Computational and mitochondrial functional studies of novel compound heterozygous variants in SPATA5 gene support a causal link with epileptogenic encephalopathy.

The SPATA5 gene encodes a 892 amino-acids long protein that has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Several studies have associated homozygous or compound heterozygous mutations in SPATA5 gene to microcephaly, intellectual disability, seizures and hearing loss. This suggests a role of the SPATA5 gene also in neuronal development. Recently, our group presented results validating the use of blood cells for the assessment of mitochondrial function for diagnosis and follow-up of mitochondrial disease, minimizing the need for invasive procedures such as muscle biopsy. In this study, we were able to diagnose a patient with epileptogenic encephalopathy using next generation sequencing. We found two novel compound heterozygous variants in SPATA5 that are most likely causative. To analyze the impact of SPATA5 mutations on mitochondrial functional studies directly on the patients' mononuclear cells and platelets were undertaken. Oxygen consumption rates in platelets and PBMCs were impaired in the patient when compared to a healthy control. Also, a decrease in mitochondrial mass was observed in the patient monocytes with respect to the control. This suggests a true pathogenic effect of the mutations in mitochondrial function, especially in energy production and possibly biogenesis, leading to the observed phenotype.

[Febrile seizures: questions and answers]. / Crisis o convulsiones febriles: certezas y preguntas.

A febrile seizure occurs in association with fever in a child aged 6 to 60 months, without central nervous system infection or other known cause of acute seizures in a child without a prior history of afebrile seizures. Febrile seizures occur in about 2-5% of children. Central nervous system infections should be considered in patients with febrile seizures, even though the frequency of this possibility is low, especially when patients do not return to baseline. Simple febrile seizures are considered benign events and there are clear guidelines about evaluation and management, but the evaluation of complex febrile seizures is controversial. They are associated with a small increased risk of epilepsy which cannot be prevented. The role of electroencephalography is controversial. We analyzed the data of many studies and concluded that epileptiform discharges have poor positive predictive value. Neuroimaging is recommended to look for acute or pre-existing hippocampal abnormalities following febrile status or focal febrile seizures that could be associated to the risk of developing mesial temporal sclerosis and temporal lobe epilepsy. The relationship between these disorders and febrile seizures remains a controversial issue. An abnormal electroencephalography or magnetic resonance imaging studies will not change the clinical management and could contribute to overdiagnosis.

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.

Two compound heterozygous variants in the CLN8 gene are responsible for neuronal cereidolipofuscinoses disorder in a child: a case report.

Background: Neuronal Ceroid Lipofuscinosis (NCL) disorders, recognized as the primary cause of childhood dementia globally, constitute a spectrum of genetic abnormalities. CLN8, a subtype within NCL, is characterized by cognitive decline, motor impairment, and visual deterioration. This study focuses on an atypical case with congenital onset and a remarkably slow disease progression. Methods: Whole-genome sequencing at 30× coverage was employed as part of a national genomics program to investigate the genetic underpinnings of rare diseases. This genomic approach aimed to challenge established classifications (vLINCL and EPMR) and explore the presence of a continuous phenotypic spectrum associated with CLN8. Results: The whole-genome sequencing revealed two novel likely pathogenic mutations in the CLN8 gene on chromosome 8p23.3. These mutations were not previously associated with CLN8-related NCL. Contrary to established classifications (vLINCL and EPMR), our findings suggest a continuous phenotypic spectrum associated with CLN8. Pathological subcellular markers further validated the genomic insights. Discussion: The identification of two previously undescribed likely pathogenic CLN8 gene mutations challenges traditional classifications and highlights a more nuanced phenotypic spectrum associated with CLN8. Our findings underscore the significance of genetic modifiers and interactions with unrelated genes in shaping variable phenotypic outcomes. The inclusion of pathological subcellular markers further strengthens the validity of our genomic insights. This research enhances our understanding of CLN8 disorders, emphasizing the need for comprehensive genomic analyses to elucidate the complexity of phenotypic presentations and guide tailored therapeutic strategies. The identification of new likely pathogenic mutations underscores the dynamic nature of CLN8-related NCL and the importance of individualized approaches to patient management.

[Neurological consequences of prematurity]. / Complicaciones neurológicas de la prematuridad.

Premature births are an important health indicator for a country. These children have a higher risk of mortality and morbidity. The main brain injuries in preterm infants include white matter injuries, intracranial hemorrhages, and cerebellar injuries. These injuries can be detected through brain ultrasound and magnetic resonance imaging (MRI), with MRI being the most sensitive technique. Perinatal brain injuries may have long-term consequences on the neurodevelopment of preterm infants, with an increased risk of cerebral palsy, cognitive, behavioral, sensory, and learning disorders, among others. It is key to implement prevention strategies and early intervention to reduce the negative consequences of brain injuries associated with prematurity. Key words: prematurity, periventricular leukomalacia, intracranial hemorrhage, neurodevelopmental disorders, cerebral palsy.

Los nacimientos prematuros representan un indicador importante de salud de un país. Estos niños tienen un mayor riesgo de mortalidad y morbilidad. Las principales lesiones encefálicas en los prematuros incluyen lesiones de la sustancia blanca, hemorragias intracraneanas y lesiones cerebelosas, que pueden ser detectadas mediante ecografía encefálica y resonancia magnética, siendo esta última la técnica más sensible. Estas lesiones pueden tener repercusión a largo plazo en el neurodesarrollo de los prematuros, con un mayor riesgo de parálisis cerebral, trastornos cognitivos, conductuales, sensoriales y del aprendizaje, entre otros. Es fundamental aplicar estrategias de prevención y atención temprana para reducir las consecuencias negativas de las lesiones encefálicas asociadas a la prematuridad.

[Venous and cerebral sinus thrombosis in newborns and children]. / Trombosis venosa y de senos cerebrales en recién nacidos y niños.

