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Las talasemias son el resultado de un desequilibrio en la síntesis entre las cadenas α y β de la hemoglobina (Hb). Están muy extendidas en todo el mundo, pero son infrecuentes en Francia. Las principales formas de talasemia β o talasemia dependiente de transfusión (TDT) se caracterizan por una anemia grave desde la infancia, que requiere un régimen de transfusión y un tratamiento quelante del hierro a largo plazo. Con un tratamiento adecuado, la sobrecarga de hierro deja de manifestarse clínicamente en la infancia, pero sigue siendo una de las principales causas de mortalidad y morbilidad (cardíaca, hepática, endocrina) en los adultos. El trasplante alogénico de células madre hematopoyéticas, que en la actualidad es el único tratamiento curativo, se propone siempre a los niños con un donante intrafamiliar de antígeno leucocítico humano (HLA) idéntico. Las β-talasemias intermedias son formas de gravedad leve que requieren poca o ninguna transfusión (talasemias no dependientes de transfusión [TNDT]). Sin embargo, se asocian a una serie de complicaciones. Las β-talasemias menores suelen ser asintomáticas, se detectan en el hemograma (microcitosis) y se confirman mediante un análisis bioquímico de la Hb. Su diagnóstico es importante para el consejo genético de las parejas portadoras de una mutación heterocigótica. La forma sintomática más frecuente de la α-talasemia es la hemoglobinosis H, caracterizada por una anemia hemolítica crónica, a menudo moderada, pero que puede agravarse, en particular en caso de infecciones. Las medidas son esencialmente preventivas (suplemento de ácido fólico, exclusión de medicamentos oxidantes) y educativas, y las transfusiones sólo son necesarias en ocasiones. Los casos excepcionales de hidropesía fetal de Bart, resultantes de la ausencia total de expresión de la cadena α, dan lugar a una anemia muy grave que suele ser letal. Las formas menores de α-talasemia, mucho más frecuentes, se sospechan en presencia de microcitosis tras la exclusión de la deficiencia de hierro y de la β-talasemia menor, cuando el origen geográfico es sugestivo. El diagnóstico es genotípico.

ObjectiveChildhood and adolescent cancer can result in high burden of distressing symptoms, particularly in high-risk malignancies. The Symptom Screening in Pediatrics Tool (SSPedi) is a reliable and valid approach to measure bothersome symptoms in paediatric patients receiving cancer treatments. Objective was to describe the feasibility of using SSPedi administration among paediatric patients with high-risk malignancies.MethodsWe conducted a single-centre, cross-sectional study of patients aged 8–18 years with high-risk malignancies in a French paediatric oncology unit. Patients self-reported the degree of bothersome symptoms using SSPedi and difficulty with SSPedi completion. The total SSPedi Score ranging from 0 to 60 (where 60 is worst) and most common moderately bothersome symptoms (scored ≥2 on 0–4 Likert Scale) were described. Feasibility was defined as more than 75% of patients agreeing to participate and more than 90% completion of SSPedi questionnaire.ResultsOut of 16 patients approached, 1 declined participation. Median age was 13 years (IQR 8–19). All were able to self-report SSPedi without difficulty. Patients experienced a median number of 6 (range 0–15) bothersome symptoms (score >0). The mean total SSPedi Score was 12 (SD=9.4). Most common moderately bothersome symptoms were pain (8/15), changes in hunger (8/15) and feeling tired (7/15).ConclusionPatient-reported symptom assessment among children and adolescents with high-risk malignancies is feasible using SSPedi. These patients experience a high burden of bothersome symptoms.

