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The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel.Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood.Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown significance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected.Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the detected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients.Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dravet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mientras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases moleculares de las EED en población latino americana.

Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid,and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.El síndrome de deficiencia del transportador de glucosa tipo 1 es una enfermedad de causa genética, que involucra el gen SLC2A1. En general, se presenta durante los primeros años de vida con retraso en la adquisición de pautas madurativas, epilepsia farmacorresistente y desórdenes del movimiento. La clínica y la disminución de glucosa en líquido cefalorraquídeo permiten sospechar el diagnóstico, el cual debe ser confirmado mediante el estudio molecular del gen SLC2A1. Debido a que se trata de una enfermedad poco frecuente y de expresión clínica variable, el diagnóstico precoz suele representar un desafío para los equipos de salud. Este es importante, ya que la implementación de la terapia cetogénica logra controlar las manifestaciones clínicas y mejora el pronóstico a largo plazo. Presentamos una revisión sobre el déficit del transportador de glucosa tipo 1, que abarca sus características clínicas, bioquímicas, moleculares y terapéuticas.

Epilepsy with eyelid myoclonia (EEM) has been associated with marked clinical heterogeneity. Early epilepsy onset has been recently linked to lower chances of achieving sustained remission and to a less favorable neuropsychiatric outcome. However, much work is still needed to better delineate this epilepsy syndrome.In this multicenter retrospective cohort study, we included 267 EEM patients from 9 countries. Data about electroclinical and demographic features, intellectual functioning, migraine with or without aura, family history of epilepsy and epilepsy syndromes in relatives were collected in each patient. The impact of age at epilepsy onset (AEO) on EEM clinical features was investigated, along with the distinctive clinical characteristics of patients showing sporadic myoclonia over body regions other than eyelids (body-MYO).Kernel density estimation revealed a trimodal distribution of AEO and Fisher-Jenks optimization disclosed three EEM subgroups: early-onset (EO-EEM), intermediate-onset (IO-EEM) and late-onset subgroup (LO-EEM). EO-EEM was associated with the highest rate of intellectual disability, antiseizure medication refractoriness and psychiatric comorbidities and with the lowest rate of family history of epilepsy. LO-EEM was associated with the highest proportion of body-MYO and generalized tonic-clonic seizures (GTCS), whereas IO-EEM had the lowest observed rate of additional findings. A family history of EEM was significantly more frequent in IO-EEM and LO-EEM compared with EO-EEM. In the subset of patients with body-MYO (58/267), we observed a significantly higher rate of migraine and GTCS but no relevant differences in other electroclinical features and seizure outcome.Based on AEO, we identified consistent EEM subtypes characterized by distinct electroclinical and familial features. Our observations shed new light on the spectrum of clinical features of this generalized epilepsy syndrome and may help clinicians towards a more accurate classification and prognostic profiling of EEM patients.

We retrospectively analyzed the electroclinical features, treatment, and outcome of patients with Panayiotopoulos syndrome (PS) who presented with unusual clinical manifestations.A retrospective, descriptive, multicenter study was conducted evaluating 44 patients with PS who had seizures with an unusual semiology. Data from patients with PS seen at eight Argentine centers between April 2000 and April 2019 were collected.Twelve patients (29.2%) had ictal syncope or syncope-like epileptic seizures. Three children (7.3%) had recurrent episodes of vomiting. Four patients (9.7%) presented with urinary incontinence associated with autonomic signs and consciousness impairment. One child had hiccups with autonomic manifestations followed by eye deviation. One boy had episodes of laughter with autonomic symptoms followed by loss of consciousness. Six patients (14.6%) had hyperthermia without acute febrile illness with autonomic symptoms as the first manifestation. Six others (14.6%) had focal motor seizures characterized by eye and head deviation in four and eyelid blinking in two. Four patients (9.7%) had ictal headache as the initial manifestation followed by nausea and vomiting. Two children (4.8%) had their first seizure while asleep associated with cardiorespiratory arrest. Two children (4.8%) had oral automatisms, such as sucking and chewing. In two children (4.8%) coughing was the initial manifestation followed by emetic symptoms. One patient (2.3%) had vertigo with a sensation of fear, with eye deviation and unresponsiveness. One child started with continuous spikes and waves during slow sleep, behavior disturbances, and emetic symptoms.In this study, evidence of the existence of unusual clinical cases of PS with typical EEG patterns was found. Outcome was excellent.