INTRODUCTION: Cerebral venous sinus thrombosis (CVST) is a well-known, although underestimated, cause of stroke in childhood. Its diagnosis requires a high index of suspicion, a correct interpretation of neuroimaging studies and an interrelation between clinicians and radiologists. The clinical features, risk factors and neuroimaging of children under 15 years of age with CVST were analyzed. METHODS: multicenter, retrospective, descriptive, study of a consecutive series of cases of children under 15 years of age, who were admitted due to CVST between January 1st, 2010, and March 1st, 2022. RESULTS: The study included 51 patients: 39% with acute symptoms and 59% with subacute symptoms. Newborns predominantly presented encephalopathic symptoms and seizures, while children exhibited signs of intracranial hypertension (ICH). Risk factors were identified in 90% of the cases. Magnetic resonance with angiography in venous time confirmed the diagnosis in 80% of the patients, with the straight sinus being the most affected in newborns and the lateral sinus in children. Hemorrhagic complications were found in 30.5%, being more frequent in newborns. Anticoagulation was initiated in 82% without complications. Sequelae were present in 44.4% of newborns and 37.9% of children, being more frequent and severe in newborns. CONCLUSIONS: To make an early diagnosis, it is essential to consider CVST in newborns with encephalopathic symptoms and/or seizures, and in children with signs of ICH in the presence of predisposing or triggering conditions.

Introducción: La trombosis de venas y senos venosos cerebrales (TVSC) constituye una causa conocida, aunque subestimada de ictus en la infancia. Su diagnóstico requiere un alto índice de sospecha, una correcta interpretación de la neuroimagen e interrelación entre el clínico y el radiólogo. OBJETIVO: Analizar las manifestaciones clínicas, factores de riesgo y neuroimagen de recién nacidos (RN) y niños menores de 15 años con TVSC. Métodos: Estudio descriptivo, retrospectivo, multicéntrico, de una serie consecutiva de casos de menores de 15 años que ingresaron por TVSC entre el 1 de enero del 2010 y el 1 de marzo de 2022. RESULTADOS: El estudio incluyó 51 pacientes: 39% con síntomas agudos y 59% subagudos. En los RN predominaron síntomas encefalopáticos y convulsiones, mientras en los niños elementos de hipertensión endocraneana (HTEC). Se identificaron factores de riesgo en el 90% de los casos. La resonancia magnética con angiografía en tiempo venoso confirmó el diagnóstico en el 80%, siendo el seno recto el más afectado en RN y el seno lateral en niños. Se encontraron complicaciones hemorrágicas en 30.5%, siendo más frecuentes en los RN. Se inició anticoagulación en el 82% sin complicaciones. Las secuelas estuvieron presentes en 44.4% de RN y 37.9% de niños, siendo más frecuentes y graves en los RN. CONCLUSIONES: Para realizar un diagnóstico precoz es fundamental pensar en TVSC en RN con síntomas encefalopáticos y/o convulsiones y en mayores con clínica de HTEC en presencia de enfermedades predisponentes o desencadenantes.

Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review.

Background: Rho-related BTB domain-containing protein 2 (RHOBTB2) is a protein that interacts with cullin-3, a crucial E3 ubiquitin ligase for mitotic cell division. RHOBTB2 has been linked to early infantile epileptic encephalopathy, autosomal dominant type 64 (OMIM618004), in 34 reported patients. Methods: We present a case series of seven patients with RHOBTB2-related disorders (RHOBTB2-RD), including a description of a novel heterozygous variant. We also reviewed previously published cases of RHOBTB2-RD. Results: The seven patients had ages ranging from 2 years and 8 months to 26 years, and all had experienced seizures before the age of one (onset, 4-12 months, median, 4 months), including various types of seizures. All patients in this cohort also had a movement disorder (onset, 0.3-14 years, median, 1.5 years). Six of seven had a baseline movement disorder, and one of seven only had paroxysmal dystonia. Stereotypies were noted in four of six, choreodystonia in three of six, and ataxia in one case with multiple movement phenotypes at baseline. Paroxysmal movement disorders were observed in six of seven patients for whom carbamazepine or oxcarbazepine treatment was effective in controlling acute or paroxysmal movement disorders. Four patients had acute encephalopathic episodes at ages 4 (one patient) and 6 (three patients), which improved following treatment with methylprednisolone. Magnetic resonance imaging scans revealed transient fluid-attenuated inversion recovery abnormalities during these episodes, as well as myelination delay, thin corpus callosum, and brain atrophy. One patient had a novel RHOBTB2 variant (c.359G>A/p.Gly120Glu). Conclusion: RHOBTB2-RD is characterized by developmental delay or intellectual disability, early-onset seizures, baseline movement disorders, acute or paroxysmal motor phenomena, acquired microcephaly, and episodes of acute encephalopathy. Early onsets of focal dystonia, acute encephalopathic episodes, episodes of tongue protrusion, or peripheral vasomotor disturbances are important diagnostic clues. Treatment with carbamazepine or oxcarbazepine was found to be effective in controlling acute or paroxysmal movement disorders. Our study highlights the clinical features and treatment response of RHOBTB2-RD.

[Tuberous sclerosis complex: diagnosis and current treatment]. / Complejo de esclerosis tuberosa: diagnóstico y tratamiento actual.

Tuberous sclerosis complex is an autosomal dominant genetic multisystemic disorder caused primarily by mutations in one of the two tumor suppressor genes TSC1 or TSC2, resulting in increased activation of the mTOR pathway. Regarding clinical manifestations, a wide range of phenotypic variability exists, with symptoms constellations that may differ in affected organs (brain, skin, heart, eyes, kidneys, lungs), age of presentation and severity, but usually with great impact in biopsychosocial aspects of health and in quality of life. Main clinical neurological features are epilepsy (frequently, antiepileptic drug-resistant epilepsy), neuropsychiatric disorders, and subependymal giant cell astrocytomas. Recently, many therapeutic strategies have developed, including preventive treatment of epilepsy, new options for treatment of epilepsy as cannabidiol, mTOR inhibitors, ketogenic diet, and a more precise epilepsy surgery. Subependymal giant cell astrocytomas may require surgical procedures or mTOR inhibitors treatment. mTOR inhibitors may also be useful for other comorbidities. To improve quality of life of patients with tuberous sclerosis complex, it is essential to be able to deliver an integrated approach by specialized multidisciplinary teams, coordinated with primary care physicians and health professionals, that include access to treatments, attention of psychosocial aspects, and an adequate health care transition from pediatric to adult care.