Formerly idiopathic, focal epilepsies (IFE) are self‐limiting, “age‐related” diseases that mainly occur during critical developmental periods. Childhood epilepsy with centrotemporal spikes, or Rolandic epilepsy (RE), is the most frequent form of IFE. Together with the Landau‐Kleffner syndrome and the epileptic Encephalopathy related to Status Epilepticus during slow Sleep syndrome (ESES), RE is part of a single and continuous spectrum of childhood epilepsies and epileptic encephalopathies with acquired cognitive, behavioral and speech and/or language impairment, known as the epilepsy‐aphasia spectrum (EAS). The pathophysiology has long been attributed to an elusive and complex interplay between brain development and maturation processes on the one hand, and susceptibility genes on the other hand. Studies based on the variable combination of molecular cytogenetics, Sanger and next‐generation sequencing tools, and functional assays have led to the identification and validation of genetic mutations in the GRIN2Agene that can directly cause various types of EAS disorders. The recent identification of GRIN2Adefects in EAS represents a first and major break‐through in our understanding of the underlying pathophysiological mechanisms. In this review, we describe the current knowledge on the genetic architecture of IFE.

Les xanthogranulomes juvéniles (XGJ), forme la plus commune d’histiocytose non langerhansienne, sont des lésions le plus souvent bénignes quand l’atteinte cutanée est isolée. À l’inverse, nous rapportons un cas de XGJ associé à une atteinte médullaire et viscérale néonatale, forme exceptionnelle.

Numerous epilepsy genes have been identified in the last years, mostly in the (rare) monogenic forms and thanks to the increased availability and the decreased cost of next-generation sequencing approaches.

Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5–10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.

The term idiopathic focal epilepsies of childhood (IFE) is not formally recognised by the ILAE in its 2010 revision (Berg et al., [Berg A.T., 2010]), nor are its members and boundaries precisely delineated. The IFEs are amongst the most commonly encountered epilepsy syndromes affecting children. They are fascinating disorders that hold many “treats” for both clinicians and researchers. For example, the IFEs pose many of the most interesting questions central to epileptology: how are functional brain networks involved in the manifestation of epilepsy? What are the shared mechanisms of comorbidity between epilepsy and neurodevelopmental disorders? How do focal EEG discharges impact cognitive functioning? What explains the age‐related expression of these syndromes? Why are EEG discharges and seizures so tightly locked to slow‐wave sleep? In the last few decades, the clinical symptomatology and the respective courses of many IFEs have been described, although they are still not widely appreciated beyond the specialist community. Most neurologists would recognise the core syndromes of IFE to comprise: benign epilepsy of childhood with centro‐temporal spikes or Rolandic epilepsy (BECTS/RE); Panayiotopoulos syndrome; and the idiopathic occipital epilepsies (Gastaut and photosensitive types). The Landau‐Kleffner syndrome and the related (idiopathic) epilepsy with continuous spikes and waves in sleep (CSWS or ESES) are also often included, both as a consequence of the shared morphology of the interictal discharges and their potential evolution from core syndromes, for example, CSWS from BECTS. Atypical benign focal epilepsy of childhood also has shared electro‐clinical features warranting inclusion. In addition, a number of less well‐defined syndromes of IFE have been proposed, including benign childhood seizures with affective symptoms, benign childhood epilepsy with parietal spikes, benign childhood seizures with frontal or midline spikes, and benign focal seizures of adolescence. The term “benign” is often used in connection with the IFEs and is increasingly being challenged. Certainly most of these disorders are not associated with the devastating cognitive and behavioural problems seen with early childhood epileptic encephalopathies, such as West or Dravet syndromes. However, it is clear that specific, and sometimes persistent, neuropsychological deficits in attention, language and literacy accompany many of the IFEs that, when multiplied by the large numbers affected, make up a significant public health problem. Understanding the nature, distribution, evolution, risk and management of these is an important area of current research. A corollary to such questions regarding comorbidities is the role of focal interictal spikes and their enduring impact on cognitive functioning. What explains the paradox that epilepsies characterised by abundant interictal epileptiform abnormalities are often associated with very few clinical seizures? This is an exciting area in both clinical and experimental arenas and will eventually have important implications for clinical management of the whole child, taking into account not just seizures, but also adaptive functioning and quality of life. For several decades, we have accepted an evidence‐free approach to using or not using antiepileptic drugs in IFEs. There is huge international variation and only a handful of studies examining neurocognitive outcomes. Clearly, this is a situation ready for an overhaul in practice. Fundamental to understanding treatment is knowledge of aetiology. In recent years, there have been several significant discoveries in IFEs from studies of copy number variation, exome sequencing, and linkage that prompt reconsideration of the “unknown cause” classification and strongly suggest a genetic aetiology. The IFE are strongly age‐related, both with regards to age of seizure onset and remission. Does this time window solely relate to a similar age‐related gene expression, or are there epigenetic factors involved that might also explain low observed twin concordance? The genetic (and epigenetic) models for different IFEs, their comorbidities, and their similarities to other neurodevelopmental disorders deserve investigation in the coming years. In so doing, we will probably learn much about normal brain functioning. This is because these disorders, perhaps more than any other human brain disease, are disorders of functional brain systems (even though these functional networks may not yet be fully defined). In June 2012, an international group of clinical and basic science researchers met in London under the auspices of the Waterloo Foundation to discuss and debate these issues in relation to IFEs. This Waterloo Foundation Symposium on the Idiopathic Focal Epilepsies: Phenotype to Genotype witnessed presentations that explored the clinical phenomenology, phenotypes and endophenotypes, and genetic approaches to investigation of these disorders. In parallel, the impact of these epilepsies on children and their families was reviewed. The papers in this supplement are based upon these presentations. They represent an updated state‐of‐the‐art thinking on the topics explored. The symposium led to the formation of international working groups under the umbrella of “Luke's Idiopathic Focal Epilepsy Project” to investigate various aspects of the idiopathic focal epilepsies including: semiology and classification, genetics, cognition, sleep, high‐frequency oscillations, and parental resources (see www.childhood-epilepsy.org). The next sponsored international workshop, in June 2014, was on randomised controlled trials in IFEs and overnight learning outcome measures.

