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Objective: Complex epilepsies such as epileptic and developmental encephalopathies require multidisciplinary care throughout life. A coordinated transition program is therefore essential to provide optimal support for patients leaving pediatric for adult care. The aim of this study is to describe and evaluate our transition program for complex epilepsies, focusing on the last step in this program, that is, the multidisciplinary transition day hospital (MTDH)., Methods: We performed a retrospective observational study including patients with complex epilepsies who underwent the full steps of the transition program at Necker-Enfants Malades Hospital between May 2021 and June 2023, with a follow-up until February 2024. We described the cohort and detailed the interventions performed during the MTDH including medical, medicosocial, educational, daily life abilities, and laboratory and imaging assessments with the participation of one member of the adult team. We evaluated two indicators of our program: (1) the "adult first clinic attendance rate," defined by the percentage of patients attending their first adult clinic; and (2) the "return rate," defined by the percentage of patients who requested a pediatric encounter after their transfer., Results: Our cohort included 70 patients with a mean age of 19.1 years (interquartile range = 16.3-19.5). Eighty percent had an epilepsy syndrome diagnosis; 72.8% were treated with three or more antiseizure medications. All patients had their appointment at the adult clinic within 6 months of the day hospital, and only two families requested a pediatric encounter after the transfer., Significance: The transition program is key for an optimal transfer of patients with complex epilepsies to adult care. It requires a comprehensive multidisciplinary approach and provides a complete summary of the medical record. Our program secures a smooth landing in adult care and is a promising model to better manage the challenging transition process, especially in patients with complex epilepsy., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Purpose: Stroke-like episodes (SLEs) are defined as acute onset of neurological symptoms mimicking a stroke and radiological lesions non-congruent to vascular territory. We aimed to analyze the acute clinical and radiological features of SLEs to determine their pathophysiology., Methods: We performed a monocenter retrospective analysis of 120 SLEs in 60 children over a 20-year period. Inclusion criteria were compatible clinical symptoms and stroke-like lesions on brain magnetic resonance imaging (MRI; performed for all 120 events) with focal hyperintensity on diffusion-weighted imaging in a non-vascular territory., Results: Three groups were identified: children with mitochondrial diseases (n = 22) involving mitochondrial DNA mutations (55%) or nuclear DNA mutations (45%); those with other metabolic diseases or epilepsy disorders (n = 22); and those in whom no etiology was found despite extensive investigations (n = 16). Age at first SLE was younger in the group with metabolic or epilepsy disorders (18 months vs. 128 months; p < 0.0001) and an infectious trigger was more frequent (69% vs. 20%; p = 0.0001). Seizures occurred in 75% of episodes, revealing 50% episodes of SLEs and mainly leading to status epilepticus (90%). Of the 120 MRI scans confirming the diagnosis, 28 were performed within a short and strict 48-h period and were further analyzed to better understand the underlying mechanisms. The scans showed primary cortical hyperintensity (n = 28/28) with decreased apparent diffusion coefficient in 52% of cases. Systematic hyperperfusion was found on spin labeling sequences when available (n = 18/18)., Conclusion: Clinical and radiological results support the existence of a vicious circle based on two main mechanisms: energy deficit and neuronal hyperexcitability at the origin of SLE., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: γ-Aminobutyric acid (GABA) A -receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABA A -receptor-related disorders as a whole and seek possible genotype-phenotype correlations., Methods: We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABA A -receptor subunit variants (GABRA1, GABRB2, GABRB3, and GABRG2) through a national French collaboration using the EPIGENE network and compared these data to the one already described in the literature., Results: We gathered the reported patients in three epileptic phenotypes: 15 patients with fever-related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABA A -receptor subunit gene, whereas N-terminal variants seemed to be related to milder phenotypes., Significance: GABA A -receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes described here was associated with a specific phenotype. On the other hand, it appears that the location of the variant on the protein may be