Inherited SCN1A missense mutation in a Dravet Syndrome family: Neuropathological correlation, family screening and implications for adult carriers.

INTRODUCTION: Neuropathological findings in Dravet Syndrome (DS) are scarce, especially in adult patients, and often do not have a genetic confirmation. Additionally, the missense SCN1A pathogenic variant found has only been described as de novo mutation in previous literature. METHODS: We describe the clinical and genetic findings of a family (including three sisters and his father), using Sanger sequencing in the three sisters and in postmortem brain tissue in the father. The present study also shows the neuropathological findings of the father. RESULTS: Despite the presence of long term drug resistant epilepsy, starting with febrile seizures between 6 and 12 months of age, and intellectual disability (ID), the three sisters were diagnosed with DS in adulthood, identifying a missense SCN1A pathogenic variant in exon 20, previously described as de novo -p.Gly1332Glu (c .3995 G>A). The oldest sister had the most severe phenotype, with severe ID and wheel chair dependency, passing away at 52. The other two sisters had a moderate phenotype, being at the present seizure free, but with significant comorbidities, such as crouch gait and parkinsonism. Several relatives from the paternal path (including the father) presented epilepsy, but without ID. The father was diagnosed with Alzheimer´s Disease (AD) at 60, and because he donated his brain, the same variant was confirmed in postmortem study. Neither the MRI nor the histopathology showed specific morphological changes for DS, consistent with previous studies. CONCLUSIONS: This work supports the need to review the clinical and genetic spectra of DS in adults with epilepsy and unknown ID. The clinical consequences of this syndrome seem to have a functional rather than a structural basis, supported by the absence of specific neuropathological findings.

Complicaciones neurológicas en pacientes sometidos a trasplante de progenitores hematopoyéticos / Neurological complications in haematopoietic stem cell transplant patients

Introducción: Las complicaciones neurológicas son algunas de las más importantes que se pueden presentar en un paciente sometido a un trasplante de progenitores hematopoyéticos (TPH), no sólo porque conllevan una mortalidad elevada, sino también por las secuelas que aparecen en los supervivientes. Las causas de dichas complicaciones son múltiples y, muy frecuentemente, coexisten en el mismo paciente: toxicidad del régimen de acondicionamiento, enfermedad del injerto contra el hospedador y su tratamiento, infecciones y su tratamiento, plaquetopenia y trastornos de la coagulación, fallo hepático o hipertensión arterial con plaquetopenia. Objetivos: El objetivo del presente estudio es el de aportar una descripción clínica y de los factores de riesgo de las complicaciones sobre el sistema nervioso central que pueden presentarse en el curso de un TPH, para ayudar en la detección precoz de estos trastornos que pueden influir negativamente en la morbimortalidad de estos pacientes. Desarrollo: Se describen los siguientes tipos de complicaciones neurológicas: infecciones sobre el sistema nervioso central, complicaciones vasculares, toxicidad farmacológica, complicaciones metabólicas, trastornos inmunomediados y carcinogenia pos-TPH, y efectos de la enfermedad del injerto contra el hospedador y de la microangiopatía trombótica sobre el sistema nervioso. Conclusiones: El paciente sometido a TPH es de especial riesgo para el desarrollo de complicaciones neurológicas. Se precisan un diagnóstico y un tratamiento precoces para intentar disminuir la elevada morbimortalidad de estos pacientes.(AU)

Introduction: Neurological complications are some of the most important complications that can occur in a patient undergoing haematopoietic stem cell transplantation (HSCT), not only because of the high mortality rate, but also because of the sequelae that appear in survivors. The causes of such complications are manifold and very often coexist in the same patient: toxicity of the conditioning regimen, graft-versus-host disease and its treatment, infections and their treatment, platelets and coagulation disorders, liver failure or arterial hypertension with low platelet count. Aims: The aim of the present study is to provide a clinical description and to describe the risk factors for complications involving the central nervous system that may occur during the course of HSCT, in order to assist in the early detection of these disorders that may have a negative influence on the morbidity and mortality of these patients. Development: The following types of neurological complications are described: central nervous system infections, vascular complications, pharmacological toxicity, metabolic complications, immune-mediated disorders and post-HSCT carcinogenesis, and effects of graft-versus-host disease and thrombotic microangiopathy on the nervous system. Conclusions: The patient undergoing HSCT is at particular risk for the development of neurological complications. Early diagnosis and treatment are needed to try to reduce the high morbidity and mortality in these patients.(AU)

Impact of COVID-19 on Spanish patients with Dravet syndrome and their caregivers: consequences of lockdown. / Impacto de la COVID-19 en pacientes españoles con síndrome de Dravet y sus cuidadores: consecuencias del confinamiento.

