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El Síndrome de Aicardi-Goutieres (SAG) se caracteriza por una encefalopatía genética, progresiva, de inicio temprano, que se asocia a un proceso inflamatorio. Además del SNC, puede afectar a la piel, con erupciones tipo sabañones, y presentar microcefalia, talla baja, disfunción hepática, disfunción tiroidea, reactantes de fase aguda elevados, anticuerpos autoinmunes positivos y asociaciones para enfermedades sistémicas autoinmunes como él LES. El SAG presenta locus heterogénicos, con mutaciones identificadas en los genes que codifican el exonucleasa TREX1 3´â5´ y las tres subunidades del complejo de endonucleasa RNASEH2. Se presenta el caso de una paciente de 2 años de edad, con retraso del desarrollo psicomotor, sin otras manifestaciones sistémicas, diagnosticada como SAG, con variante c.529G(A (p.Ala177Thr) con efecto patogénico en homocigosis en el gen RNASEH2B.
Aicardi-Goutieres Syndrome (AGS) is characterized by an early-onset, progressive, genetic encephalopathy associated with an inflammatory process. In addition to the CNS, it can affect the skin, with chilblain-like eruptions, and present with microcephaly, short stature, liver dysfunction, thyroid dysfunction, elevated acute phase reactants, positive autoimmune antibodies, and associations for autoimmune systemic diseases such as SLE. SAG presents heterogeneous loci, with mutations identified in the genes encoding the TREX1 3'â5' exonuclease and the three subunits of the RNASEH2 endonuclease complex. We present the case of a female 2-year-old patient, with delayed psychomotor development, without other systemic manifestations, diagnosed as SAG, with variant c.529G>A (p.Ala177Thr) with a pathogenic effect in homozygosis in the RNASEH2B gene.
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The use of antidepressants during pregnancy benefits the mother's well-being, but the effects of such substances on neurodevelopment remain poorly understood. Moreover, the consequences of early exposure to antidepressants may not be immediately apparent at birth. In utero exposure to selective serotonin reuptake inhibitors (SSRIs) has been related to developmental abnormalities, including a reduced white matter volume. Several reports have observed an increased incidence of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) after prenatal exposure to SSRIs such as sertraline, the most widely prescribed SSRI. The advent of human-induced pluripotent stem cell (hiPSC) methods and assays now offers appropriate tools to test the consequences of such compounds for neurodevelopment in vitro. In particular, hiPSCs can be used to generate cerebral organoids - self-organized structures that recapitulate the morphology and complex physiology of the developing human brain, overcoming the limitations found in 2D cell culture and experimental animal models for testing drug efficacy and side effects. For example, single-cell RNA sequencing (scRNA-seq) and electrophysiological measurements on organoids can be used to evaluate the impact of antidepressants on the transcriptome and neuronal activity signatures in developing neurons. While the analysis of large-scale transcriptomic data depends on dimensionality reduction methods, electrophysiological recordings rely on temporal data series to discriminate statistical characteristics of neuronal activity, allowing for the rigorous analysis of the effects of antidepressants and other molecules that affect the developing nervous system, especially when applied in combination with relevant human cellular models such as brain organoids.
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Transtorno do Espectro Autista , Inibidores Seletivos de Recaptação de Serotonina , Gravidez , Feminino , Recém-Nascido , Animais , Humanos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/epidemiologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Encéfalo , OrganoidesRESUMO
Abstract Background: The field of neurodegenerative dementia genetics has advanced significantly over the past two decades, but there are still more to be discovered (such as the gene mutation in some familial forms of dementia). Objective: to provide a brief review of the most recent discoveries regarding monogenic dementia, and covering the most frequent genetic diseases that can cause dementia (neurodegenerative or not). Methods: a review of the literature will be carried out. Results: neurodegenerative dementias, vascular dementias and leukoencephalopathies caused by single pathogenic variants are presented. Conclusion: The spectrum of clinical presentations for most of the genes discussed is wide, and hence genetic testing in clinic should try to cover as many genes as possible.