El complejo de esclerosis tuberosa es un trastorno genético autosómico dominante multisistémico, causado primariamente por mutaciones en uno de los genes supresores de tumores TSC1 o TSC2, que generan una sobre-activación de la vía mTOR. En relación a las manifestaciones clínicas, existe una gran variabilidad fenotípica, con constelaciones de síntomas que pueden diferir tanto en los órganos afectados (encéfalo, piel, corazón, ojos, riñones, pulmones), como en la edad de presentación y la gravedad, pero que generalmente impactan fuertemente en los aspectos biopsicosociales y en la calidad de vida. Las principales manifestaciones clínicas neurológicas incluyen la epilepsia (con frecuencia, fármaco-resistente), los trastornos neuropsiquiátricos y los síntomas relacionados a los astrocitomas de células gigantes. En los últimos años han surgido nuevos abordajes terapéuticos, incluyendo el tratamiento preventivo de la epilepsia, nuevas opciones de tratamiento para la epilepsia como el uso de cannabidiol, de inhibidores de mTOR, la terapia cetogénica y cirugía de epilepsia. Los astrocitomas de células gigantes pueden requerir tratamientos quirúrgicos o con inhibidores de mTOR. Estos últimos también pueden utilizarse para el tratamiento de otras comorbilidades. Para mejorar la calidad de atención de los pacientes con esclerosis tuberosa, el desafío es poder brindar un abordaje integral por equipos interdisciplinarios especializados, en coordinación con sus médicos de cabecera y los equipos de salud del primer nivel de atención, que incluya el acceso a los tratamientos, la atención de los aspectos psicosociales, y una adecuada transición desde la atención pediátrica a la de adultos.

Blood cell respiration rates and mtDNA copy number: A promising tool for the diagnosis of mitochondrial disease.

Human mitochondrial diseases are a group of heterogeneous diseases caused by defects in oxidative phosphorylation, due to mutations in mitochondrial (mtDNA) or nuclear DNA. The diagnosis of mitochondrial disease is challenging since mutations in multiple genes can affect mitochondrial function, there is considerable clinical variability and a poor correlation between genotype and phenotype. Herein we assessed mitochondrial function in peripheral blood mononuclear cells (PBMCs) and platelets from volunteers without known metabolic pathology and patients with mitochondrial disease. Oxygen consumption rates were evaluated and respiratory parameters indicative of mitochondrial function were obtained. A negative correlation between age and respiratory parameters of PBMCs from control individuals was observed. Surprisingly, respiratory parameters of PBMCs normalized by cell number were similar in patients and young controls. Considering possible compensatory mechanisms, mtDNA copy number in PBMCs was quantified and an increase was found in patients with respect to controls. Hence, respiratory parameters normalized by mtDNA copy number were determined, and in these conditions a decrease in maximum respiration rate and spare respiratory capacity was observed in patients relative to control individuals. In platelets no decay was seen in mitochondrial function with age, while a reduction in basal, ATP-independent and ATP-dependent respiration normalized by cell number was detected in patients compared to control subjects. In summary, our results offer promising perspectives regarding the assessment of mitochondrial function in blood cells for the diagnosis of mitochondrial disease, minimizing the need for invasive procedures such as muscle biopsies, and for following disease progression and response to treatments.

[Mechanisms of brain injury of the premature baby]. / Mecanismos de lesión cerebral en niños prematuros.

Preterm birth is one of the main country health indicators. It is associated with high mortality and significant morbidity in preterm newborns with cerebral palsy and potential long-term neurodevelopmental disabilities like cognitive and learning problems. The main lesions could be: a) white matter injuries, generally associated with cortical and other regions of grey matter neuronal-axonal disturbances; b) intracranial hemorrhage that includes germinal matrix, intraventricular and parenchymal, c) cerebellum injuries. The white matter lesions include cystic and non-cystic (with microscopic focal necrosis) periventricular leukomalacia and non-necrotic diffuse white matter injury. Multiple etiologic factors are associated with these injuries. Anatomical and physiological characteristics of periventricular vascular structures predispose white matter to cerebral ischemia and, interacting with infection/inflammation factors, activate microglia, generating oxidative stress (mediated by free oxygen and nitrogen radicals), pro-inflammatory cytokine and glutamate toxicity, energetic failure and vascular integrity disturbances. All these factors lead to a particular vulnerability of pre-oligodendrocytes that will affect myelination. Hypoxia-ischemia also may produce selective neuronal necrosis in different cerebral regions. Germinal matrix is a highly vascularized zone beneath ependymal or periventricular region that constitutes a capillary bed with a particular structural fragility that predispose it to hemorrhage.

Los nacimientos prematuros son uno de los principales indicadores de salud de un país. Están asociados a una alta mortalidad e importante morbilidad en niños con parálisis cerebral y otros trastornos del neurodesarrollo, incluyendo problemas cognitivos y del aprendizaje. Los principales tipos de lesión encefálica en los recién nacidos prematuros son: a) las lesiones de la sustancia blanca, generalmente asociadas a alteraciones neuronales y axonales en la corteza cerebral y otras zonas de sustancia gris; b) hemorragias intracraneanas que incluyen las de la matriz germinal, intraventriculares e intraparenquimatosas y c) del cerebelo. Las lesiones de sustancia blanca incluyen la leucomalacia periventricular quística, no quística (con focos de necrosis microscópicos) y lesiones difusas de sustancia blanca, no necróticas. Estas lesiones tienen múltiples factores etiológicos. Las características anatómicas y fisiológicas de las estructuras vasculares periventriculares predisponen a la sustancia blanca a ser muy vulnerable a las situaciones de isquemia cerebral y, en interacción con factores infecciosos/inflamatorios, activan a las microglías generando estrés oxidativo (por liberación de radicales libres del oxígeno y del nitrógeno), liberación de citoquinas proinflamatorias, liberación de glutamato, fallo energético y alteración de la integridad vascular. Todo lo anteriormente mencionado genera una particular vulnerabilidad de los pre-oligodendrocitos que termina alterando la mielinización. La hipoxia-isquemia también puede producir necrosis neuronal selectiva en diferentes regiones encefálicas. La matriz germinal es un área altamente vascularizada en la región subependimaria periventricular con una estructura capilar muy frágil que la predispone a las hemorragias.