INTRODUCTION: The COVID-19 pandemic caused a state of alarm in Spain in March 2020. The necessary approach to the care of patients with Dravet syndrome (DS) makes them and their caregivers a vulnerable group in emergency situations. OBJECTIVES: To explore the impact of the COVID-19 pandemic on the management and condition of Spanish patients with DS and their caregivers and families. MATERIALS AND METHODS: Analysis of data belonging to Spanish families taken from a European online survey (14 April-17 May 2020). It included data on DS patients, on the disease and on caregivers before and after lockdown during the state of alarm. RESULTS: Sixty-nine Spanish families participated; average age of patients: 12.6 years. Except in 19% of the cases that were isolated, protective/isolation measures for patients were followed without increasing. Epilepsy remained stable, with no medication or resource/personnel availability issues. Sleep-wake pattern (61%) and behavior (41%) of patients changed. Behavior change was associated with seizures during lockdown and with caregiver emotional state (changes in 76%). Psychological support was offered to only 9% of caregivers. Thirty-eight per cent of patients did not receive remote care. CONCLUSIONS: The experience gathered during the lockdown has allowed the detection of points of improvement to ensure the proper management of DS and to keep the situation of patients and caregivers stable. All of this with a prominent role of telemedicine.

TITLE: Impacto de la COVID-19 en pacientes españoles con síndrome de Dravet y sus cuidadores: consecuencias del confinamiento.Introducción. La pandemia por COVID-19 implicó el estado de alarma en España en marzo de 2020. El abordaje necesario para el cuidado de los pacientes con síndrome de Dravet (SD) los convierte, junto con sus cuidadores, en un grupo vulnerable en situaciones de emergencia. Objetivos. Explorar el impacto de la pandemia por COVID-19 en el manejo y la condición de los pacientes españoles con SD, y de sus cuidadores y familias. Materiales y métodos. Análisis de los datos pertenecientes a familias españolas extraídos de una encuesta en línea europea (14 de abril-17 de mayo de 2020). Incluía datos de los pacientes con SD, de la enfermedad y de los cuidadores antes y después del confinamiento, durante el estado de alarma. Resultados. Participaron 69 familias españolas; edad media de los pacientes: 12,6 años. Excepto en el 19% de los casos que fueron aislados, las medidas de protección/aislamiento del paciente continuaron sin incrementar. La epilepsia se mantuvo estable, sin problemas de medicación ni disponibilidad de recursos/personal. Cambió el patrón de sueño/vigilia (61%) y la conducta (41%) de los pacientes. El cambio de conducta se asoció con las crisis durante el confinamiento y el estado anímico del cuidador (cambios en el 76%). Sólo se ofreció apoyo psicológico al 9% de los cuidadores. El 38% de los pacientes no recibió atención telemática. Conclusiones. La experiencia recogida durante el confinamiento ha permitido detectar puntos de mejora para asegurar el apropiado manejo del SD y mantener estable la situación de los pacientes y cuidadores, todo ello con un papel destacado de la telemedicina.

[Neurological complications in haematopoietic stem cell transplant patients]. / Complicaciones neurológicas en pacientes sometidos a trasplante de progenitores hematopoyéticos.

