporter protein 1 (GLUT1) is the principal glucose transporter of the blood–brain barrier. In GLUT1 deficiency syndrome (GLUT1DS), glucose transport into the brain is disturbed, which leads to the clinical symptomatology as well as characteristic (and diagnostic) abnormalities in cerebrospinal fluid.1 In approximately 90% of patients with GLUT1DS, heterozygous mutations in the SLC2A1 gene, encoding the GLUT1 protein, can be demonstrated.1 So far, this is the only gene known to be associated with this condition. The classic phenotype of GLUT1DS includes microcephaly, mild to severe developmental delay, infantile-onset drug-resistant epilepsy, and movement disorders, including spasticity, ataxia and dystonia.1 Recognising GLUT1DS is crucial because it can be treated with the ketogenic diet, as ketone bodies serve as alternative energy source for the brain.1 In the past decade, the range of clinical syndromes associated with GLUT1DS has expanded tremendously. Various paroxysmal or episodic disorders have now been described in patients with GLUT1DS, including several seizure types, paroxysmal lethargy, autonomic attacks with sweating and yawning, hemiplegic migraine and eye movement disorders. Moreover, many different movement disorders, including ataxia and intention tremor, dystonia, chorea, spasticity, myoclonus and nocturnal painful muscle cramps in the legs, are a recognised part of the clinical spectrum and included in the phenotype of many individual patients.1 2 These movement disorders can be continuous, paroxysmal or …

Item does not contain fulltext Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Objective: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome.Methods: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course.Results: Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (similar to 20%) R201C variant had arisen by postzygotic mosaicism.Significance: Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches.

Item does not contain fulltext KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.

Contains fulltext : 137474.pdf (Publisher’s version ) (Closed access) Alpha-fetoprotein (AFP) is present in fetal serum in concentrations up to 5,000,000 mug/l. After birth, AFP gene expression is turned down with a subsequent fall of the serum concentrations of this albumin-like protein to 'adult values' of circa 0.5-15 mug/l from the age of 2 years onwards. Irrespective of its assumed important functions, individuals with AFP deficiency appear fully healthy. The other way around, the presence of AFP in the circulation after the first years of life doesn't seem to harm, since individuals with 'hereditary persistence of AFP' are also without clinical abnormalities. During pregnancy, AFP (in maternal serum) has long been recognized as a marker for congenital anomalies of the fetus. Equally well known is AFP as biomarker for hepatocellular carcinoma and some other malignancies. There are at least four neurodegenerative disorders, all inherited as autosomal recessive traits and characterized by the presence of cerebellar ataxia, abnormal ocular movements, and neuropathy, for which an elevated concentration of serum AFP is an important diagnostic biomarker. The availability of a reliable biomarker is not only important during screening or diagnostic processes, but is also relevant for objective follow-up during (future) therapeutic interventions.

Purpose: Differentiating between Dravet syndrome and non-Dravet SCN1A-related phenotypes is important for prognosis regarding epilepsy severity, cognitive development, and comorbidities. When a child is diagnosed with genetic epilepsy with febrile seizures plus (GEFS+) or febrile seizures (FS), accurate prognostic information is essential as well, but detailed information on seizure course, seizure freedom, medication use, and comorbidities is lacking for this milder patient group. In this cross-sectional study, we explore disease characteristics in milder SCNTA-related phenotypes and the nature, occurrence, and relationships of SCN1A-related comorbidities in both patients with Dravet and non-Dravet syndromes.Methods: A cohort of 164 Dutch participants with SCN1A-related seizures was evaluated, consisting of 116 patients with Dravet syndrome and 48 patients with either GEFS+, febrile seizures plus (FS+), or FS. Clinical data were collected from medical records, semi-structured telephone interviews, and three questionnaires: the Functional Mobility Scale (FMS), the Pediatric Quality of Life Inventory (PedsQL) Measurement Model, and the Child or Adult Behavior Checklists (CBCL/ABCL).Results: Walking disabilities and severe behavioral problems affect 71% and 43% of patients with Dravet syndrome respectively and are almost never present in patients with non-Dravet syndromes. These comorbidities are strongly correlated to lower quality-of-life (QoL) scores. Less severe comorbidities occur in patients with non-Dravet syndromes: learning problems and psychological/behavioral problems are reported for 27% and 38% respectively. The average QoL score of the non-Dravet group was comparable with that of the general population. The majority of patients with non-Dravet syndromes becomes seizure-free after 10 years of age (85%).Conclusions: Severe behavioral problems and walking disabilities are common in patients with Dravet syndrome and should receive specific attention during clinical management. Although the epilepsy course of patients with non-Dravet syndromes is much more favorable, milder comorbidities frequently occur in this group as well. Our results may be of great value for clinical care and informing newly diagnosed patient and their parents about prognosis. (C) 2018 The Authors. Published by Elsevier Inc.