Complicaciones neurológicas de la prematuridad / Neurological consequences of prematurity

Resumen Los nacimientos prematuros representan un in dicador importante de salud de un país. Estos niños tienen un mayor riesgo de mortalidad y morbilidad. Las principales lesiones encefálicas en los prematuros incluyen lesiones de la sustancia blanca, hemorragias intracraneanas y lesiones cerebelosas, que pueden ser detectadas mediante ecografía encefálica y resonancia magnética, siendo esta última la técnica más sensible. Estas lesiones pueden tener repercusión a largo plazo en el neurodesarrollo de los prematuros, con un mayor riesgo de parálisis cerebral, trastornos cognitivos, con ductuales, sensoriales y del aprendizaje, entre otros. Es fundamental aplicar estrategias de prevención y aten ción temprana para reducir las consecuencias negativas de las lesiones encefálicas asociadas a la prematuridad.

Abstract Premature births are an important health indicator for a country. These children have a higher risk of mor tality and morbidity. The main brain injuries in preterm infants include white matter injuries, intracranial hem orrhages, and cerebellar injuries. These injuries can be detected through brain ultrasound and magnetic reso nance imaging (MRI), with MRI being the most sensitive technique. Perinatal brain injuries may have long-term consequences on the neurodevelopment of preterm infants, with an increased risk of cerebral palsy, cogni tive, behavioral, sensory, and learning disorders, among others. It is key to implement prevention strategies and early intervention to reduce the negative consequences of brain injuries associated with prematurity.

Trombosis venosa y de senos cerebrales en recién nacidos y niños / Venous and cerebral sinus thrombosis in newborns and children

Resumen Introducción : La trombosis de venas y senos venosos cerebrales (TVSC) constituye una causa conocida, aun que subestimada de ictus en la infancia. Su diagnóstico requiere un alto índice de sospecha, una correcta in terpretación de la neuroimagen e interrelación entre el clínico y el radiólogo. Objetivo : Analizar las manifestaciones clínicas, fac tores de riesgo y neuroimagen de recién nacidos (RN) y niños menores de 15 años con TVSC. Métodos: Estudio descriptivo, retrospectivo, multi céntrico, de una serie consecutiva de casos de menores de 15 años que ingresaron por TVSC entre el 1 de enero del 2010 y el 1 de marzo de 2022. Resultados : El estudio incluyó 51 pacientes: 39% con síntomas agudos y 59% subagudos. En los RN predomi naron síntomas encefalopáticos y convulsiones, mien tras en los niños elementos de hipertensión endocranea na (HTEC). Se identificaron factores de riesgo en el 90% de los casos. La resonancia magnética con angiografía en tiempo venoso confirmó el diagnóstico en el 80%, siendo el seno recto el más afectado en RN y el seno lateral en niños. Se encontraron complicaciones hemorrágicas en 30.5%, siendo más frecuentes en los RN. Se inició anti coagulación en el 82% sin complicaciones. Las secuelas estuvieron presentes en 44.4% de RN y 37.9% de niños, siendo más frecuentes y graves en los RN. Conclusiones : Para realizar un diagnóstico precoz es fundamental pensar en TVSC en RN con síntomas en cefalopáticos y/o convulsiones y en mayores con clínica de HTEC en presencia de enfermedades predisponentes o desencadenantes.

Abstract Introduction : Cerebral venous sinus thrombosis (CVST) is a well-known, although underestimated, cause of stroke in childhood. Its diagnosis requires a high index of suspicion, a correct interpretation of neuroim aging studies and an interrelation between clinicians and radiologists. The clinical features, risk factors and neuroimaging of children under 15 years of age with CVST were analyzed. Methods : multicenter, retrospective, descriptive, study of a consecutive series of cases of children under 15 years of age, who were admitted due to CVST between January 1st, 2010, and March 1st, 2022. Results : The study included 51 patients: 39% with acute symptoms and 59% with subacute symptoms. Newborns predominantly presented encephalopathic symptoms and seizures, while children exhibited signs of intracranial hypertension (ICH). Risk factors were 96 identified in 90% of the cases. Magnetic resonance with angiography in venous time confirmed the diagnosis in 80% of the patients, with the straight sinus being the most affected in newborns and the lateral sinus in chil dren. Hemorrhagic complications were found in 30.5%, being more frequent in newborns. Anticoagulation was initiated in 82% without complications. Sequelae were present in 44.4% of newborns and 37.9% of children, being more frequent and severe in newborns. Conclusions : To make an early diagnosis, it is essen tial to consider CVST in newborns with encephalopathic symptoms and/or seizures, and in children with signs of ICH in the presence of predisposing or triggering conditions.

Recertificación médica en Uruguay: múltiples miradas de una obligación impostergable / Medical recertification in Uruguay: multiple perspectives of an imperative need / Recertificação médica no Uruguai: múltiplas visões de uma obrigação urgente

Resumen: La recertificación es el resultado de un acto por el que una entidad legalmente acreditada, asegura que el profesional médico (previamente certificado) mantiene actualizados sus conocimientos y destrezas, y que ha desarrollado su actividad dentro del marco ético y científico adecuado al progreso del "saber" y del "hacer" propio de su especialidad. A pesar de un largo camino recorrido, en Uruguay no se ha podido establecer un proceso de recertificación universal. Múltiples actores (usuarios del sistema, médicos, Facultad de Medicina, programas de Desarrollo Profesional Médico Continuo) consideran que es una necesidad, sin embargo es necesario vencer algunas barreras para que se establezca un programa de recertificación. Se recorren algunos de estos aspectos en este documento, desarrollados en el contexto de un grupo de trabajo para el Congreso por los 100 años del Sindicato Médico del Uruguay.