INTRODUCTION: Neurological complications are some of the most important complications that can occur in a patient undergoing haematopoietic stem cell transplantation (HSCT), not only because of the high mortality rate, but also because of the sequelae that appear in survivors. The causes of such complications are manifold and very often coexist in the same patient: toxicity of the conditioning regimen, graft-versus-host disease and its treatment, infections and their treatment, platelets and coagulation disorders, liver failure or arterial hypertension with low platelet count. AIMS: The aim of the present study is to provide a clinical description and to describe the risk factors for complications involving the central nervous system that may occur during the course of HSCT, in order to assist in the early detection of these disorders that may have a negative influence on the morbidity and mortality of these patients. DEVELOPMENT: The following types of neurological complications are described: central nervous system infections, vascular complications, pharmacological toxicity, metabolic complications, immune-mediated disorders and post-HSCT carcinogenesis, and effects of graft-versus-host disease and thrombotic microangiopathy on the nervous system. CONCLUSIONS: The patient undergoing HSCT is at particular risk for the development of neurological complications. Early diagnosis and treatment are needed to try to reduce the high morbidity and mortality in these patients.

TITLE: Complicaciones neurológicas en pacientes sometidos a trasplante de progenitores hematopoyéticos.Introducción. Las complicaciones neurológicas son algunas de las más importantes que se pueden presentar en un paciente sometido a un trasplante de progenitores hematopoyéticos (TPH), no sólo porque conllevan una mortalidad elevada, sino también por las secuelas que aparecen en los supervivientes. Las causas de dichas complicaciones son múltiples y, muy frecuentemente, coexisten en el mismo paciente: toxicidad del régimen de acondicionamiento, enfermedad del injerto contra el hospedador y su tratamiento, infecciones y su tratamiento, plaquetopenia y trastornos de la coagulación, fallo hepático o hipertensión arterial con plaquetopenia. Objetivos. El objetivo del presente estudio es el de aportar una descripción clínica y de los factores de riesgo de las complicaciones sobre el sistema nervioso central que pueden presentarse en el curso de un TPH, para ayudar en la detección precoz de estos trastornos que pueden influir negativamente en la morbimortalidad de estos pacientes. Desarrollo. Se describen los siguientes tipos de complicaciones neurológicas: infecciones sobre el sistema nervioso central, complicaciones vasculares, toxicidad farmacológica, complicaciones metabólicas, trastornos inmunomediados y carcinogenia pos-TPH, y efectos de la enfermedad del injerto contra el hospedador y de la microangiopatía trombótica sobre el sistema nervioso. Conclusiones. El paciente sometido a TPH es de especial riesgo para el desarrollo de complicaciones neurológicas. Se precisan un diagnóstico y un tratamiento precoces para intentar disminuir la elevada morbimortalidad de estos pacientes.

Impacto de la COVID-19 en pacientes españoles con síndrome de Dravet y sus cuidadores: consecuencias del confinamiento / Impact of COVID-19 on Spanish patients with Dravet syndrome and their caregivers: consequences of lockdown

Introducción: La pandemia por COVID-19 implicó el estado de alarma en España en marzo de 2020. El abordaje necesario para el cuidado de los pacientes con síndrome de Dravet (SD) los convierte, junto con sus cuidadores, en un grupo vulnerable en situaciones de emergencia. Objetivos: Explorar el impacto de la pandemia por COVID-19 en el manejo y la condición de los pacientes españoles con SD, y de sus cuidadores y familias. Materiales y métodos: Análisis de los datos pertenecientes a familias españolas extraídos de una encuesta en línea europea (14 de abril-17 de mayo de 2020). Incluía datos de los pacientes con SD, de la enfermedad y de los cuidadores antes y después del confinamiento, durante el estado de alarma. Resultados: Participaron 69 familias españolas; edad media de los pacientes: 12,6 años. Excepto en el 19% de los casos que fueron aislados, las medidas de protección/aislamiento del paciente continuaron sin incrementar. La epilepsia se mantuvo estable, sin problemas de medicación ni disponibilidad de recursos/personal. Cambió el patrón de sueño/vigilia (61%) y la conducta (41%) de los pacientes. El cambio de conducta se asoció con las crisis durante el confinamiento y el estado anímico del cuidador (cambios en el 76%). Sólo se ofreció apoyo psicológico al 9% de los cuidadores. El 38% de los pacientes no recibió atención telemática. Conclusiones: La experiencia recogida durante el confinamiento ha permitido detectar puntos de mejora para asegurar el apropiado manejo del SD y mantener estable la situación de los pacientes y cuidadores, todo ello con un papel destacado de la telemedicina.(AU)