RESUMO Antecedentes: O campo da genética das demências neurodegenerativas avançou significativamente nas últimas duas décadas, mas ainda há mais a ser descoberto (como a mutação genética em algumas formas familiares de demência). Objetivo: fornecer uma breve revisão das descobertas mais recentes sobre demência monogênica, e abrangendo as doenças genéticas mais frequentes que podem causar demência (neurodegenerativa ou não). Métodos: será realizada uma revisão da literatura. Resultados: são apresentadas demências neurodegenerativas, demências vasculares e leucoencefalopatias causadas por variantes patogênicas únicas. Conclusão: O espectro de apresentações clínicas para a maioria dos genes discutidos é amplo e, portanto, os testes genéticos na clínica devem tentar cobrir o maior número possível de genes.
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RESUMEN INTRODUCCIÓN: La leucoencefalopatia tóxica es una afección que compromete la sustancia blanca por exposición a sustancias tóxicas. La heroina es una de las implicadas en el desarrollo de la leucoencefalopatia con diferencias exclusivas que suceden con la inhalación según las diversas técnicas en comparación al uso intravenoso, bien sea de la heroína o de otras sustancias psicoactivas. En esta serie describimos cinco casos, de sexo masculino, que desarrollaron leucoencefalopatia espongiforme por heroína (LEH) posterior a la inhalación de vapores, en un hospital del sistema de salud público en la ciudad de Armenia, Colombia. OBJETIVO: El objetivo de este estudio es describir las características demográficas, clínicas, hallazgos de laboratorio e imágenes diagnósticas, así como la mortalidad asociada a LEH en la muestra estudiada. MÉTODOS: Recolección de datos de historias clinicas y búsqueda de imágenes registradas en el Hospital San Juan de Dios de Armenia durante el periodo 2017-2018. RESULTADOS: Se obtienen cinco casos clínicos de pacientes usuarios de vapores inhalados de heroina, quienes ingresan con signos neurológicos de predominio motores y extrapiramidales, con el signo radiológico clásico de "Chasing the Dragon" en estudios de TC cerebral simple en todos los casos. De los cinco casos se presenta un deceso, determinando una mortalidad de 20% comparado con un 25% de mortalidad reportado en la literatura. CONCLUSIONES: La LEH suele estar subdiagnosticada dado que suele confundirse con un trastorno neuropsiquiatríco o de la conducta asociada al consumo de sustancias psicoactivas (SPA), el diagnóstico se realizó con los hallazgos típicos en las imágenes de TC cerebral simple. Se debe tener en cuenta las estadísticas sobre consumo de heroína a la hora de realizar el abordaje de un paciente con historial de consumo de SPA y los signos neurológicos para relacionarlos con esta etiologia y dar un manejo integral a estos pacientes.
ABSTRACT IlNTRODUCTION: Toxic leukoencephalopathy is a condition that compromises the encephalic white matter due to exposure to toxic substances. Heroin is one of those involved in the development of leukoencephalopathy and there are certain differences that occur with its inhalation with the different techniques compared to intravenous use, either heroin or other psychoactive substances. In this serie, we describe five cases of male sex who developed heroin spongiform leukoencephalopathy (HSLE) after inhalation of vapors, in a Hospital of the public health system in the city of Armenia, Colombia. OBJECTIVES: The objective of this study is to describe the demographic and clinical characteristics, laboratory findings and diagnostic images, as well as the mortality associated with HSLE in the sample studied. METHODS: Collection of data from medical records and search of images registered at the San Juan de Dios Hospital in Armenia during the period 2017-2018. RESULTS: Five clinical cases were obtained of patients who were users of inhaled heroin vapors and were admitted to the hospital with predominantly motor and extrapyramidal neurological signs, with simple brain CT studies showing the classic radiological sign of "Chasing the Dragon" in all five cases. One death was presented, with a mortality of 20% compared to the 25% mortality that has been reported in the scientific literature. CONCLUSIONS: HSLE is usually underdiagnosed since it is often confused with a neuropsychiatric or behavioral disorder associated with the consumption of psychoactive substances (PAS). The diagnosis was made with the typical findings in simple brain CT images. Statistics on heroin use must be considered when approaching a patient with a history of PAS use and neurological signs, to relate them to this etiology and provide comprehensive management to these patients.