Abstract: Recertification is the result of an act by which a legally accredited entity ensures that medical professionals (previously certified) keep their knowledge and skills up to date, and that they have practiced their profession within the ethical and scientific framework that regulates the process that evolves from "knowing" to "knowing how" in their areas of specialization. Despite a long journey in Uruguay, it has not been possible to establish a universal recertification process. Multiple actors (system users, doctors, the School of Medicine, Continuing Medical Professional Development programs) regard it as a need, although some barriers must be overcome in order to define a recertification program. This document covers a few of these aspects and is the result of a working group created for the Congress held in commemoration of the 100 years of the Uruguayan Medical Association.

Resumo: A recertificação é o resultado de um ato pelo qual uma entidade legalmente credenciada garante que o profissional médico (previamente certificado) mantém os seus conhecimentos e competências atualizados, e que desenvolveu a sua atividade dentro do quadro ético e científico adequado ao progresso do "conhecimento" e o "fazer" da sua especialidade. Apesar do longo caminho percorrido no Uruguai, ainda não foi possível estabelecer um processo de recertificação universal. Múltiplos atores (usuários do sistema, médicos, Faculdade de Medicina, programas de Desenvolvimento Continuado do Profissional Médico) consideram isso uma necessidade, porém é necessário superar algumas barreiras para que um programa de recertificação seja estabelecido. Alguns desses aspectos são abordados neste documento, desenvolvido no contexto de um grupo de trabalho para o Congresso pelos 100 anos do Sindicato Médico del Uruguay.

Tratamiento con toxina botulínica en niños con parálisis cerebral espástica. Análisis del tratamiento en tríceps sural durante 2017-2018 en el / Centro de Rehabilitación Infantil Teletón, Uruguay / Botulinum toxin in the treatment of children with spastic cerebral palsy. Analysis of sural tricep therapy during 2017-2018 at the Teletón Children's Rehabilitation Center, Uruguay / Tratamento com toxina botulínica em crianças com paralisia cerebral espástica. Análise do tratamento do tríceps sural durante 2017-2018 no Centro de Rehabilitación Infantil Teletón, Uruguai

Resumen: Introducción: la parálisis cerebral (PC) es la causa más frecuente de discapacidad motriz en niños y adolescentes. En el 85% de los casos, la manifestación motora predominante es la espasticidad. Las inyecciones de toxina botulínica tipo A (TB-A) se han usado para reducir la espasticidad en niños con PC. No existen investigaciones a nivel nacional que comprueben si los resultados son comparables a los reportados en la literatura. Objetivo: determinar el efecto del tratamiento con TB-A en el tríceps sural en conjunto con la rehabilitación física en niños con PC espástica durante los años 2017-2018 en el Centro de Rehabilitación Infantil Teletón, Uruguay. Métodos: se realizó un estudio descriptivo, retrospectivo, de cohorte histórica única con seguimiento longitudinal, mediante la revisión de historias clínicas de los pacientes con PC con marcha independiente o asistida que recibieron tratamiento con TB-A para el tratamiento de la espasticidad del tríceps sural durante el período 2017-2018. Resultados: se analizaron 40 procedimientos de inyección de TB-A. Se observó una buena respuesta al mes y a los 3 meses del tratamiento con TB-A, con mejoría del ángulo de dorsiflexión del pie con la rodilla en flexión y en extensión, mejoría del puntaje de la escala de espasticidad de Ashworth modificada y, en el 95% de los procedimientos, de la percepción subjetiva de los padres. Se observó una disminución del efecto hacia los 6 meses de la aplicación. Conclusión: la aplicación de TB-A en el Centro Teletón muestra resultados positivos, comparables con los reportados en la bibliografía internacional.

Abstract: Introduction: cerebral palsy (CP) is the most common source of motor disability in children and adolescents. In 85% of cases, the prevailing motor manifestation is spasticity. Botulinum toxin Type A injections (TB-A) have been used to reduce spasticity in children with cerebral palsy (CP). There are no studies at the national level that show whether the results are comparable to those reported in literature. Objective: to determine the effect of TB-A therapy in the triceps surae along with the physical rehabilitation in children with spastic cerebral palsy (CP) during 2017-2018 at the Teleton Children´s Rehabilitation Center, Uruguay. Method: retrospective, descriptive study of a single cohort with a longitudinal follow-up was conducted, through the review of medical records belonging to patients with CP with independent or assisted gait, who received TB-A therapy to treat sural triceps spasticity during 2017-2018. Results: 40 TB-A injection procedures were analysed. A good response was observed one month and three months after being treated with TB-A, evidencing improvement in the dorsiflexion angle between the foot and the knee in flexion and extension, improvement on the modified Ashworth spasticity scale score and, in 95% of procedures, the subjective perception of parents. The effect was observed to decrease towards 6 months after the procedure. Conclusion: application of TB-A at the Teletón Center shows positive results, comparable to those reported by international blibliography.

