Xq25 microduplication involving exclusively STAG2 is a new distinctive cohesinopathy including mild to moderate intellectual disability, speech delay and facial dysmorphism. Seizures seem to be scarce, but detailed seizure type descriptions are missing. We report the case of an 8-year-old boy with mild intellectual disability and eyelid myoclonia with onset at age of 3 years, initially misinterpreted as tics. An ictal VIDEO-EEG documented eye closure elicited generalized 3 Hz spike-waves or polyspike-waves concomitant to eyelid myoclonia, sometimes associated to brief clinically observable absences. Intermittent photic stimulation revealed a photoparoxysmal response. Array CGH identified a 199 kb copy number gain in Xq25 including the whole STAG2 gene, inherited from his asymptomatic mother. To the best of our knowledge, this is the first case of STAG2 encephalopathy fulfilling all electroclinical criteria for epilepsy with eyelid myoclonia and absences (EMA), formally named Jeavons syndrome (JS). As for other Genetic Generalized Epilepsy syndromes, EMA/JS usually occurs in normally developing children. Intellectual disability of variable degree is occasionally reported. On the background of other genes responsible for Developmental and Epileptic Encephalopathies, linked to specific generalized seizure types or seizure combinations, we discuss the contribution of pathogenic variants in CHD2, SYNGAP1 and some other genes as, RORB, NEXMIF and KCNB1 to this peculiar EMA phenotype.

Objectives and Background: This study aims to review and contribute to electroclinical features of inverted duplication of proximal chromosome 15 (inv dup [15]) syndrome. Inv dup (15) syndrome results from the instability of chromosome region 15q11-q13 and is most frequently associated with autism spectrum disorders. Affected patients also typically present with developmental delay and intellectual disability, hypotonia, expressive, and comprehensive language disorders, movement disorders and epilepsy. All of these patients carry a supernumerary chromosome 15 marker resulting in tetrasomy 15q, a region that involves the critical for neurodevelopment genes: UBE3A and SNRPN. Although epilepsy is recognized as a major challenge in the management of inv dup (15) syndrome, electroclinical data are limited and heterogenic.

Purpose: Hyperinsulinism is a rare genetic disorder with a heterogeneous presentation. Its severity ranges from severe, life-threatening hypoglycemia in newborns to mildly symptomatic hypoglycemia beginning in childhood, adolescence, or adulthood. Hypoglycemic loss of consciousness and seizures are the most common presentations. Electroencephalography (EEG) patterns are not well known, and patients may be erroneously diagnosed with epilepsy. We tried to better characterize EEG datas in a cohort of patients with hyperinsulinism.

Objective: Mutations in QARS, encoding glutaminyl-tRNA synthetase, have been recently reported in 7 children with early-onset epileptic encephalopathy with intractable seizures and progressive microcephaly. We report on a 3.5-year-old girl with West syndrome due to QARS mutations. Methods: Genetic screening was performed using a 82-gene panel for Mendelian epilepsies. Results: The patient was born at term after an uneventful pregnancy. Birth parameters were normal: head circumference 33.5cm –(−0.5SD). There is no familial history of epilepsy. Epilepsy started at 5.5 months, following a viral infection, with partial seizures and infantile spasms associated with developmental regression, hypotonia, loss of eye contact and smiling. EEG showed modified hypsarythmia with multifocal spikes, predominant in the right temporal occipital area. Two partial seizures were recorded, staring with diffuse or left hemispheric fast activity, corresponding to motion arrest, followed by eye and head deviation to the right, consistent with left occipital temporal involvement of the discharge. Association of vigabatrin, hydrocortisone and ACTH led to spasm cessation. Persistent focal seizures were partially controlled with Valproate at 7 months of life. At 3.5 years of age, she had an average of 4 partial seizures per year. Head circumference was 46.7 cm (−2DS). She had moderate development delay. She could stand up, started walking with help, but had no language and displayed manual stereotypies. EEG showed normal background activity with some residual left-occipital or right-frontal temporal paroxysmal abnormalities during sleep. Brain MRI, normal at 6 months, showed moderate cerebellar and cerebral atrophia at 27 months. Array-CGH, screening of CDKL5 gene and extensive metabolic screening in blood, urine and CSF, were normal. Heterozygous compound mutations of QARS were identified (c.[1389-3C>A];[134G>T], p.[?];[Gly45Val]). Conclusion: This observation expands the phenotype associated to QARS mutations that can have onset out of the neonatal period, such as West syndrome.