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Tomografia Computadorizada por Raios X , Hipóxia Encefálica , Inalação , Heroína , LeucoencefalopatiasRESUMO
Leukoencephalopathy is a myelin disorder caused by multiple agents, including substance abuse. A 28-year-old man arrived at the emergency department having suffered from asthenia, dizziness, disorientation and ataxia for two months. He had a two-year history of heroin inhalation. He arrived in a normal physical condition. Brain magnetic resonance showed bilateral diffuse hypointense lesions in the white matter. At day 3 after admission, he presented neurological deterioration, stupor, haemodynamic instability, respiratory failure, and died. Toxic leukoencephalopathy symptoms start with inattention, memory and personality changes, and may eventually cause dementia and death. Heroin inhalation is a common practice and can lead to leukoencephalopathy. Leukoencephalopathy associated with heroin inhalation is a rare entity that mainly affects young adults and has a high social impact. Its aetiology is unclear, it has no effective treatment and there is a high mortality rate. Heroin consumption is on the rise in Colombia, so TL should be considered by medical staff.
La leucoencefalopatía es una patología de la mielina producida por múltiples agentes, incluidas las sustancias de abuso. Un varón de 28 años llegó urgencias por 2 meses de astenia, mareo, desorientación y ataxia. Tenía antecedentes de consumo inhalado de heroína por 2 años. Presentaba condiciones físicas regulares. La resonancia magnética cerebral mostró lesiones hipointensas difusas bilaterales en la sustancia blanca. Al tercer día presentó empeoramiento de su estado neurológico, estupor, inestabilidad hemodinámica, insuficiencia respiratoria y muerte. Los síntomas de leucoencefalopatía tóxica (LT) comienzan con falta de atención, cambios en la memoria y la personalidad, y finalmente demencia y muerte. El consumo de heroína inhalada es una práctica frecuente con riesgo de que produzca LT. La leucoencefalopatía asociada con el uso de heroína inhalada es una entidad rara que afecta principalmente a adultos jóvenes y tiene un alto impacto social. Su etiología no está clara, no tiene un tratamiento efectivo y tiene altas tasas de mortalidad. El consumo de heroína está aumentando en Colombia, por lo que el personal médico debe tener en cuenta la LT.