Purpose Accurate classification of epileptic seizures, epilepsies, and epilepsy syndromes is mandatory in both clinical practice and epilepsy research. In 2010, the International League Against Epilepsy (ILAE) proposed a new classification scheme. The aim of this study is to determine whether application of this new classification for epileptic seizures and epilepsies has improved interobserver agreement compared to the classification schemes used previously. Methods Three pediatric neurologists working in different university hospitals retrospectively classified seizures and epilepsies of 80 children (165 seizures) referred to the University Center Utrecht, based on anonymized data, according to the newly proposed (2010) as well as the old (1981/1989) ILAE classification schemes. We determined interobserver agreement of the application of both ILAE classifications with kappa statistics. Key Findings Interobserver agreement of the new classification for seizures and epilepsies is comparable to that of previous classifications. There is substantial agreement on the newly introduced etiologic axis. Significance Introduction of the new epilepsy classification has not substantially improved interobserver agreement. This study shows which items cause considerable interobserver disagreement and therefore need specification.

Purpose The purpose of this paper was to study the incidence and clinical significance of fever after intraventricular neuroendoscopic procedures in children. Methods We retrospectively assessed all children subjected to an intraventricular neuroendoscopic procedure between 2004 and 2015. Body temperature 6 days postoperatively, symptoms and signs, and eventual cerebrospinal fluid analysis were evaluated. Fever was defined as temperature above 38 °C. Results Fifty-five children (mean age 4.8 years) had 67 procedures. Forty-three children (47 procedures, 70 %) developed fever, mostly the day of surgery (n = 17; 25 %) or the next day (n = 33; 49 %). All children who were clinically ill (n = 9, including 7 with fever) suffered serious illness, as opposed to none of the children with fever without being clinically ill (n = 36). Fever was unrelated to gender, indication for, and type of procedure and did not influence ETV success rate at 3 months. Children under 1 year less frequently developed fever (p = 0.032). Conclusions Fever frequently develops after intraventricular neuroendoscopic procedures in children and follows a rather predictable course, peaking the day of surgery and/or the next day, and rapidly subsiding thereafter. Fever is not a cardinal symptom except when combined with other symptoms in children who are clinically ill (which most of them are not). Close observation avoiding invasive diagnostic tests may suffice for those who are not clinically ill, while extra attention should be paid to those whose temperature rises after day 2 especially when clinically ill, as they likely suffer serious illness. We recommend to closely observe children after any intraventricular neuroendoscopic procedure for at least 5 days.

Purpose PCDH19 mutations cause epilepsy and mental retardation limited to females (EFMR) or Dravet-like syndromes. Especially in the first years of life, epilepsy is known to be highly pharmacoresistant. The aim of our study was to evaluate the effectiveness of antiepileptic therapy in patients with PCDH19 mutations. Methods We report a retrospective multicenter study of antiepileptic therapy in 58 female patients with PCDH19 mutations and epilepsy aged 2–27 years (mean age 10.6 years). Results The most effective drugs after 3 months were clobazam and bromide, with a responder rate of 68% and 67%, respectively, where response was defined as seizure reduction of at least 50%. Defining long-term response as the proportion of responders after 12 months of treatment with a given drug in relation to the number of patients treated for at least 3 months, the most effective drugs after 12 months were again bromide and clobazam, with a long-term response of 50% and 43%, respectively. Seventy-four percent of the patients became seizure-free for at least 3 months, 47% for at least one year. Significance The most effective drugs in patients with PCDH19 mutations were bromide and clobazam. Although epilepsy in PCDH19 mutations is often pharmacoresistant, three quarters of the patients became seizure-free for at least for 3 months and half of them for at least one year. However, assessing the effectiveness of the drugs is difficult because a possible age-dependent spontaneous seizure remission must be considered.