Resumo: Introdução: a paralisia cerebral (PC) é a causa mais freqüente de deficiência motora em crianças e adolescentes. Em 85% dos casos, a manifestação motora predominante é a espasticidade. As injeções de toxina botulínica tipo A (TB-A) têm sido usadas para reduzir a espasticidade em crianças com PC. Não há pesquisas nacionais que verifiquem se os resultados são comparáveis aos relatados na literatura. Objetivo: determinar o efeito do tratamento da TB-A no tríceps sural em conjunto com a reabilitação física em crianças com PC espástica durante os anos 2017-2018 no Centro de Rehabilitación Infantil Teletón, Uruguai. Métodos: estudo descritivo, retrospectivo, com coorte histórica única com acompanhamento longitudinal, realizado por meio da revisão de prontuários de pacientes com PC com deambulação independente ou assistida que receberam tratamento com TB-A para o tratamento da espasticidade do tríceps sural, no período 2017-2018. Resultados: 40 procedimentos de injeção de TB-A foram analisados. Observou-se boa resposta um mês e três meses após o tratamento com TB-A, com melhora no ângulo de dorsiflexão do pé com o joelho em flexão e extensão, melhora no escore da escala de espasticidade de Ashworth modificada e, em 95% dos procedimentos, a partir da percepção subjetiva dos pais. Uma diminuição no efeito foi observada 6 meses após a aplicação. Conclusão: a aplicação do TB-A no Centro de Rehabilitación Infantil Teletón apresentou resultados positivos, comparáveis aos relatados na literatura internacional.

3697G>A in MT-ND1 is a causative mutation in mitochondrial disease.

Mitochondrial diseases are a group of clinically heterogeneous disorders that can be difficult to diagnose. We report a two and a half year old girl with clinical symptoms compatible with Leigh disease but with no definitive diagnosis. Using next generation sequencing we found that mutation 3697G>A was responsible for the patient's clinical symptoms. Corroboration was performed via segregation analysis in mother and sister and by evolutionary analysis that showed that the mutation is located in a highly conserved region across a wide range of species. Functional analyses corroborated the mutation effect and indicated that the pathophysiological alterations were partially restored by Coenzyme Q10. In addition, we proposed that the presence of the mutation at high frequencies causes the phenotype in the patient, while other family members with intermediate levels of heteroplasmy are symptoms-free.

Encefalopatía subaguda adquirida del lactante por deficiencia de vitamina B12 materna / Subacute acquired encephalopathy secondary to maternal vitamin B12 deficiency / Encefalopatia subaguda adquirida em lactente devida à deficiência materna de vitamina B12

Resumen: Introducción: la deficiencia de vitamina B12 es infrecuente en la edad pediátrica. Puede producir síntomas neurológicos y hematológicos de diferente severidad. Si no se diagnostica y trata oportunamente, puede determinar secuelas neurológicas permanentes. Objetivos: presentar una serie de casos clínicos de encefalopatía secundaria a déficit materno de vitamina B12, discutir su potencial severidad y resaltar la importancia de las medidas de prevención. Metodología: estudio observacional basado en la revisión de las historias clínicas de lactantes con criterios clínicos y de laboratorio compatibles con encefalopatía por deficiencia de vitamina B12 materna. Resultados: se incluyeron cuatro casos clínicos, con edades entre 7 y 15 meses, que presentaron una encefalopatía subaguda por deficiencia de vitamina B12 secundaria a déficit materno luego de un período libre de síntomas, con rechazo del alimento, detención del crecimiento, adelgazamiento, irritabilidad, apatía, regresión del desarrollo, movimientos extrapiramidales y desaceleración de la velocidad del crecimiento del perímetro craneano. Los exámenes complementarios revelaron anemia megaloblástica, niveles bajos de vitamina B12 en el suero, hiperhomocisteinemia y aciduria metilmalónica. Se realizó tratamiento con vitamina B12 con buena evolución posterior. Discusión: la deficiencia de vitamina B12 debe considerarse en el diagnóstico diferencial de lactantes con regresión del desarrollo, movimientos involuntarios de inicio agudo o subagudo, convulsiones y apatía, especialmente si se asocian a anemia megaloblástica. Dado que la sintomatología es relativamente inespecífica, se requiere un alto grado de sospecha para realizar el diagnóstico precoz. El tratamiento es sencillo y eficaz y, de ser precoz, puede prevenir el daño cerebral permanente o la muerte.

Summary: Introduction: cobalamin or vitamin B12 deficiency is unusual in childhood. It may cause neurologic and hematologic symptoms of diverse severity. If not diagnosed and treated on time, it can lead to a severe clinical case of permanent neurological sequelae. The purpose of this study is to report four clinical cases of infants with subacute encephalopathy due to vitamin B12 deficiency after a maternal deficit, discuss its potential severity and emphasize the importance of preventive measures. Methods: observational study based on a review of clinical records of infants that showed clinical and laboratory criteria compatible with encephalopathy secondary to maternal vitamin B12 deficiency. Results: four infants between 7 and 15 months of age were included. They were diagnosed with vitamin B12 deficiency secondary to a maternal deficit. Clinically, they had had a symptom-free period followed by rejection of food, growth arrest, failure to thrive, irritability, apathy, regression of development, extrapyramidal movements and deceleration of cranial perimeter growth. They showed megaloblastic anemia, low serum B12 vitamin levels, hyperhomocysteinemia, and methylmalonic aciduria. They were treated with parenteral B12 vitamin and showed a favorable evolution. Discussion: vitamin B12 deficiency should always be analyzed in the differential diagnosis of infants with developmental regression, involuntary acute onset movements, seizures and apathy, especially associated with megaloblastic anemia. Due to its fairly unspecific clinical features, it high levels of suspicion and an early diagnosis are required. Treatment is simple and effective and can prevent permanent brain damage if started early.

Resumo: Introdução: a deficiência de vitamina B12 é pouco frequente na idade pediátrica. Pode produzir sintomas neurológicos e hematológicos de diferentes níveis de gravidade. Se não for diagnosticada e tratada prontamente, pode determinar sequelas neurológicas permanentes. Objetivos: apresentar uma série de casos clínicos de encefalopatia devida à deficiência materna de vitamina B12, discutir sua potencial gravidade e destacar a importância de medidas preventivas. Metodologia: estudo observacional baseado na revisão de prontuários de lactentes com critérios clínicos e laboratoriais compatíveis com encefalopatia por deficiência materna de vitamina B12. Resultados: foram incluídos 4 casos clínicos, com idades entre 7 e 15 meses, que apresentaram encefalopatia subaguda por deficiência de vitamina B12 devida à deficiência materna após período livre de sintomas, com rejeição alimentar, parada de crescimento, perda de peso, irritabilidade, apatia, regressão do desenvolvimento, movimentos extrapiramidais e desaceleração da taxa de crescimento do perímetro cefálico. Os exames complementares revelaram anemia megaloblástica, baixos níveis séricos de vitamina B12, hiper-homocisteinemia e acidúria metilmalônica. O tratamento com vitamina B12 foi realizado com boa evolução subsequente. Discussão: a deficiência de vitamina B12 deve ser avaliada no diagnóstico diferencial de lactentes com regressão do desenvolvimento, movimentos involuntários de início agudo ou subagudo, convulsões e apatia, principalmente se estiverem associados à anemia megaloblástica. Como os sintomas são relativamente inespecíficos, é necessário um alto grau de suspeição para poder realizar o diagnóstico precoce. O tratamento é simples e eficaz e, se realizado precocemente, pode prevenir danos cerebrais permanentes ou morte.