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Introducción: Las leucodistrofias primarias son un grupo de trastornos hereditarios que afectan la sustancia blanca cerebral de forma predominante. El término leucodistrofias primarias unifica las enfermedades que afectan las células gliales con compromiso de la mielina y el axón de base genética. Es un grupo de entidades, más de 30 en la actualidad, en expansión gracias a los avances en resonancia magnética y en genética. Objetivo: Contribuir al conocimiento de esta rara enfermedad con énfasis en la utilidad de su conocimiento clínico y en los estudios de imágenes evolutivos para el diagnóstico. Presentación del caso: Paciente con macrocranea detectada por la familia a los tres meses de nacida, al inicio refirieron que la circunferencia cefálica creció rápidamente y a partir del segundo semestre de vida el crecimiento se hizo más lento. La valoración clínica al año de edad comprobó una discreta dificultad para el control cefálico, intentaba dar pasos con apoyo, lenguaje de 3 a 4 palabras y ninguna otra afectación del neurodesarrollo. Al examen físico, una circunferencia cefálica de 55 cm (por encima de dos desviaciones estándar para la edad cronológica y sexo). Conclusiones: La evolución clínica favorable conjuntamente con el patrón de la resonancia magnética cerebral, que inicialmente mostró afectación de la sustancia blanca compatible con leucodistrofia inespecífica y en estudios evolutivos detecta presencia de quistes subtemporales, permitieron el diagnóstico de esta rara enfermedad infantil. La paciente recibió tratamiento sintomático para la espasticidad, apoyo pedagógico y control de sus crisis epilépticas(AU)
Introduction: Primary leukodistrophies are a group of hereditary disorders that affect in a predominant way the white substance of the brain. The term ´´primary leukodistrophies´´ unifies the diseases that affect the glial cells compromising myelin and the genetic based axon. They are a group of entities, more tan 30 nowadays, which are expanding due to the advances in magnetic resonance and genetics. Objective: To contribute to the understanding of this rare disease with emphasis in the usefulness of its clinical knowledge and in the evolutive studies of images for diagnosis. Case presentation: Female patient with macrocranea detected by the family at 3 months old. At the beginning, the family referred that the cephalic circumference grew quickly and from the second semester of life growing process was slower. The clinical assessment at first year of life proved a discreet difficulty for cephalic control; the patient tried to do support footsteps, and had a language of 3 to 4 words without any other affectation in the neurodevelopment. In the physical examination, she presented a cephalic circumference of 55 cm (higher than the two stantard deviations for the cronological age and sex). Conclusiones: The clinical evolution was favorable jointly with the pattern of brain magnetic resonance that initially showed affectation in the white substance compatible with inespecific leukodistrophy and in the evolutive studies it was detected the presence of subtemporal cysts which allowed to diagnose this rare children disease. The patient received symptomatic treatment for spasticity, pedagogical support and control of the epileptic crisis(AU)
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Humanos , Feminino , Lactente , Leucodistrofia de Células Globoides/diagnóstico por imagemRESUMO
INTRODUCTION AND OBJECTIVES: Leukodystrophies and genetic leukoencephalopathies constitute a vast group of pathologies of the cerebral white matter. The large number of etiopathogenic genes and the frequent unspecificity on the clinical-radiological presentation generate remarkable difficulties in the diagnosis approach. Despite recent and significant developments, molecular diagnostic yield is still less than 50%. Our objective was to develop and explore the usefulness of a new diagnostic procedure using standardized molecular diagnostic tools, and next-generation sequencing techniques. MATERIALS AND METHODS: A prospective, observational, analytical study was conducted in a cohort of 46 patients, evaluated between May 2008 and December 2016, with a suspected genetic leukoencephalopathy or leukodystrophy. A diagnostic procedure was set up using classical monogenic tools in patients with characteristic phenotypes, and next-generation techniques in nonspecific ones. RESULTS: Global diagnostic procedure yield was 57.9%, identifying the etiological pathogenesis in 22 of the 38 studied subjects. Analysis by subgroups, Sanger method, and next-generation sequencing showed a yield of 64%, and 46.1% respectively. The most common pathologies were adrenoleukodystrophy, cerebral autosomal-dominant arteriopathy with subcortical infarcts (CADASIL), and vanishing white matter disease. CONCLUSIONS: Our results confirm the usefulness of the proposed diagnostic procedure expressed in a high diagnostic yield and suggest a more optimal cost-effectiveness in an etiological analysis phase.
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Biomarcadores/análise , Genômica/métodos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Adolescente , Adulto , Idoso , Argentina , Criança , Pré-Escolar , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Leucodistrofia Metacromática/classificação , Leucoencefalopatias/classificação , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto JovemRESUMO
La epilepsia con retardo mental ligado al cromosoma X por mutación del gen PCDH19, es una condición que solo se presenta en las mujeres. El cuadro clínico suele verse complicado con retardo global del desarrollo y epilepsia. En la edad adulta puede manifestarse con discapacidad intelectual y hasta 20 % de las mujeres afectadas no presentan convulsiones ni retardo intelectual. Se presenta el caso de una niña con epilepsia, retardo del desarrollo y conversión autista, asociados con leucoencefalopatía y tractopatía posterior reversible por mutación del PCDH19 (c.142G>T/ p.Glu48X).
