Infantile epileptic encephalopathy, transient choreoathetotic movements, and hypersomnia due to a De Novo missense mutation in the SCN2A gene

Mutations of the SCN2A gene have originally been described in association with benign familial neonatal-infantile seizures (BFNIS). Recently, single patients with more severe phenotypes and persisting epileptic encephalopathies have been recognized. We report the case of a girl with severe infantile onset epileptic encephalopathy and a de novo missense mutation in the SCN2A gene (c.4025T > C/ = ; p.L1342P/ = ), who presented with a transient choreatic movement disorder, hypersomnia, and progressive brain atrophy. Whole exome sequencing did not reveal any other disease causing mutation. Our patient contributes to the expanding phenotypic spectrum of SCN2A-related disorders and underlines the importance of genetic workup in epileptic encephalopathies

Changing the system by changing the workforce: employing consumers to increase access, cultural diversity, and engagement

Services to families have traditionally been delivered in a medical model. This presents challenges including workforce shortages, lack of cultural diversity, lack of training in strength-based work, and difficulty in successfully engaging and retaining families in the therapy process. The system of care (SOC) effort has worked to establish formal roles for caregivers in SOC to improve services. This paper provides an example of one community\u27s efforts to change the SOC by expanding the roles available to caregivers in creating systems change. It describes the model developed by Communities of Care (CoC), a SOC in Central Massachusetts, and its evolution over a 10 year period. First person accounts by system partners, caregivers hired into professional roles as well as a family receiving services, demonstrate how hiring caregivers at all levels can change systems and change lives, not only for those being served but for the caregiver/professionals doing the work. It also demonstrates, however, that change at the system level is incremental, takes time, and can be fleeting unless an ongoing effort is made to support and sustain those changes

Engineering Regulated Open Multiagent Systems

Actualmente existe una creciente demanda de sistemas flexibles, adaptables y con gran escalabilidad para apoyar las interacciones de personas e instituciones distribuidas en entornos heterogéneos. Esto se debe principalmente al incremento en la necesidad de trabajo colaborativo y la descentralización de los procesos en muchos dominios de aplicación. Por lo general, estas aplicaciones de software deben seguir legislaciones y normativas específicas, es decir, las entidades que participan en el sistema tienen derechos, deberes y restricciones específicas. Al igual que en otros trabajos del área, en esta tesis se utiliza el término sistemas normativos abiertos para referirse a los sistemas de este tipo. El desarrollo de sistemas normativos abiertos puede producir importantes beneficios para las compañías que los usen, ya que permiten la comunicación de instituciones, entidades heterogéneas y diferentes dispositivos con el fin de lograr tanto los objetivos globales del sistema como los individuales de cada institución y entidad. Sin embargo, también hay algunas cuestiones importantes que potencialmente pueden complicar el análisis, diseño e implementación de estos sistemas. La mayoría de estos problemas están relacionados con la interoperabilidad de sus procesos, la privacidad, la combinación de los objetivos individuales y la combinación de las restricciones y la legislación de cada una de las entidades del sistema. Por lo tanto, es necesario el uso de métodos de ingeniería del software y herramientas de desarrollo para hacer frente a estos problemas y guiar a los desarrolladores durante el proceso de desarrollo. La tecnología basada en sistemas multiagente (SMA) es considerada una buena candidata para el desarrollo de sistemas normativos abiertos. Durante los últimos años, el uso de las tecnologías SMA se ha incrementado no sólo en el ámbito académico, sino también en el desarrollo e implementación de aplicaciones industriales. Los SMA se han establecido como un paradigma de la ingeniería de software para la creación de sistemas adaptativos complejos, en entornos distribuidos y heterogéneos. Esta tesis se centra en el análisis y diseño de sistemas normativos abiertos utilizando la tecnología SMA. Algunas metodologías SMA se dedican al desarrollo de sistemas de este tipo. Sin embargo, después de analizar en qué medida las metodologías SMA actuales soportan el análisis y el diseño de estos sistemas, podemos concluir que todavía hay importantes problemas a resolver en el área. Algunos de estos problemas son la integración del contexto normativo del sistema durante el proceso de desarrollo, la falta de directrices para identificar y formalizar este contexto normativo, la falta de técnicas de validación y verificación que garanticen la coherencia del diseño final respecto a los requisitos del sistema, la coherencia entre los objetivos individuales, y la coherencia de las restricciones de cada entidad respecto al contexto normativo del sistema global. La principal aportación de esta tesis es una nueva metodología SMA llamada ROMAS (Sistemas Multiagente Regulados y Abiertos), que se centra en el análisis y diseño de procesos para el desarrollo de sistemas multiagente organizacionales, donde los agentes interactúan por medio de servicios estándares, y donde las relaciones sociales y contractuales se formalizan mediante normas y contratos. La metodología ROMAS define un proceso de desarrollo orientado a agentes y proporciona guías específicas para identificar y formalizar el marco normativo del sistema, así como las comunicaciones y los intercambios de servicios y recursos. ROMAS especifica tanto el comportamiento global del sistema como las características individuales de cada entidad. En la metodología ROMAS, agentes, roles y organizaciones se definen a través de una estructura social formal basada en un arquitectura orientada a servicios. Aquí, las organizaciones representan un conjunto de personas e instituciones que tienen que coorGarcia Marques, ME. (2013). Engineering Regulated Open Multiagent Systems [Tesis doctoral no publicada]. Universitat Politècnica de València. doi:10.4995/Thesis/10251/28588.Alfresc

Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes

Abstract Background Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood. Methods To further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling. Results The two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings. Conclusions Our findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Nav1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants

ModFetch: A modular system for automating queries to relational databases

Computer Science

Patterns of paediatric end-of-life care: a chart review across different care settings in Switzerland

Abstract Background Paediatric end-of-life care is challenging and requires a high level of professional expertise. It is important that healthcare teams have a thorough understanding of paediatric subspecialties and related knowledge of disease-specific aspects of paediatric end-of-life care. The aim of this study was to comprehensively describe, explore and compare current practices in paediatric end-of-life care in four distinct diagnostic groups across healthcare settings including all relevant levels of healthcare providers in Switzerland. Methods In this nationwide retrospective chart review study, data from paediatric patients who died in the years 2011 or 2012 due to a cardiac, neurological or oncological condition, or during the neonatal period were collected in 13 hospitals, two long-term institutions and 10 community-based healthcare service providers throughout Switzerland. Results Ninety-three (62%) of the 149 reviewed patients died in intensive care units, 78 (84%) of them following withdrawal of life-sustaining treatment. Reliance on invasive medical interventions was prevalent, and the use of medication was high, with a median count of 12 different drugs during the last week of life. Patients experienced an average number of 6.42 symptoms. The prevalence of various types of symptoms differed significantly among the four diagnostic groups. Overall, our study patients stayed in the hospital for a median of six days during their last four weeks of life. Seventy-two patients (48%) stayed at home for at least one day and only half of those received community-based healthcare. Conclusions The study provides a wide-ranging overview of current end-of-life care practices in a real-life setting of different healthcare providers. The inclusion of patients with all major diagnoses leading to disease- and prematurity-related childhood deaths, as well as comparisons across the diagnostic groups, provides additional insight and understanding for healthcare professionals. The provision of specialised palliative and end-of-life care services in Switzerland, including the capacity of community healthcare services, need to be expanded to meet the specific needs of seriously ill children and their families

Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life