Introduction: The COVID-19 pandemic caused a state of alarm in Spain in March 2020. The necessary approach to the care of patients with Dravet syndrome (DS) makes them and their caregivers a vulnerable group in emergency situations. Objectives: To explore the impact of the COVID-19 pandemic on the management and condition of Spanish patients with DS and their caregivers and families. Materials and methods: Analysis of data belonging to Spanish families taken from a European online survey (14 April-17 May 2020). It included data on DS patients, on the disease and on caregivers before and after lockdown during the state of alarm. Results: Sixty-nine Spanish families participated; average age of patients: 12.6 years. Except in 19% of the cases that were isolated, protective/isolation measures for patients were followed without increasing. Epilepsy remained stable, with no medication or resource/personnel availability issues. Sleep-wake pattern (61%) and behavior (41%) of patients changed. Behavior change was associated with seizures during lockdown and with caregiver emotional state (changes in 76%). Psychological support was offered to only 9% of caregivers. Thirty-eight per cent of patients did not receive remote care. Conclusions: The experience gathered during the lockdown has allowed the detection of points of improvement to ensure the proper management of DS and to keep the situation of patients and caregivers stable. All of this with a prominent role of telemedicine.(AU)

Pediatric Klüver-Bucy Syndrome: Report of Two Cases and Review of the Literature.

Klüver-Bucy syndrome (KBS) is a rare behavioral phenotype described in monkeys and humans that appears most often after bilateral temporal damage. The main features of KBS are compulsion to examine objects orally, increased sexual activity, placidity, hypermetamorphosis, visual agnosia, and amnesia. Cases in children are scarce, and the most frequently reported etiology is herpes encephalitis. Hyperorality (90%), hypersexuality (82%), and epilepsy (70%) were the most common features of the 51 cases reported in the literature to date. Carbamazepine, selective serotonin reuptake inhibitors (SSRIs), and neuroleptics have been used for symptomatic treatment with variable control. Corticosteroids or immunosupressive agents, such as rituximab, can be an option to use in some cases, according to etiology suspicion. Cognitive and behavioral disturbances after KBS are often severe, but improvement can occur over a long time and residual disabilities vary from major to fairly mild.We report two new encephalitis-associated pediatric patients and review all of the pediatric KBS cases in the literature to better describe the clinical features of this rare neurobehavioral condition.

Seizures and electroencephalography findings in 61 patients with fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD) cause neurodevelopmental abnormalities. However, publications about epilepsy and electroencephalographic features are scarce. In this study, we prospectively performed electroencephalography (EEG) and brain magnetic resonance (MR) imaging in 61 patients with diagnosis of FASD. One patient had multiple febrile seizures with normal EEGs. Fourteen children showed EEG anomalies, including slow background activity and interictal epileptiform discharges, focal and/or generalized, and 3 of them had epilepsy. In one patient, seizures were first detected during the EEG recording and one case had an encephalopathy with electrical status epilepticus during slow sleep (ESES). Focal interictal discharges in our patients did not imply the presence of underlying visible focal brain lesions in the neuroimaging studies, such as cortical dysplasia or polymicrogyria. However, they had nonspecific brain MR abnormalities, including corpus callosum hypoplasia, vermis hypoplasia or cavum septum pellucidum. The latter was significantly more frequent in the group with EEG abnormal findings (p < 0.01).

Correlation between morphological MRI findings and specific diagnostic categories in fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD) include physical and neurodevelopmental abnormalities related to prenatal alcohol exposure. Some neuroimaging findings have been clearly related to FASD, including corpus callosum and cerebellar anomalies. However, detailed studies correlating with specific FASD categories, that is, the fetal alcohol syndrome (FAS), partial FAS (pFAS) and alcohol related neurodevelopmental disorders (ARND), are lacking. We prospectively performed clinical assessment and brain MR imaging to 72 patients with suspected FASD, and diagnosis was confirmed in 62. The most frequent findings were hypoplasia of the corpus callosum and/or of the cerebellar vermis. Additional findings were vascular anomalies, gliosis, prominent perivascular spaces, occipito-cervical junction and cervical vertebral anomalies, pituitary hypoplasia, arachnoid cysts, and cavum septum pellucidum.