Epilepsy and mental retardation produced by mutations in gene PCDH19 (protocadherin 19) is an X-linked syndrome restricted to females. It starts with global and speech developmental delay and epilepsy; intellectual disability may continue in adults. At least in 20% of cases, there are no seizures or intellectual retardation. We report the case of a girl with epilepsy, developmental delay, and autistic conversion associated with posterior reversible leukoencephalopathy and tractopathy produced by PCDH19 mutation (c.142G>T/ p.Glu48X).
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Epilepsia , Encefalopatias , Convulsões Febris , Leucoencefalopatias , Deficiência IntelectualRESUMO
Upgaze or sustained elevation of the eyes, is an alteration of ocular motility initially described in hypoxic coma. We report a 65-year-old woman admitted with hypotension and alteration of sensorium due to the ingestion of 9.5 g of Bupropion. She presented two seizures of short duration, without epileptic activity on the EEG. She had a persistent asynchronous myoclonus in extremities, tachycardia and prolonged Q-t. She suffered a cardiac arrest caused by asystole, which recovered quickly in five minutes. At that moment, upgaze appeared, associated with a persistent ocular opening, which persisted for days, but finally disappeared, without remission of coma. A magnetic resonance imaging done at the eighth day, showed hyperintensity of the oval center and corpus callosum which disappeared in a new imaging study done 30 days later, where images of hypoxia in the basal nuclei and cortex appeared. The patient died forty seven days after admission. Up-gaze is an ominous oculomotor alteration linked to an important but incomplete damage in the cerebral cortex, a condition that perverts some sequences of the ocular opening, reversing the Bell phenomenon and producing eyelid retraction.
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Humanos , Feminino , Idoso , Transtornos da Motilidade Ocular/induzido quimicamente , Hipóxia Encefálica/induzido quimicamente , Bupropiona/efeitos adversos , Coma/induzido quimicamente , Antidepressivos de Segunda Geração/efeitos adversos , Overdose de Drogas/complicações , Transtornos da Personalidade/tratamento farmacológico , Suicídio , Imageamento por Ressonância Magnética , Evolução FatalRESUMO
La neurotoxicidad de los medicamentos antineoplásicos es un fenómeno de relativa frecuencia, que ocurre principalmente sobre el sistema nervioso periférico y más comúnmente con fármacos citotóxicos como platinos, taxanos y derivados de la vinca. La toxicidad sobre el sistema nervioso central asociado al uso del 5-fluorouracilo es por el contrario un evento poco común, pero no por ello menos importante. El clínico debe aprender a reconocer y tratar las dos variedades de esta condición médica: la encefalopatía aguda y la leucoencefalopatía subaguda; cada una con fisiopatología, manifestaciones clínicas y tratamiento diferentes. La siguiente presentación de casos ejemplifica estas dos variedades y brinda elementos diagnósticos y terapéuticos para cada una de ellas. (ActaMed Colomb 2015; 40: 338-344).
The neurotoxicity of anticancer drugs is a relatively common phenomenon, occurring mainly on the peripheral nervous system, most commonly with cytotoxic drugs such as platinum, taxanes and vinca derivatives. Toxicity on the central nervous system associated with the use of 5-fluorouracil is on the contrary a rare event, which does not make it less important. The clinician must learn to recognize and treat the two varieties of this medical condition: acute encephalopathy and sub-acute leukoencephalopathy, each with different pathophysiology, clinical manifestations and treatment. The following case presentation illustrates these two varieties and provides diagnostic and therapeutic elements for each one of them. (Acta Med Colomb 2015; 40: 338-344).