Objective: Childhood Absence Epilepsy (CAE) is frequent and associated with neuropsychological impairments that are poorly referenced, especially for language. The aim was to highlight morphosyntactic impairment in CAE and to test whether rhythmic stimulation could alleviate these difficulties, as it has been shown in dyslexic, specific language impairment, deaf (with cochlear implant), and healthy children. Rhythmic primes could improve grammatical analysis by pre-orienting the temporal distribution of attention using the synchronization of cerebral oscillators. Methods: Twenty children with CAE and 20 age-matched controls were tested with two experiments. In Experiment 1, grammatical judgments had to be made on spoken sentences after listening to musical primes characterized either by salient regular rhythm or by no rhythmic regularity. In Experiment 2, grammatical judgments were made after regular musical primes or regular musical-visual ones. Furthermore, children with CAE underwent a neuropsychological examination (behavior, reasoning, morphosyntax, attention and reading) which provided a measure of priming efficiency based on their cognitive profile. Results: Results showed a morphosyntactic impairment in CAE children as compared to controls. The regular musical prime had a beneficial effect over the non-regular one for all controls and CAE children only with the following profile: no anxiety disorder (r=−.45, p<.04) and no reading impairment (r=.55, p<.01). The regular musical-visual prime had a beneficial effect for controls but a negative effect for CAE children (t(19)=2.06, p<.05). Conclusion: CAE children have a morphosyntactic impairment. However, the rehabilitation method used seems to have a limited impact in case of generalized cerebral invasion of slow waves (e.g. CAE), when it's been proven to work in other diseases. Based on our results in CAEs we are currently replicating the study in children with Rolandic Epilepsy, to investigate whether the success of this method depends upon the distribution and extent of the epileptic focus.

Objective: Cognitive impairments and emotional dysregulations are frequently encountered in children with all types of epilepsy. Retrospective studies highlight these difficulties but fail to determine their chronology of appearance which might be influenced by many factors (syndrome, seizure frequency, treatment…). Early detection of pre-existing or progressively developing deficits represent real challenges for global epilepsy-care programs. Methods: We developed a comprehensive approach for an early detection of behavioral and cognitive deficits in newly diagnosed epilepsies. During the first visit, children were received in a day hospital for a global evaluation including a sleep and awake EEG, somatic and neurological examination, an epilepsy nurse interview and a preliminary evaluation of behavior and social competences using the Child Behavior Checklist (CBCL, Achenbach, 1991). A first neuropsychological screening was conducted to assess attention abilities and executive functions using EpiTrack Junior (Helmstaedter, 2013). Depending on the results, a full neuropsychological evaluation can be scheduled. At the follow-up outpatient clinics, an epilepsy nurse interviewed the patient and his family using questionnaires on AEDs side effects and on “living with epilepsy”. A re-test with EpiTrack Junior is performed. Results: Preliminary results of the CBCL evaluation for idiopathic epilepsies (IE) – 36 children without epilepsy (NE); 37 children with IE (11 under AED treatment) – showed that at maximum 6 months from epilepsy onset, even benign forms of epilepsy score lower than NE in the Competences scale, assessing scholar, extrascholar and social skills (t(71)=2,01, p<.05), especially when under AEDs (t(45)=2,53, p<.02). Externalization scale showed that IE have more aggressive and delinquent behaviors as compared to NE (t(71)=2,16, p<.03) especially when under treatment (t(45)=2,55, p<.01). Conclusion: Our results underscore the need for an early multidisciplinary approach and detection of neuropsychological or behavioral deficits to engage appropriate reeducations.

Objective: Christianson syndrome (CS) is a syndromic form of X-linked severe ID associated to progressive microcephaly, ataxia, autistic behaviour, near absent speech and epilepsy in 90% of cases. The natural history of seizures and EEG abnormalities is insufficiently known. We report two additional families including patients with electrical status epilepticus in sleep (ESES) previously described in only two patients. Methods: We describe two unrelated families with CS caused by SLC9A6 mutations (one frameshift and one partial deletion), each including two boys. One family has been followed for over 20 years, providing insights into the natural course of epilepsy in this syndrome. Results: Onset of epilepsy occurred within the first two years of life in all patients. Seizures were of various types. First EEG recordings showed abnormal fast-background activity with poor antero-posterior organization as reported in the literature. In the two boys with a 20 year follow-up, epilepsy was drug-resistant during childhood, then became less active in early adolescence. EEG background rhythm slowed over time to 4–5Hz after the age of 8 years. One patient from the first family fulfilled the electrical criteria of ESES, between 6 and 8 years of age, while sleep-EEG had not been performed in his brother during this range of age. ESES was diagnosed in the older brother from the second family since the age of 4 years and 10 months. The four boys presented severe ID, autistic features with agitation limiting frequent sleep EEG recordings. Conclusion: Our observations and previous reports, suggest that ESES might be an underestimated feature in CS and may participate to the psychomotor degradation of the patients. Interestingly, SLC9A6 mutations underlie dysfunction in the sodium-hydrogen exchanger NHE6 implicated in plasticity of glutamatergic synapses. Sleep EEGs should be performed in these infants between 4 and 8 years of age.

Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole‐exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain magnetic resonance imaging (MRI), metabolic screening, array‐comparative genomic hybridization (CGH) and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in‐frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs.

Epilepsies have long remained refractory to gene identification due to several obstacles, including a highly variable inter- and intrafamilial expressivity of the phenotypes, a high frequency of phenocopies, and a huge genetic heterogeneity. Recent technological breakthroughs, such as array comparative genomic hybridization and next generation sequencing, have been leading, in the past few years, to the identification of an increasing number of genomic regions and genes in which mutations or copy-number variations cause various epileptic disorders, revealing an enormous diversity of pathophysiological mechanisms. The field that has undergone the most striking revolution is that of epileptic encephalopathies, for which most of causing genes have been discovered since the year 2012. Some examples are the continuous spike-and-waves during slow-wave sleep and Landau-Kleffner syndromes for which the recent discovery of the role of GRIN2A mutations has finally confirmed the genetic bases. These new technologies begin to be used for diagnostic applications, and the main challenge now resides in the interpretation of the huge mass of variants detected by these methods. The identification of causative mutations in epilepsies provides definitive confirmation of the clinical diagnosis, allows accurate genetic counselling, and sometimes permits the development of new appropriate and specific antiepileptic therapies. Future challenges include the identification of the genetic or environmental factors that modify the epileptic phenotypes caused by mutations in a given gene and the understanding of the role of somatic mutations in sporadic epilepsies.Les épilepsies sont longtemps restées en retrait par rapport au reste de la neurologie en ce qui concerne l'identification de facteurs génétiques pathogènes ou de prédisposition. Ce retard s'expliquait, en partie, par une grande variabilité inter- et intrafamiliale des phénotypes, une fréquence importante de phénocopies et une grande hétérogénéité génétique sous-jacente. Les développements technologiques récents, comme la CGH-array ou le séquençage haut débit, ont permis, ces dernières années, l'identification d'un nombre croissant de gènes dont les mutations ou les variations de nombre de copies sont responsables de différents syndromes épileptiques. Le domaine qui a connu les bouleversements les plus importants est celui des encéphalopathies épileptiques, jusqu'alors particulièrement réfractaires aux approches génétiques, et dont la grande majorité des gènes responsables a été identifiée depuis 2012. Un exemple particulièrement éloquent est celui des encéphalopathies avec pointe-ondes continues du sommeil et du syndrome de Landau-Kleffner, pour lesquels la récente identification de mutations du gène GRIN2A a définitivement confirmé l'implication de facteurs génétiques. Ces nouvelles technologies sont en cours de transfert diagnostique et l'enjeu majeur devient progressivement l'interprétation du grand volume de données qu'elles génèrent pour chaque patient. La caractérisation précise des mutations responsables d'une épilepsie est un élément de confirmation diagnostique, permettant un conseil génétique approprié. Elle peut également, dans certains cas, contribuer à la mise au point de nouveaux traitements adaptés et personnalisés. Les grandes questions qui demeurent encore non résolues sont la caractérisation des facteurs génétiques ou environnementaux modulant le phénotype lié aux mutations d'un gène donné, ainsi que le rôle joué par les mutations somatiques dans la survenue des épilepsies sporadiques.

Le diagnostic d’hépatite médicamenteuse peut être difficile et son incidence est sous-estimée. Il doit être évoqué de principe devant un tableau d’hépatite survenant dans les 3 mois après le début d’un traitement comprenant des médicaments potentiellement hépatotoxiques. En cas de maladie chronique du foie, il doit être envisagé en cas d’une aggravation inexpliquée du bilan hépatique. Évoquer le diagnostic d’hépatite toxique doit conduire à interrompre très rapidement l’administration de tout produit suspect. L’évolution est le plus souvent favorable après l’arrêt du traitement, mais des hépatites graves sont toujours possibles.The incidence of drug-induced liver injury is probably underestimated in children, and its diagnosis may be difficult to make. It must be suspected in cases of children presenting with hepatitis in the 3 months following initiation of a new treatment with hepatotoxic drugs. In children with chronic liver disease, it must be suspected when there is worsening of laboratory test results. As soon as a drug-induced liver injury is suspected, any suspect drug must be discontinued. The outcome is generally favourable, but severe hepatitis may sometimes occur.