Summary Purpose: Educational difficulties or even severe cognitive deterioration is seen in many childhood epilepsy syndromes. Many of those cognitive deficits are related directly to the brain disorder underlying the epilepsy syndrome. However, in other types of epilepsy, the epileptic seizures and/or epileptiform activity can be the dominant factor. This is especially unknown for the more “subtle” short nonconvulsive seizure types. For this reason, we analyzed a new cohort of children. Methods: A cross-sectional study of 188 children with epilepsy. Electroencephalography (EEG)–video recordings and cognitive testing were performed simultaneously. The results of children with short nonconvulsive seizures during a 2-h testing session were compared with all children with epilepsy without seizures during the 2-h cognitive testing session and with controls without epilepsy. In a second analysis the cognitive effects of frequency of epileptiform EEG discharges were analyzed. Key Findings: The cognitive effects of short nonconvulsive seizures were large, ranging from 0.5 to 1 standard deviation and concerned global cognitive function, speed of central information processing, and memory function. In children without seizures during cognitive testing, the occurrence of frequent epileptiform discharges showed more subtle effects. These effects were independent from the occurrence of short nonconvulsive seizures. Significance: We concluded that although the effect is less pronounced in number of areas involved and magnitude, the type of association between frequent epileptiform activity (>1% of the time) and cognitive function in children with epilepsy is comparable to the association between short nonconvulsive seizures and cognitive function.

Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14-16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3-1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considered.

Delirium in children is a serious but understudied neuropsychiatric disorder. So there is little to guide the clinician in terms of identifying those at risk.To study, in a pediatric intensive care unit (PICU), the predictive power of widely used generic pediatric mortality scoring systems in relation to the occurrence of pediatric delirium (PD).Four-year prospective observational study, 2002-2005. Predictors used were the Pediatric Index of Mortality (PIM) and Pediatric Risk of Mortality (PRISM II).A tertiary 8-bed PICU in The Netherlands.877 critically ill children who were acutely, nonelectively, and consecutively admitted.Pediatric delirium.Out of 877 children with mean age 4.4 yrs, 40 were diagnosed with PD (Cumulative incidence: 4.5%), 85% of whom (versus 40% with nondelirium) were mechanically ventilated. The area under the curve was 0.74 for PRISM II and 0.71 for the PIM, with optimal cut-off points at the 60th centile (PRISM: sensitivity: 76%; specificity: 62%; PIM: sensitivity: 82%; specificity: 62%). A PRISM II or PIM score above the 60th centile was strongly associated with later PD in terms of relative risk (PRISM II: risk ratio = 4.9; 95% confidence interval: 2.3-10.1; PIM: RR = 6.7; 95% confidence interval: 3.0-15.0). Given the low incidence of PD, values for positive predictive value were lower (PRISM II: 8.3%; PIM: 8.9%, rising to, respectively, 10.1% and 10.6% in mechanically ventilated patients) and values for negative predictive value were higher (PRISM II: 98.3%; PIM: 98.7%).Given the relatively low incidence of delirium, a low detection rate biased toward the most severe cases cannot be excluded.Given the fact that PIM and PRISM II are widely used mortality scoring instruments, prospective associations with PD suggest additional value for ruling in, or out, patients at risk of PD.

SummaryWe describe four children with Dravet syndrome treated with the combination of valproic acid (VPA) and topiramate (TPM) who developed transient liver toxicity. The time-interval between fever, administration of acetaminophen, epileptic status and liver enzyme disturbances in our four cases suggests that accumulation of toxic acetaminophen-metabolites is possibly responsible for liver toxicity. If acetaminophen and its metabolites cause those liver problems in children treated with the combination of VPA and TPM, the advice to use acetaminophen for treating fever in children using this combination, should be changed. Only future clinical observations and research can solve this clinical dilemma.

