RESUMEN
We conducted an observational study from January 2016 through January 2017 of patients admitted to a reference pediatric hospital in Madrid, Spain, for neurologic symptoms and enterovirus infection. Among the 30 patients, the most common signs and symptoms were fever, lethargy, myoclonic jerks, and ataxia. Real-time PCR detected enterovirus in the cerebrospinal fluid of 8 patients, nasopharyngeal aspirate in 17, and anal swab samples of 5. The enterovirus was genotyped for 25 of 30 patients; enterovirus A71 was the most common serotype (21/25) and the only serotype detected in patients with brainstem encephalitis or encephalomyelitis. Treatment was intravenous immunoglobulins for 21 patients and corticosteroids for 17. Admission to the pediatric intensive care unit was required for 14 patients. All patients survived. At admission, among patients with the most severe disease, leukocytes were elevated. For children with brainstem encephalitis or encephalomyelitis, clinicians should look for enterovirus and not limit testing to cerebrospinal fluid.
Asunto(s)
Encefalitis Viral/virología , Encefalomielitis/virología , Enterovirus Humano A/aislamiento & purificación , Infecciones por Enterovirus/virología , Epidemias , Enfermedades del Sistema Nervioso/virología , Niño , Preescolar , Encefalitis Viral/epidemiología , Encefalomielitis/epidemiología , Infecciones por Enterovirus/epidemiología , Femenino , Humanos , Lactante , Masculino , Enfermedades del Sistema Nervioso/epidemiología , Estudios Prospectivos , España/epidemiologíaRESUMEN
PURPOSE: Pyridoxine-dependent epilepsy seizure (PDE; OMIM 266100) is a disorder associated with severe seizures that can be controlled pharmacologically with pyridoxine. In the majority of patients with PDE, the disorder is caused by the deficient activity of the enzyme α-aminoadipic semialdehyde dehydrogenase (antiquitin protein), which is encoded by the ALDH7A1 gene. The aim of this work was the clinical, biochemical, and genetic analysis of 12 unrelated patients, mostly from Spain, in an attempt to provide further valuable data regarding the wide clinical, biochemical, and genetic spectrum of the disease. METHODS: The disease was confirmed based on the presence of α-aminoadipic semialdehyde (α-AASA) in urine measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and pipecolic acid (PA) in plasma and/or cerebrospinal fluid (CSF) measured by high performance liquid chromatography (HPLC)/MS/MS and by sequencing analysis of messenger RNA (mRNA) and genomic DNA of ALDH7A1. KEY FINDINGS: Most of the patients had seizures in the neonatal period, but they responded to vitamin B6 administration. Three patients developed late-onset seizures, and most patients showed mild-to-moderate postnatal developmental delay. All patients had elevated PA and α-AASA levels, even those who had undergone pyridoxine treatment for several years. The clinical spectrum of our patients is not limited to seizures but many of them show associated neurologic dysfunctions such as muscle tone alterations, irritability, and psychomotor retardation. The mutational spectrum of the present patients included 12 mutations, five already reported (c.500A>G, c.919C>T, c.1429G>C c.1217_1218delAT, and c.1482-1G>T) and seven novel sequence changes (c.75C>T, c.319G>T, c.554_555delAA, c.757C>T, c.787 + 1G>T, c.1474T>C, c.1093-?_1620+?). Only one mutation, p.G477R (c.1429G>C), was recurrent; this was detected in four different alleles. Transcriptional profile analysis of one patient's lymphoblasts and ex vivo splicing analysis showed the silent nucleotide change c.75C>T to be a novel splicing mutation creating a new donor splice site inside exon 1. Antisense therapy of the aberrant mRNA splicing in a lymphoblast cell line harboring mutation c.75C>T was successful. SIGNIFICANCE: The present results broaden our knowledge of PDE, provide information regarding the genetic background of PDE in Spain, afford data of use when making molecular-based prenatal diagnosis, and provide a cellular proof-of concept for antisense therapy application.