Prenatal Ultrasound Diagnosis of a Cyst of the Oral Cavity: An Unusual Case of Thyroglossal Duct Cyst Located on the Tongue Base.

We describe a case of a lingual thyroglossal duct cyst diagnosed prenatally by ultrasound at 26 weeks of gestation. The follow-up ultrasound scans revealed no changes in the cyst measurement. Surgical treatment was performed without any complication 72 hours after delivery with good results.

Gel-free proteomic methodologies to study reversible cysteine oxidation and irreversible protein carbonyl formation.

Oxidative modifications in proteins have been traditionally considered as hallmarks of damage by oxidative stress and aging. However, oxidants can generate a huge variety of reversible and irreversible modifications in amino acid side chains as well as in the protein backbones, and these post-translational modifications can contribute to the activation of signal transduction pathways, and also mediate the toxicity of oxidants. Among the reversible modifications, the most relevant ones are those arising from cysteine oxidation. Thus, formation of sulfenic acid or disulfide bonds is known to occur in many enzymes as part of their catalytic cycles, and it also participates in the activation of signaling cascades. Furthermore, these reversible modifications have been usually attributed with a protective role, since they may prevent the formation of irreversible damage by scavenging reactive oxygen species. Among irreversible modifications, protein carbonyl formation has been linked to damage and death, since it cannot be repaired and can lead to protein loss-of-function and to the formation of protein aggregates. This review is aimed at researchers interested on the biological consequences of oxidative stress, both at the level of signaling and toxicity. Here we are providing a concise overview on current mass-spectrometry-based methodologies to detect reversible cysteine oxidation and irreversible protein carbonyl formation in proteomes. We do not pretend to impose any of the different methodologies, but rather to provide an objective catwalk on published gel-free approaches to detect those two types of modifications, from a biologist's point of view.

Tuberous sclerosis complex without tubers and subependymal nodules: a phenotype-genotype study.

Tuberous sclerosis complex (TSC) is caused by a mutation in the TSC1 or TSC2 genes. However, 15% of patients have no mutation identified. Tubers and subependymal nodules (SENs) are the typical brain lesions in TSC and are present in 90-95% of patients. The objective of this study is to characterize the specific genotype-phenotype of patients without these lesions. We analyzed the features of 11 patients without typical TSC neuroanatomic features. Ten had TSC1/TSC2 mutational analysis, which was negative. Clinically they had lesions thought to be of neural crest (NC) origin, such as hypomelanotic macules, facial angiofibromas, cardiac rhabdomyomas, angiomyolipomas, and lymphangioleiomyomatosis. We hypothesize that patients without tubers and SENs reflect mosaicism caused by a mutation in TSC1 or TSC2 in a NC cell during embryonic development. This may explain the negative results in TSC1 and TSC2 testing in DNA from peripheral leukocytes.

Specific deactivation of the mouse mammary tumor virus long terminal repeat promoter upon continuous hormone treatment.

We have studied the transcriptional behavior of the mouse mammary tumor virus long repeat (MMTV-LTR) promoter during a prolonged exposure to glucocorticoids. When integrated into XC-derived cells, MMTV-LTR expression reached its maximum during the first day of dexamethasone treatment, but longer exposure to the hormone resulted in the deactivation of the promoter. In contrast, glucocorticoid-responsive resident genes or MMTV-based transiently transfected plasmids maintained or even increased their mRNA levels during the same period of hormone treatment. An integrated chimeric construct containing the hormone-responsive elements from MMTV-LTR but in different sequence context became also deactivated after a prolonged hormone treatment but with a deactivation kinetics significantly slower than constructs containing the entire, chromatin-positioning MMTV-LTR sequence. The decrease on MMTV-LTR-driven transcription was concomitant with a parallel closure of the MMTV-LTR chromatin and with a decrease in glucocorticoid receptor (GR) concentration in the cell. We concluded that the chromatin-organized MMTV-LTR promoter is particularly sensitive to any decrease on GR levels. We propose that chromatin structure may contribute decisively to the differential expression of MMTV-LTR by two mechanisms: limiting MMTV-LTR accessibility to activating transcription factors and accelerating its shutting down upon a decrease on GR levels.