Summary Purpose: Learning and behavioral difficulties often occur in benign childhood epilepsy with centrotemporal spikes (BCECTS). In recent years, several electroencephalogram (EEG) characteristics have been related to the occurrence of learning and behavioral problems. Methods: From 28 children medical, school and psychological reports were present and children were rated according to a 4-point scale for educational and behavioral impairment (Part 1). Thirty 24-h EEG recordings were reanalyzed for spike frequency, the presence of atypical EEG criteria, and the presence of a nondipole spike. EEGs were scored during wakefulness, first hour of sleep and whole night sleep (minus the first hour of sleep) separately (Part 2). Results: The presence of I: an intermittent slow-wave focus during wakefulness, II: a high number of spikes in the first hour of sleep (and during whole night sleep), and III: multiple asynchronous bilateral spike-wave foci in the first hour of sleep correlates significantly with a sum score ≥ 3 which indicates a complicated course with educational or behavioral impairment. It is sufficient to analyze an EEG during wakefulness and a sleep EEG for only the first hour of sleep instead of a whole night recording to demonstrate those EEG criteria. Conclusions: On basis of our reanalysis we can possibly conclude that the aforementioned EEG characteristics correlate with educational impairments, and that analysing an EEG recording during wake and the first hour of sleep is sufficient to look adequately for those EEG criteria in children with BCECTS.

Item does not contain fulltext BACKGROUND: Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels. METHODS: The functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype-phenotype correlations of these and other cases were related to the functional analyses. RESULTS: The first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel. CONCLUSIONS: Comparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing. 01 mei 2015

This review addresses the effects of subclinical localized epileptiform discharges during sleep in children with benign childhood epilepsy with centrotemporal spikes (BCECTS) on cognition and behavior. A diversity of educational deficits, behavioral impairments, language delay, and neuropsychological test results have been reported in children with BCECTS. The occurrence of atypical seizure characteristics seems to be related to language delay, and several atypical EEG characteristics are related to cognitive or behavioral problems. It remains to be shown whether treatment of nocturnal discharges in children with BCECTS is indicated to improve cognitive and behavioral problems.

Nat. Genet. 49, 223–237 (2017); published online 19 December 2016; corrected after print 20 April 2017 Following publication of this article, the authors were asked to remove a clinical image and some video footage of one of the affected individuals. Although consent was obtained, in keeping with their ethical consent framework, the authors allow for withdrawal of consent and are carrying out the wishes of the research subjects under their consent process.

In daily clinical practice, doctors are frequently confronted with the issue whether treatment is necessary when the patient is without (further) seizures, but nevertheless still shows interictal discharges on the EEG. Will these discharges influence cognition temporarily and in time correlated with the discharges or is there a longer-lasting or even cumulative impairment? Which children are most at risk and when? Based on available literature in this field and own research in patients with Benign Epilepsy with Centro-Temporal spikes (BECTS), an inventory has been made of all issues that has to be addressed to answer these crucial questions. Prospective studies in drug naive children with BECTS (with or without behavioral comorbidity) are highly recommended.

We report a 5-year-old girl who presented with fever, drooling, dysphagia, and anarthria. Moreover, voluntary facial movements were disturbed, but the emotional facial movements were completely normal. This clinical phenomenon is known as the anterior opercular syndrome. There was a positive polymerase chain reaction for herpes simplex in the cerebrospinal fluid. The diagnosis herpes simplex encephalitis was supported by both magnetic resonance images (MRI) as by electroencephalogram (EEG). Herpes simplex encephalitis is a rare, but severe, cause of the anterior opercular syndrome that demands treatment as soon as possible in order to prevent high morbidity or mortality. The phenomenon of autonomic-voluntary dissociation, associated with other clinical and radiologic findings related to an underlying neurologic disorder, alerts clinicians to the anterior opercular syndrome as a critical diagnostic observation with time-dependent therapeutic consequences.