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Epilepsia/tratamiento farmacológico , Epilepsia/genética , Terapia Genética/métodos , Oligonucleótidos Antisentido/uso terapéutico , Deficiencia de Vitamina B 6/complicaciones , Aldehído Deshidrogenasa/genética , Línea Celular , Análisis Mutacional de ADN , Epilepsia/etiología , Exones/genética , Femenino , Humanos , Hiperlisinemias/orina , Lactante , Recién Nacido , Linfocitos/efectos de los fármacos , Masculino , Mutación/genética , Polimorfismo de Nucleótido Simple , Empalme del ARN , Sacaropina Deshidrogenasas/deficiencia , Sacaropina Deshidrogenasas/orina , Espectrometría de Masas en TándemRESUMEN
Niemann-Pick type C (NP-C) disease is a neurovisceral atypical lysosomal lipid storage disorder with a poor prognosis. We present the 5-year neuropsychological follow-up of a patient with juvenile onset NP-C, spanning the pre-diagnostic stage to the period after treatment with miglustat (Actelion Pharmaceuticals Inc., CA, US). In the initial stages of the disease, the patient presented behavioral dysexecutive symptoms resembling those frequently observed in adult-onset forms and frontotemporal dementia, which frequently makes early diagnosis difficult in children. After 4 years of treatment, the impaired cognitive function and behavioral dysexecutive syndrome had been completely reversed. The variability of NP-C disease makes early diagnosis challenging. Evaluations of long-term neuropsychological development can help diagnose this neurodegenerative disease and document its progression.
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Enfermedad de Niemann-Pick Tipo C/psicología , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapéutico , Adolescente , Niño , Cognición , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Humanos , Estudios Longitudinales , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológicoRESUMEN
Fundamento: la insuficiencia placentaria es la causa más común del retardo del crecimiento intrauterino, que puede provocar alteraciones cardiovasculares. Recientemente, se han desarrollado terapias con eritropoyetina que protegen los tejidos cardiacos con hipoxia. Objetivo: evaluar la influencia de la eritropoyetina recombinante humana con bajo contenido de ácido siálico (NeuroEPO) en el corazón fetal en un modelo de insuficiencia placentaria en ratas. Métodos: se utilizaron 14 ratas Wistar gestadas con ligadura unilateral de la arteria uterina derecha en el día 16 de la gestación. Ese mismo día, a siete ratas se le administró NeuroEPO (0,5 mg/kg/día subcutáneo por tres días) y al resto placebo. En el día 20 de la gestación los fetos se dividieron en cuatro grupos: un grupo control, un grupo con retardo del crecimiento intrauterino, un grupo control NeuroEPO y un grupo con retardo del crecimiento intrauterino y NeuroEPO. En los fetos se obtuvo el peso placentario, peso fetal y la eficacia placentaria. En el estudio histológico se cuantificó el número de cardiomiocitos, número de vasos sanguíneos y cantidad de las fibras de colágenos. Resultados: el grupo con retardo del crecimiento intrauterino presentó una disminución del peso fetal, del número de cardiomiocitos, del número de vasos sanguíneos y un aumento en la cantidad de fibras colágenas (p<0.05). Al tratar con NeuroEPO a los fetos con retardo en el crecimiento intrauterino, aumentó el peso fetal, aunque el peso no fue similar al control. El resto de las variables se comportaron semejantes al control. Conclusiones: la administración de esta molécula mejoró el peso fetal y permitió un equilibrio adecuado en el desarrollo del corazón fetal, quizás, debido a los efectos citoprotectores de esta molécula.