a marker of severity. Variant location may have important weight in the development of targeted therapeutics., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In the last few years, with the advent of next generation sequencing (NGS), our knowledge of genes associated with monogenic epilepsies has significantly improved. NGS is also a powerful diagnostic tool for patients with epilepsy, through gene panels, exomes and genomes. This has improved diagnostic yield, reducing the time between the first seizure and a definitive molecular diagnosis. However, these developments have also increased the complexity of data interpretation, due to the large number of variants identified in a given patient and due to the phenotypic variability associated with many of the epilepsy-related genes. In this paper, we present examples of variant classification in "real life" clinic situations. We emphasize the importance of accurate phenotyping of the epilepsies including recognising variable/milder phenotypes and expansion of previously described phenotypes. There are some important issues specific to rare epilepsies - mosaicism and reduced penetrance - which affect genetic counselling. These challenges may be overcome through multidisciplinary meetings including epileptologists, pediatric neurologists, and clinical and molecular geneticists, in which every specialist learns from the others in a process which leads to for rapid and accurate diagnosis. This is an important milestone to achieve as targeted therapiesbased on the functional effects of pathogenic variants become available., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

De novo missense variants in KCNH1 encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap between these two syndromes suggests that they belong to a spectrum of KCNH1 -related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (present in 20/23 reported cases).We report a series of seven patients with ID and de novo pathogenic KCNH1 variants identified by whole-exome sequencing or an epilepsy gene panel in whom the diagnosis of TBS/ZLS had not been first considered. Four of these variants, p.(Thr294Met), p.(Ala492Asp), p.(Thr493Asn) and p.(Gly496Arg), were located in the transmembrane domains S3 and S6 of Kv10.1 and one, p.(Arg693Gln), in its C-terminal cyclic nucleotide-binding homology domain (CNBHD). Clinical reappraisal by the referring clinical geneticists confirmed the absence of the distinctive gingival and nail features of TBS/ZLS.Our study expands the phenotypical spectrum of KCNH1 -related encephalopathies to individuals with an attenuated extraneurological phenotype preventing a clinical diagnosis of TBS or ZLS. This subtype may be related to recurrent substitutions of the Gly496, suggesting a genotype-phenotype correlation and, possibly, to variants in the CNBHD domain., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The EPIGENE network was created in 2014 by four multidisciplinary teams composed of geneticists, pediatric neurologists and neurologists specialized in epileptology and neurophysiology. The ambition of the network was to harmonize and improve the diagnostic strategy of Mendelian epileptic disorders using next-generation sequencing, in France. Over the years, five additional centers have joined EPIGENE and the network has been working in close collaboration, since 2018, with the French reference center for rare epilepsies (CRéER)., Results: Since 2014, biannual meetings have led to the design of four successive versions of a monogenic epilepsy gene panel (PAGEM), increasing from 68 to 144 genes. A total of 4035 index cases with epileptic disorders have been analyzed with a diagnostic yield of 31% (n = 1265/4035). The top 10 genes, SCN1A, KCNQ2, STXBP1, SCN2A, SCN8A, PRRT2, PCDH19, KCNT1, SYNGAP1, and GRIN2A, account for one-sixth of patients and half of the diagnoses provided by the PAGEM., Conclusion: These results suggest that a gene-panel approach is an efficient first-tier test for the genetic diagnosis of Mendelian epileptic disorders. In a near future, French patients with "drug-resistant epilepsies with seizure-onset in the first two-years of life" can benefit from whole-genome sequencing (WGS), as a second line genetic screening with the implementation of the 2025 French Genomic Medicine Plan. The EPIGENE network has also promoted scientific collaborations on genetic epilepsies within CRéER., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Aim: KCNB1 encephalopathy encompasses a broad phenotypic spectrum associating intellectual disability, behavioral disturbances, and epilepsies of various severity. Using standardized parental questionnaires, we aimed to capture the heterogeneity of the adaptive and behavioral features in a series of patients with KCNB1 pathogenic variants., Methods: We included 25 patients with a KCNB1 encephalopathy, aged from 3.2 to 34.1 years (median = 10 years). Adaptive functioning was