Crisis o convulsiones febriles: certezas y preguntas / Febrile seizures: questions and answers

Las crisis febriles están asociadas a fiebre en niños entre 6 y 60 meses de edad, sin infección del sistema nervioso central u otras causas de crisis sintomáticas agudas y sin historia de crisis afebriles previas. Ocurren en aproximadamente el 2-5% de los niños. Se debe considerar la posibilidad de una infección del sistema nervioso, a pesar de que la frecuencia es extremadamente baja cuando el examen físico posterior a la crisis no es orientador. Mientras que el manejo clínico de los niños con crisis febriles simples está bien definido, considerándolas como eventos benignos auto-limitados, la conducta en los niños con crisis febriles complejas es controvertida. Se asocian con un aumento relativamente pequeño del riesgo de epilepsia, el cual no puede ser prevenido mediante ninguna forma de tratamiento. El rol del electroencefalograma también es controvertido. Analizamos los datos de varios estudios y concluimos que las descargas epileptiformes tienen valores predictivos positivos bajos e implican pequeñas variaciones entre la probabilidad pre y post-prueba para el desarrollo de epilepsia posterior. Se ha propuesto realizar resonancias magnéticas encefálicas para detectar cambios a nivel hipocampal previos, agudos o posteriores a crisis focales o estatus febriles que pudieran relacionarse con el riesgo de esclerosis mesial temporal y de epilepsia temporal. La relación etiológica entre estas entidades continúa siendo un tema controvertido. En cualquier caso, los estudios alterados no van a cambiar el manejo clínico de las crisis febriles y pueden contribuir al sobre-diagnóstico.

A febrile seizure occurs in association with fever in a child aged 6 to 60 months, without central nervous system infection or other known cause of acute seizures in a child without a prior history of afebrile seizures. Febrile seizures occur in about 2-5% of children. Central nervous system infections should be considered in patients with febrile seizures, even though the frequency of this possibility is low, especially when patients do not return to baseline. Simple febrile seizures are considered benign events and there are clear guidelines about evaluation and management, but the evaluation of complex febrile seizures is controversial. They are associated with a small increased risk of epilepsy which cannot be prevented. The role of electroencephalography is controversial. We analyzed the data of many studies and concluded that epileptiform discharges have poor positive predictive value. Neuroimaging is recommended to look for acute or pre-existing hippocampal abnormalities following febrile status or focal febrile seizures that could be associated to the risk of developing mesial temporal sclerosis and temporal lobe epilepsy. The relationship between these disorders and febrile seizures remains a controversial issue. An abnormal electroencephalography or magnetic resonance imaging studies will not change the clinical management and could contribute to overdiagnosis.

Unusual Case of Phenylketonuria With Atypical Brain Magnetic Resonance Imaging Findings.

Phenylketonuria is a treatable inborn error of amino acid metabolism caused by deficiency of the enzyme phenylalanine hydroxylase, responsible for converting phenylalanine to tyrosine. We report a 10-month-old boy with psychomotor regression and infantile spasms. He was diagnosed with classic phenylketonuria and West syndrome. Treatment was initiated with phenylalanine-restricted diet and vigabatrin. After 5 months of treatment, he persists with developmental delay, severe hypotonia, swallowing disorder, and drug-resistant epilepsy. Brain magnetic resonance imaging showed the typical abnormalities in supratentorial white matter and exceptional infratentorial and basal ganglia compromise. Severity of white matter abnormalities and neurologic symptoms correlates with blood levels of phenylalanine. Infratentorial changes occur in severe cases. Other mechanisms could take part in cases like this with atypical neuroimaging abnormalities of the basal ganglia.

Encefalopatía posterior reversible en el curso de una emergencia hipertensiva, serie de cuatro niños hospitalizados en el Centro Hospitalario Pereira Rossell / Posterior reversible encephalopathy during a hypertensive emergency in 4 children hospitalized at the Pereira Rossell Pediatric Hospital / Encefalopatia reversível durante uma emergência hipertensiva em 4 crianças hospitalizadas no Centro Hospitalar Pereira Rossell

Introducción: la encefalopatía posterior reversible (PRES) es un complejo sindromático caracterizado por cefaleas, crisis epilépticas, trastornos visuales y alteración del sensorio asociado a cambios en la sustancia blanca de lóbulos occipitales y parietales en la resonancia nuclear magnética. Se relaciona con diversas causas que provocan edema cerebral, entre las que se destaca la hipertensión arterial (HTA) y los tratamientos inmunosupresores. Descripción de casos: se incluyeron cuatro niños hospitalizados entre el 1 de enero de 2005 y el 31 de diciembre de 2015 en el Centro Hospitalario Pereira Rossell. La mediana de edad fue 11,5 años. La manifestación clínica inicial en tres de los cuatro pacientes fue disnea y edemas generalizados. Todos presentaron hipertensión endocraneana y convulsiones generalizadas. La tomografía computada fue la primera imagen solicitada en todos los pacientes, evidenciado lesiones hipodensas córtico-subcorticales occipitales, parietales y frontales. Se realizó resonancia magnética en tres casos con hallazgos característicos. Todos presentaron síndrome nefrítico con cifras de tensión arterial mayores al P99, insuficiencia renal reversible, disminución de C3 y aumento del antiestreptolisina O (AELO). El control de HTA requirió politerapia en unidad de cuidado crítico. Ninguno presentó secuelas neurológicas. Conclusiones: la PRES es una asociación o manifestación poco habitual de la emergencia hipertensiva. Es necesaria la sospecha e identificación por parte del pediatra con el fin de realizar un abordaje terapéutico adecuado y precoz.