The aim of this retrospective study was to evaluate efficacy and tolerability of sulthiame (STM) as add-on treatment in 35 patients with myoclonic atonic epilepsy (MAE) resistant to other antiseizure medications (ASMs) and/or non-pharmacological treatment.Patients were selected according to the diagnostic definition of MAE and were resistant to at least four previous to ASM, alone or in combination. Neurologic examinations, brain magnetic resonance imaging, and repeated prolonged electroencephalography (EEG) or video-EEG studies as well as neurometabolic studies were performed in all cases. Genetic studies were performed in 15 patients. Data on school achievements and/or neuropsychological evaluations were obtained over a mean follow-up of 30 months. Sulthiame was added in doses ranging from 10 to 30 mg/kg/day. Efficacy was assessed by comparing seizure frequency before and after initiating STM therapy.Twenty-one of 35 patients (60%) who received STM as add-on therapy had a greater than 50% seizure decrease after a mean follow-up of 30 months. Complete seizure freedom was achieved in two patients (5.8%). The remaining 14 patients (40%) had a 25-50% seizure reduction. Adverse effects, consisting of hyperpnea and dyspnea, decreased appetite, nausea, drowsiness, headache, and irritability, were observed in 11 (31.4%). The adverse effects were mild and transient in all cases. Discontinuation of STM was not necessary.Add-on STM led to a more than 50% seizure reduction in 21 of 35 patients with MAE with only mild or moderate adverse effects.

Report a series of children with West syndrome (WS) treated with vigabatrin (VGB) who developed characteristic MRI alterations. In the majority, these adverse events were asymptomatic; however, some of the patients developed movement disorders and acute encephalopathy.This is a retrospective analysis of our epilepsy clinical and EEG database of 288 patients with WS seen between 2014 and 2020. All patients who received VGB alone or with concomitant therapies, such as adrenocorticotropic hormone (ACTH), high-dose oral corticosteroids, ketogenic diet, valproate, levetiracetam, or topiramate, were evaluated.In 44 of 288 patients with WS receiving VGB, MRI findings compatible with VGB-associated brain abnormalities were identified; median age at diagnosis was 6.29 months (range, 2 weeks to 11 months). The etiology of WS with vigabatrin-associated brain abnormalities on MRI (VABAM) was unknown in 22 (52.27%), genetic in seven (15.9%), genetic-structural in three (6.8%), structural malformative in three others (6.8%), and structural acquired in eight patients (18.2%). Vigabatrin-associated brain abnormalities on MRI was asymptomatic in 25 of 44 patients. Ten of 44 (22.7%) infants were reported to have had a movement disorder (choreoathetosis, dystonic posturing). Nine of 42 infants exhibited progressive psychomotor deterioration associated with signs and symptoms of encephalopathy.MRI abnormalities were observed in infants treated with VGB and they appeared to be dose dependent. In our study common locations for MRI abnormalities included globi pallidi and brainstem, followed by thalami and dentate nuclei. Risk factors for the development of VABAM may include age younger than 11 months and higher VGB dose of VGB (165 mg/kg/day). Vigabatrin-associated brain abnormalities on MRI usually resolved following VGB discontinuation, probably after a period of 3 months.

A female patient with electroclinical and neuroradiological features compatible with Rasmussen syndrome developed a particular clinical and EEG pattern. As the seizures were refractory to valproate at 750 mg/kg/day, oxcarbazepine (OXC) at 30 mg/kg/day was added. Seizures became more frequent and on neurological examination, no hemiparesis was detected. The interictal EEG showed focal spikes and diffuse paroxysms in the right fronto-temporal regions. Brain MRI revealed right hemiatrophy, mainly at the Sylvian fissure. After initiating OXC daily, brief absence seizures, lasting less than 20 seconds and associated with bilateral and synchronous 2.5-3-Hz spike-and-waves compatible with typical absences, were observed. OXC was discontinued and the typical absences disappeared. Treatment with intravenous gammaglobulin was started. At the last control visit, at nine years of age, no absence seizures were observed either by the parents or on the EEG recording. Our patient who met the diagnostic criteria for Rasmussen syndrome presented with absence seizures that may have been induced by OXC. The absence seizures disappeared after OXC was discontinued.

Background Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases. Objective To identify rare, causal CNV in patients with RE. Methods We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India. Results We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin. Conclusion Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.

Idiopathic generalized epilepsies (IGEs) may start in infancy, childhood, or adolescence, but some have an onset in adulthood. They are genetically determined and affect otherwise healthy people of both sexes and all races, and are generally lifelong. Some, however, are age related. IGEs account for nearly a third of all epilepsies. According to the International League Against Epilepsy (ILAE) proposed classification, the following IGEs are recognized in accordance with the age at onset (Engel, 2001): benign myoclonic epilepsy in infancy (BMEI), generalized epilepsies with febrile seizures plus (GEFS+), epilepsy with myoclonic-astatic seizures (EMAS), epilepsy with myoclonic absences (EMA), childhood absence epilepsy (CAE), and IGEs with variable phenotypes (IGEVP) that include juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic-clonic seizures only (EGTCSO). These IGEs raise a conceptual issue since some conditions are epilepsy syndromes (a combination of a given age of onset, seizure type(s), and interictal and clinical and EEG features) (i.e., BMEI, EMAS, EMA, CAE, JAE, JME) whereas others join several types of epilepsy in a given family (i.e., GEFS+and eventually IGEVP and EGTCSO). This chapter describes the electroclinical features, evolution, and therapeutic aspects of IGEs.

The ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.