Foundation: placental insufficiency is the most common cause of intrauterine growth retardation, which can cause cardiovascular alterations. Recently, erythropoietin therapies have been developed that protect hypoxic cardiac tissues. Objective: To evaluate the influence of human recombinant erythropoietin with low sialic acid content (NeuroEPO) on the fetal heart in a rat model of placental insufficiency. Methods: 14 Wistar rats gestated with unilateral ligation of the right uterine artery on day 16 of gestation were used. That same day, seven rats were administered NeuroEPO (0.5 mg/kg/day subcutaneously for three days) and the rest received placebo. On day 20 of gestation, the fetuses were divided into four groups: a control group, a group with intrauterine growth retardation, a NeuroEPO control group, and a group with intrauterine growth retardation and NeuroEPO. In the fetuses, placental weight, fetal weight and placental efficiency were obtained. In the histological study, the number of cardiomyocytes, number of blood vessels and quantity of collagen fibers were quantified. Results: the group with intrauterine growth retardation presented a decrease in fetal weight, the number of cardiomyocytes, the number of blood vessels and an increase in the amount of collagen fibers (p<0.05). When fetuses with intrauterine growth retardation were treated with NeuroEPO, fetal weight increased, although the weight was not similar to the control. The rest of the variables behaved similar to the control. Conclusions: the administration of this molecule improved fetal weight and allowed an adequate balance in the development of the fetal heart, perhaps due to the cytoprotective effects of this molecule.
RESUMEN
Congenital mirror movements (CMM) are involuntary movements of one side of the body that mirror intentional movements of the other side. Heterozygous missense, frameshift and nonsense variants and small intragenic deletions in DCC cause CMM, isolated agenesis of the corpus callosum (ACC) or both. We report here the clinical phenotype and natural history of ten individuals with CMM carrying five different monoallelic DCC variants, including the missense variant p.(Trp273Arg), two duplications, one deletion and one deletion-insertion; all are novel and absent from databases. We re-evaluated the 15 known disease-associated DCC missense variants by determining minor allele frequency (MAF) and pathogenicity using four in silico tools combining previous pathogenicity scores and the ACMG/AMP standards and guidelines and classified them in three groups. Group I contains three DCC missense variants that are rather unlikely to be associated with a higher risk to CMM and/or ACC. The five variants in group II may represent susceptibility factors to altered midline crossing in the central nervous system. Group III includes seven variants absent in publically available databases and representing possible pathogenic alleles, with four predicted to have a severe impact on protein function. Based on this data and the variable expressivity and incomplete penetrance present in heterozygous carriers of a DCC variant, classification and clinical interpretation of missense variants is challenging in the absence of evidence of pathogenicity originated from functional studies. Evaluation of missense variants by MAF and a weighted combination of several computational algorithms is recommended.
Asunto(s)
Receptor DCC/genética , Trastornos del Movimiento/genética , Mutación Missense , Niño , Preescolar , Potenciales Evocados Motores , Femenino , Frecuencia de los Genes , Heterocigoto , Humanos , Masculino , Trastornos del Movimiento/congénito , Trastornos del Movimiento/fisiopatología , Trastornos del Movimiento/terapia , Linaje , Análisis de Secuencia de ADN , Estimulación Magnética TranscranealRESUMEN
Delirium Tremens is quite rare in children and it is usually caused by withdrawal or abstinence from alcohol, barbiturates and other major tranquilizers. The usual symptoms of Delirium Tremens include severe altered mental status with confusion, delusions, hallucinations, and severe agitation. Although psychosis is a recognized manifestation of Phenytoin toxicity, visual hallucinations are not. This study reports the case of a 4-year-old male with febrile seizures plus syndrome who developed acute complex visual hallucinations and psychomotor agitation early after therapy with intravenous Phenytoin was administered. These visual hallucinations mimicked those linked to Delirium Tremens and were not associated with an encephalopathy or other known neuropsychiatric side effects of this drug. Moreover, the hallucinations occurred while serum Phenytoin concentrations were below therapeutic range. We made an extensive investigation in order to exclude a non-convulsive Status Epilepticus, a Central Nervous System infection, a metabolic disorder, an underlying psychiatric disease and a possible drug toxicity. The temporal relationship between initiation of Phenytoin and onset of visual hallucinations and resolution of symptoms with withdrawal of Phenytoin suggests that the visual disturbances were probably due to that antiepileptic drug.