Introduction: posterior reversible encephalopathy (PRES) is a complex syndrome characterized by headaches, epileptic seizures, visual disturbances and sensorial alterations associated to changes of white matter in parieto-occipital regions shown in magnetic nuclear resonance. It is linked to various causes that provoke cerebral edema including arterial hypertension (AH) and immunosuppressive treatments. Clinical cases: 4 children admitted between January 1st, 2005 and December 31st, 2015 at the Pereira Rossell Pediatric Hospital. Median age: 11.5 years. The initial clinical manifestation in 3 of 4 patients was dyspnea and generalized edema. All of them presented endocranial hypertension and generalized convulsions. CT was the first requested image to all patients, and it was clear that all of them had experienced occipital cortical-subcortical, parietal and frontal hypodense lesions. In three of the cases we performed a Magnetic Resonance that showed typical findings. All of them presented nephritic syndrome with arterial hypertension over P99, reversible renal failure, a decrease of C3 and an increase of Antistreptolysin O (AELO). HTA control required polytherapy at the critical care unit. None of them presented neurological sequelae. Conclusions: PRES is an association or unusual manifestation of hypertensive emergency. Early detection by pediatricians seems essential to provide an appropriate therapeutic approach.

Introdução: a encefalopatia posterior reversível (PRES) é uma síndrome complexa caracterizada por dores de cabeça, convulsões epilépticas, distúrbios visuais e alterações sensoriais associadas à mudança da substância branca nas regiões parieto-occipitais observadas na ressonância magnética nuclear. Está ligada a várias causas que provocam o edema cerebral, incluindo hipertensão arterial (HA) e tratamentos imunossupressores. Casos clínicos: 4 crianças internadas entre 1º de janeiro de 2005 e 31 de dezembro de 2015 no Hospital Pediátrico Pereira Rossell. Idade mediana: 11,5 anos. A manifestação clínica inicial em 3 dos 4 pacientes foi dispneia e edema generalizado. Todos apresentaram hipertensão endocraniana e convulsões generalizadas. A TC foi a primeira imagem solicitada e todos os pacientes mostraram lesões occipitais corticais-subcorticais, parietais e hipodensas frontais evidentes. Em três dos casos, a Ressonância Magnética mostrou achados típicos. Todos apresentaram síndrome nefrítica com hipertensão arterial acima de P99, insuficiência renal reversível, diminuição de C3 e aumento de antiestreptolisina O (AELO). O controle de HTA requereu politerapia na unidade de terapia intensiva. Nenhum dos pacientes apresentou sequelas neurológicas. Conclusões: A PRES é uma associação ou manifestação de emergência hipertensiva pouco comum. A detecção precoce do pediatra é essencial para fornecer uma abordagem terapêutica adequada.

Impacto negativo de los medios tecnológicos en el neurodesarrollo infantil / Negative impact of technological media on child neurodevelopment

Resumen La exposición y el uso de medios electrónicos por parte de la mayoría de los niños es una realidad desde los primeros años de vida. Esta realidad se ha instalado en la vida de nuestros niños y de nuestra sociedad antes de que investigaciones cientí cas hayan podido evaluar su real impacto en el neurodesarrollo infantil. En los lactantes y pre-escolares, la exposición a pantallas electrónicas se ha asociado a un menor nivel de desarrollo cognitivo y del lenguaje. Asimismo, a mediano plazo, se ha relacionado con mayor riesgo de sobrepeso, dé cit de atención, y el riesgo de adoptar una actitud pasiva frente al mundo. En la edad escolar y en la adolescencia, el uso de estos instrumentos tecnológicos puede brindar oportunidades positivas para los aprendizajes y para la socialización. Sin embargo, más frecuentemente se observa un uso excesivo de estos dispositivos electrónicos, que repercute sobre la capacidad de concentración, el rendimiento escolar y sobre la cantidad y calidad del sueño nocturno. Algunos adolescentes que utilizan demasiado las redes sociales presentan síntomas de depresión, de déficit de sueño, sobrepeso, aislamiento social (afectados por el ciber-bullying), o están expuestos a contenidos y contactos inapropiados o riesgosos, y comprometen su privacidad y la con dencialidad de sus datos personales. Por todo ello, la comunidad académica debe informar sobre estos serios riesgos a la población, al mismo tiempo que continúa desarrollando investigaciones para conocer mejor el impacto que tienen los diferentes medios electrónicos sobre el neurodesarrollo y el bienestar de los niños y adolescentes.

Abstract Exposure and use of electronic media by the majority of children is part of their reality since the first years of life. This reality has installed in the life of our kids and our society before scientific research has been able to assess their real impact in child neurodevelopment. In infants, toddlers and preschoolers, exposure to electronic screens has been related to cognitive and language delay. Additionally, in the medium term, it has been related to a greater risk of overweight, lack of concentration and attention deficit, and a greater risk to adopt a passive attitude. In school age and in adolescence, these technological devices may bring positive opportunities towards learning and socialization. Nevertheless, more frequently, an overuse of these technologies is being seen, that affect the attention ability, the school performance and the amount and quality of nocturnal sleep of children and adolescents. Some adolescents that overuse social media develop symptoms of depression, insuffcient sleep, overweight and social isolation (affected by cyber-bullying) or are exposed to inappropriate or risky contents and contacts, and they endanger their privacy and the confidentiality of their personal data. For all these reasons, academic community has to inform the society about these serious risks, at the same time that continues developing researches to assess more profoundly the impact of the different electronic media to the neurodevelopment and well-being of our children and adolescents.