An 11-month-old girl presented with episodic severe stridor from birth, often resulting in cyanosis. Her parents had noted recurrent unilateral ptosis. Later she developed spasms of her hands during exercise. Psychomotor development was normal. Neurologic examination showed generalized hypertonia. Cerebral MRI excluded a Chiari malformation. Laryngoscopy under general anesthesia showed no abnormalities. We observed retraction of one eye and ptosis, as shown on the video. The recognition of myotonia, confirmed by EMG, led to the diagnosis of a sodium channel myotonia,1 with severe neonatal episodic laryngospasms.2 A mutation in the SCN4A gene (c.3917G>A, p.Gly1306Glu) confirmed the diagnosis.2

Educational difficulties or even severe cognitive deterioration is seen in many childhood epilepsy syndromes. Many of those cognitive deficits are related directly to the brain disorder underlying the epilepsy syndrome. However, in other types of epilepsy, the epileptic seizures and/or epileptiform activity can be the dominant factor. This is especially unknown for the more "subtle" short nonconvulsive seizure types. For this reason, we analyzed a new cohort of children.A cross-sectional study of 188 children with epilepsy. Electroencephalography (EEG)-video recordings and cognitive testing were performed simultaneously. The results of children with short nonconvulsive seizures during a 2-h testing session were compared with all children with epilepsy without seizures during the 2-h cognitive testing session and with controls without epilepsy. In a second analysis the cognitive effects of frequency of epileptiform EEG discharges were analyzed.The cognitive effects of short nonconvulsive seizures were large, ranging from 0.5 to 1 standard deviation and concerned global cognitive function, speed of central information processing, and memory function. In children without seizures during cognitive testing, the occurrence of frequent epileptiform discharges showed more subtle effects. These effects were independent from the occurrence of short nonconvulsive seizures.We concluded that although the effect is less pronounced in number of areas involved and magnitude, the type of association between frequent epileptiform activity (1% of the time) and cognitive function in children with epilepsy is comparable to the association between short nonconvulsive seizures and cognitive function.

An association between impaired school performance and rolandic epilepsy is frequently reported. Language outcome, in particular, seems to be affected, although rolandic epilepsy originates from the motor-sensory cortex. In this study we tried to find a correlation between locomotion problems and language impairment.In this noncontrolled, open, clinical cohort study of 48 children with rolandic epilepsy, a 24-hour EEG and a neuropsychological assessment were obtained for all children.Children with rolandic epilepsy had a significant delay in reading skills (reading words: mean=6 months, SD=11.9, P0.002; reading sentences: mean=8.6 months, SD=12.7, P0.001), compared with the healthy population. There was a significant correlation between problems in motor development and delays in reading skills (reading words: r=-0.426, P=0.006; reading sentences: r=-0.343, P=0.03).Reading performance is impaired in children with rolandic epilepsy. Reading of sentences is more impaired than reading of words. There is a significant correlation between problems in motor development and language, suggesting their interaction at the level of the cortex.