Whole genome sequencing and the screening of 103 families recently led us to identify PRRT2(proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKDIC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKDIC or PKDIC with migraine.

Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2in the vast majority (24/25) of well-characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. PRRT2encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture, and mutants associated with PKD/IC lead to dramatically reduced PRRT2 levels, leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC.

As a key component of the plasminogen activation system, uPAR, the receptor for the plasminogen activator of the urokinase type, is involved in many physiological and pathological processes. Besides its classical roles, there has been increased evidence that uPAR or uPAR-associated pathways, participate in the development, in the functioning and in the pathology of the central nervous system. Qualitative and quantitative changes in the expressions of uPAR and of its canonical ligand uPA have been observed in a large variety of epileptic disorders, either in human or in animal models, as well as in other brain diseases (stroke and brain trauma, multiple sclerosis, Alzheimers disease, cerebral malaria, HIV-associated leukoencephalopathy and encephalitis). The variety of such pathological conditions and the different brain areas and cell types involved, likely reflects the wide range and the complexity of the multiple and somehow intertwined pathophysiological mechanisms related with uPAR. In the mouse, the knock-out of the Upar-encoding gene (Plaur) leads to significant and nearly complete loss in parvalbumin-containing interneurons during brain development. This is associated with increased susceptibility to spontaneous and chemically-induced seizures and with increased anxiety and impaired social interactions. The recent identification of the novel uPAR ligand SRPX2 (Sushi repeat protein, X-linked 2) and the regulation of both the SRPX2 and PLAUR genes by transcription factor FOXP2 has shed novel and exciting insights into the role of uPAR-related molecular networks in rolandic epilepsy, in developmental verbal dyspraxia, in perisylvian polymicrogyria, and generally in disorders of the speech areas and circuits. uPAR, its regulators and partners, as well as other proteins containing Ly-6/uPAR/alpha-neurotoxin domains, represent key entry points for present and future studies not only on speech-related disorders but also on epilepsy and autism spectrum disorders.