assessed in all patients using the French version of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) questionnaire. We screened global behavior with the Childhood Behavioral Check-List (CBCL, Achenbach) and autism spectrum disorder (ASD) with the Social Communication Questionnaire (SCQ). We used a cluster analysis to identify subgroups of adaptive profiles., Results: VABS-II questionnaire showed pathological adaptive behavior in all participants with a severity of adaptive deficiency ranging from mild in 8/20 to severe in 7/20. Eight out of 16 were at risk of Attention Problems at the CBCL and 13/18 were at risk of autism spectrum disorder (ASD). The adaptive behavior composite score significantly decreased with age (Spearman's Rho=-0.72, p<0.001) but not the equivalent ages, suggesting stagnation and slowing but no regression over time. The clustering analysis identified two subgroups of patients, one showing more severe adaptive behavior. The severity of the epilepsy phenotype predicted the severity of the behavioral profile with a sensitivity of 70% and a specificity of 90.9%., Conclusion: This study confirms the deleterious consequences of early-onset epilepsy in addition to the impact of the gene dysfunction in patients with KCNB1 encephalopathy. ASD and attention disorders are frequent. Parental questionnaires should be considered as useful tools for early screening and care adaptation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Channelopathies caused by mutations in genes encoding ion channels generally produce a clear change in channel function. Accordingly, mutations in KCNC1 , which encodes the voltage-dependent Kv3.1 potassium channel, result in progressive myoclonus epilepsy as well as other developmental and epileptic encephalopathies, and these have been shown to reduce or fully abolish current amplitude. One exception to this is the mutation A513V Kv3.1b, located in the cytoplasmic C-terminal domain of the channel protein. This de novo variant was detected in a patient with epilepsy of infancy with focal migrating seizures (EIFMS), but no difference could be detected between A513V Kv3.1 current and that of wild-type Kv3.1. Using both biochemical and electrophysiological approaches, we have now confirmed that this variant produces functional channels but find that the A513V mutation renders the channel completely insensitive to regulation by phosphorylation at S503, a nearby regulatory site in the C-terminus. In this respect, the mutation resembles those in another channel, KCNT1, which are the major cause of EIFMS. Because the amplitude of Kv3.1 current is constantly adjusted by phosphorylation in vivo, our findings suggest that loss of such regulation contributes to EIFMS phenotype and emphasize the role of channel modulation for normal neuronal function. NEW & NOTEWORTHY Ion channel mutations that cause serious human diseases generally alter the biophysical properties or expression of the channel. We describe a de novo mutation in the Kv3.1 potassium channel that causes severe intellectual disability with early-onset epilepsy. The properties of this channel appear identical to those of wild-type channels, but the mutation prevents phosphorylation of the channel by protein kinase C. Our findings emphasize the role of channel modulation in normal brain function.

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy., Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature., Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants., Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis., (© 2020 International League Against Epilepsy.)

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel K v 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of K v 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms., (© 2019 Wiley Periodicals, Inc.)

Disease-causing mutations in ion channels generally alter intrinsic gating properties such as activation, inactivation, and voltage dependence. We examined nine different mutations of the KCNT1 (Slack) Na(+)-activated K(+) channel that give rise to three distinct forms of epilepsy. All produced many-fold increases in current amplitude compared to the wild-type channel. This could not be accounted for by increases in the intrinsic open probability of individual channels. Rather, greatly increased opening was a consequence of cooperative interactions between multiple channels in a patch. The degree of cooperative gating was much greater for all of the mutant channels than for the wild-type channel, and could explain increases in current even in a mutant with reduced unitary conductance. We also found that the same mutation gave rise to different forms of epilepsy in different individuals. Our findings indicate that a major consequence of these mutations is to alter channel-channel interactions., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders., (© The Author 2014. Published by Oxford University Press.)

Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709C>T [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(∗)] and c.6232G>T [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Dravet syndrome (DS) is currently considered as an epileptic encephalopathy, a condition in which epilepsy causes deterioration or developmental delay but preliminary data suggested that cognitive course may worsen independently from epilepsy. Our objective was to prospectively analyze the neuropsychological features in a large cohort of DS patients and its relationships with epilepsy and SCN1A mutation., Methods: 81 examinations were performed in 67 patients with typical DS (9m-24y, 15 longitudinally studied) using Brunet-Lezine (developmental/intelligence quotient [DQ/IQ] and DQ sub-scores), Achenbach, Conners, and a semi-quantitative psychomotor score (SQPS). We studied the correlation between DQ/IQ/SQPS and age, epilepsy characteristics, and whether patients presented SCN1A mutation., Results: DQ/IQ significantly decreased with age (r = -.53, p < .001), from normal before 2y (mean 80, range 64-105) to low after 3y (mean 48, range 30-69), with hyperactivity and attention disorders hampering learning abilities especially up to 6y. However, raw (not age-adjusted) DQ sub-scores increased with age during the first decade, showing that there is no regression. We did not find any significant correlation between DQ/IQ at last evaluation and epilepsy data, i.e. first seizure (age, type, duration, fever), seizures during the course (type, fever sensitivity), status epilepticus (age of onset, number, fever), photosensitivity, and treatment, except for myoclonus and focal seizures which were associated with a lower QD/IQ after 3y. SCN1A mutated patients (n = 58) seemed to exhibit worse psychomotor course than non-mutated ones (n = 9) (severe SQPS in 26% vs 0%), although their epilepsy tended to be less severe (tonic seizures in 12% vs 44% [p = 0.04], first status epilepticus before 6 m in 26% vs 67% [p = .02], mean number of SE 2.5 vs 4.5 [p = .09]). DQ sub-scores were dissociated throughout the whole course: from onset hand-eye coordination was significantly lower than language, posture and sociability (p < .01). Dissociation seemed to be more frequent in mutated than in non-mutated patients (motor SQPS was normal for in 77% vs 44% [p = 0.017] whereas language SQPS was normal for 47% vs 100%)., Conclusions: Although psychomotor/cognitive delay declines with age, there is no regression. In addition, encephalopathy is not a pure consequence of epilepsy but SCN1A mutation seems to play an additional, direct role.

The occurrence of epilepsy in autism is variable; nevertheless, EEG paroxysmal abnormalities (PA) are frequently recorded in patients with autism, although the influence of epilepsy and/or EEG PA on the autistic regression has not been clarified yet. We examine a large sample of 345 inpatients with autism, divided into three groups: (1) patients without epilepsy and EEG PA; (2) patients with EEG PA but no seizures; (3) patients with epilepsy including febrile convulsions. The prevalence of epilepsy (24.9%) and EEG PA (45.5%) was higher than that reported in the general population. The significant differences among the three groups concerned autistic regression (comparison between groups 1 and 2, p<0.05; comparison between groups 1 and 3, p<0.01), cerebral lesions (comparison between groups 1 and 2, p<0.05; between groups 1 and 3, p<0.001), and symptomatic autism (comparison between groups 1 and 2 as much as comparison between groups 1 and 3, p<0.001), which were prevalent in groups 2 and 3; while severe/profound mental retardation was more frequent in group 3 compared to group 1 (p<0.01). Focal epilepsy (43.0%) and febrile convulsions (33.7%) were frequent in the third group with epilepsy. EEG PA were mainly localized in temporal and central areas (31.4%). Only 2.6% of patients had subcontinuous/continuous EEG PA during sleep. Seizures and EEG PA were not related to autistic regression. EEG PA occurred mainly in childhood, while epilepsy tended to occur (p<0.001) as age increased. The age at onset of seizures had two peaks: between 0 and 5 and between 10 and 15 years with no difference between idiopathic and symptomatic cases. In 58.5% of subjects aged > or = 20 years, epilepsy including febrile seizures occurred at some point of their lives, while cases with only EEG PA were less frequent (9.7%). The relationship among autism, EEG PA and epilepsy should be clarified and investigated. In autism, seizures and EEG PA could represent an epiphenomenon of a cerebral dysfunction independent of apparent lesions., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Abstract: STXBP1 (MUNC18.1), encoding syntaxin binding protein 1, has been reported in Ohtahara syndrome, a rare epileptic encephalopathy with suppression burst pattern on EEG, in patients with infantile spasms and in a few patients with nonsyndromic mental retardation without epilepsy. We report a patient who presented late onset infantile spasms. Epilepsy was controlled but the patient developed severe mental delay. A first diagnosis of mitochondrial disease was based on clinical presentation and on a partial deficit of respiratory chain complex IV, but molecular screening for mitochondrial genes was negative. The sequencing of STXBP1 gene found a de novo nonsense mutation (c.585C>G/p.Tyr195X). This observation widens the clinical spectrum linked to STXBP1 mutations with the description of a patient with late onset infantile spasms. It raises the question of the value of epilepsy genes screening in patients with uncertain, partial or unconfirmed mitochondrial dysfunction. [Copyright &y& Elsevier]