Dear Sirs, Niemann–Pick disease type C (NP-C) is a rare autosomal recessive disorder with a wide clinical neuropsychiatric spectrum resulting from a disorder of intracellular cholesterol trafficking and synthesis caused by mutations in the NPC1 or NPC2 gene [1, 2]. We describe a 51-year-old man with a long disease course who showed a remarkable photomyogenic (photomyoclonic) response at photic flash stimulation during EEG recordings. Thirty years after the initial presentation of symptoms, the patient was referred for the evaluation of an early onset dementia, progressive behavioural disturbances, tremors, and gait disturbances. Until puberty a normal intelligence and psychomotor development were reported. After puberty he gradually deteriorated in daily functioning and intelligence, and at the age of 46 his IQ score was below 70. He increasingly presented action tremors, gait disturbances, falls, myoclonic jerks in the limbs and the body, and an increased startle response. He showed severe obsessive traits and a sexual preoccupation towards young girls and women for which he was transferred to a psychiatric hospital. Neurological examination revealed poor facial mimics with a staring gaze. Speech was dysarthric and he had an aphasia. There were myoclonic jerks which increased on motor action and startle. Motor exam showed a severe ataxia of the extremities and muscle tendon reflexes were increased, but not pathologic. Until that moment, laboratory tests, genetic counselling, and imaging studies never revealed a diagnosis. Brain MRI studies showed diffuse cerebral atrophy, most severely of the frontal and temporal lobes. Consecutive EEG recordings showed a background pattern of 8–9 Hz which slowed towards 7–8 Hz. These recordings increasingly showed repetitive runs of bilateral synchronous theta activity of 4–6 Hz frontotemporally, which lasted 1–3 s. Photic flash stimulation provoked a photomyogenic response (Fig. 1). Stimulation with repetitive flashes caused time-locked muscle artefacts at the rate of flashing with increasing amplitude on faster frequencies and a sudden ending on the cessation of flash stimulation. The muscle activation bursts started 48 ms after the flash and had a duration of approximately 150–200 ms. The posterior regions showed a normal photic driving response. NP-C was diagnosed when the accumulation of unesterified cholesterol by positive fibroblast Filipin staining and reduced LDL cholesterol esterification in fibroblasts was demonstrated. Fig. 1 EEG recording during 1 and 6 Hz photic flash stimulation. Rhythmic muscle activity appears in phase with the repetitive light flashes and ends at the moment photic flash stimulation is stopped At the age of 53 he succumbed from an aspiration pneumonia. Myoclonic contractions are not a typical feature of NP-C and a photomyogenic reaction has been described only once before in NP-C [3]. Two cases of cortical myoclonus and one case on a progressive cortical action myoclonus on motor activity have been described [4, 5]. The photomyogenic response results from stimulus time-locked rhythmic contractions of periocular and facial muscles in phase with the flash stimulus frequency which can extend to myoclonic jerking of the muscles of the upper body. It ceases directly after flash stimuli are stopped. It is considered to be a normal physiological response which can, however, expand under emotional circumstances or metabolic or toxic states. In our patient, EMG activity was mostly dominant in the posterior regions. Its physiological mechanism was originally thought to be of muscular origin. Myoclonus can have a cortical origin or it can be generated by the brain stem showing mechanisms similar to the blink reflex or in the reticular formation. A startle reflex induces a facial muscle reaction comparable to the blink reflex with a latency shorter than the latency we measured. Myoclonic responses generated by the reticular formation typically induce a motor reflex of the orbucularis oculi muscle 40 ms after the stimulus. These EMG bursts typically show a rostro-caudal recruitment starting with activiation of the cranial nerves-innervated muscles and traversing downwards to the muscles of the arms and legs [6–9]. We did not dispose of more extensive EMG recordings covering muscles of face, neck, and limbs, so we cannot be conclusive about the generator mechanism. However, EMG activity bursts in our patient were of a long duration of 150–200 ms. Moreover, the reticular reflex myoclonus is a response typically induced by touch, noise, tendon reflex, or muscle stretch. More recently, research findings suggest a cortical origin of the photomyogenic reaction, which, however, remains to be elucidated [9–11]. Myoclonic disorders have repeatedly been associated with cortical hyperexcitability [10, 12, 13]. Such a mechanism is, for instance, the case in the progressive myoclonic epilepsies. This is a progressive neurodegenerative disease characterized by seizures which can be provoked by stimuli and myoclonus of variable morphology. These patients show exaggerated evoked potentials after somatosensory and light stimuli as a result of cortical hyperexcitability. This may also occur in NP-C cases as described in this report. However, in our patient, evoked potential studies were not performed. Our patient did not have seizures, making the clinical state of our patient more consistent with a progressive myoclonic ataxia. In the literature the neurophysiological findings of NP-C are described in only a number of reports [2, 4, 5]. EEG features reported consist of unspecific diffuse slowing of background activity. Epilepsy is described sporadically [2]. The recognition of vertical gaze palsy by electro-oculography has been described [14]. Neurophysiologic investigations may help to better understand the pathophysiological mechanism of NP-C with respect to the nervous system, may help to reveal a diagnosis, and may help to evaluate the effects of treatment.