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Hyperpolarization activated Cyclic Nucleotide (HCN) gated channels are crucial for various neurophysiological functions, including learning and sensory functions, and their dysfunction are responsible for brain disorders, such as epilepsy. To date, HCN2 variants have only been associated with mild epilepsy and recently, one monoallelic missense variant has been linked to developmental and epileptic encephalopathy. Here, we expand the phenotypic spectrum of HCN2- related disorders by describing twenty-one additional individuals from fifteen unrelated families carrying HCN2 variants. Seventeen individuals had developmental delay/intellectual disability (DD/ID), two had borderline DD/ID, and one had borderline DD. Ten individuals had epilepsy with DD/ID, with median age of onset of 10 months, and one had epilepsy with normal development. Molecular diagnosis identified thirteen different pathogenic HCN2 variants, including eleven missense variants affecting highly conserved amino acids, one frameshift variant, and one in-frame deletion. Seven variants were monoallelic of which five occurred de novo, one was not maternally inherited, one was inherited from a father with mild learning disabilities, and one was of unknown inheritance. The remaining six variants were biallelic, with four homozygous and two compound heterozygous variants. Functional studies using two-electrode voltage-clamp recordings in Xenopus laevis oocytes were performed on three monoallelic variants, p.(Arg324His), p.(Ala363Val), and p.(Met374Leu), and three biallelic variants, p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp). The p.(Arg324His) variant induced a strong increase of HCN2 conductance, while p.(Ala363Val) and p.(Met374Leu) displayed dominant negative effects, leading to a partial loss of HCN2 channel function. By confocal imaging, we found that the p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp) pathogenic variants impaired membrane trafficking, resulting in a complete loss of HCN2 elicited currents in Xenopus oocytes. Structural 3D-analysis in depolarized and hyperpolarized states of HCN2 channels, revealed that the pathogenic variants p.(His205Gln), p.(Ser409Leu), p.(Arg324Cys), p.(Asn369Ser) and p.(Gly460Asp) modify molecular interactions altering HCN2 function. Taken together, our data broadens the clinical spectrum associated with HCN2 variants, and disclose that HCN2 is involved in developmental encephalopathy with or without epilepsy.
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BACKGROUND: Cerebellar mutism syndrome (CMS) occurs in 8-29 % of children undergoing posterior fossa tumor surgery. Its main symptoms are mutism and emotional lability. Although it is always transient, recovery time can be lengthy with long-term cognitive sequelae. There is no approved drug treatment for CMS, but some drugs are used in everyday medical practice. One of these is fluoxetine, which has been used for many years in our institution. The main objective of this study was to establish the safety profile of fluoxetine in this condition. MATERIALS AND METHODS: The records of patients admitted to the pediatric intensive care unit after brain surgery at Angers University Hospital from 2010 to 2020 were reviewed. Children aged 2 years and older who underwent a posterior fossa tumor surgery and were diagnosed with CMS were included. Data on patient characteristics, prescription of fluoxetine treatment, side effects if any, and complete mutism duration were collected. RESULTS: Among 246 patients admitted to the pediatric intensive care unit for brain surgery during the study period, 23 had CMS and eight were prescribed fluoxetine. No serious adverse event related to fluoxetine was reported. Complete mutism duration did not differ significantly between the fluoxetine group and the non-fluoxetine group(p = 0.22). However, the treatment was initiated after recovery from complete mutism in half of the treated patients. CONCLUSION: This study suggests a positive safety profile of fluoxetine used in postoperative CMS. It does not answer the question of whether the treatment is effective for this indication. A randomized controlled trial based on a syndrome severity scale should be conducted to provide a more reliable assessment of the efficacy and safety of fluoxetine.
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Fluoxetina , Mutismo , Complicaciones Posoperatorias , Humanos , Fluoxetina/uso terapéutico , Fluoxetina/efectos adversos , Mutismo/tratamiento farmacológico , Mutismo/etiología , Masculino , Niño , Femenino , Preescolar , Complicaciones Posoperatorias/tratamiento farmacológico , Estudios Retrospectivos , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Neoplasias Infratentoriales/cirugía , Enfermedades Cerebelosas/cirugía , Adolescente , Síndrome , Procedimientos Neuroquirúrgicos/efectos adversos , Procedimientos Neuroquirúrgicos/métodosRESUMEN
OBJECTIVES: To assess the test-retest reliability of the corticokinematic coherence (CKC), an electrophysiological marker of proprioception, in children with cerebral palsy (CP). METHODS: Electroencephalography (EEG) signals from 15 children with unilateral or bilateral CP aged 23 to 53 months were recorded in two sessions 3 months apart using 128-channel EEG caps. During each session, children's fingers were moved at 2 Hz by an experimenter, in separate recordings for the more-affected (MA) and less-affected (LA) hands. The CKC was computed at the electrode and source levels, at movement frequency F0 (2 Hz) and its first harmonic F1 (4 Hz). A two-way mixed-effects model intraclass-correlation coefficient (ICC) was computed for the maximum CKC strength across electrodes at F0 and F1 obtained during the two sessions. RESULTS: ICC of the CKC strength acquired from LA and MA hands pooled together were respectively 0.51 (95% CI: 0.30-0.68) at F0 and 0.96 (95% CI: 0.93-0.98) at F1. The mean distances separating the CKC peaks in the source space at the two evaluation times were in the order of a centimeter. CONCLUSION: CKC is a robust electrophysiologic marker to study the longitudinal changes in cortical processing of proprioceptive afferences in young children with CP.
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Parálisis Cerebral , Electroencefalografía , Propiocepción , Humanos , Parálisis Cerebral/fisiopatología , Masculino , Femenino , Electroencefalografía/métodos , Estudios Longitudinales , Preescolar , Lactante , Reproducibilidad de los Resultados , Propiocepción/fisiologíaRESUMEN
PURPOSE: Interneuronopathies are a group of neurodevelopmental disorders characterized by deficient migration and differentiation of gamma-aminobutyric acidergic interneurons resulting in a broad clinical spectrum, including autism spectrum disorders, early-onset epileptic encephalopathy, intellectual disability, and schizophrenic disorders. SP9 is a transcription factor belonging to the Krüppel-like factor and specificity protein family, the members of which harbor highly conserved DNA-binding domains. SP9 plays a central role in interneuron development and tangential migration, but it has not yet been implicated in a human neurodevelopmental disorder. METHODS: Cases with SP9 variants were collected through international data-sharing networks. To address the specific impact of SP9 variants, in silico and in vitro assays were carried out. RESULTS: De novo heterozygous variants in SP9 cause a novel form of interneuronopathy. SP9 missense variants affecting the glutamate 378 amino acid result in severe epileptic encephalopathy because of hypomorphic and neomorphic DNA-binding effects, whereas SP9 loss-of-function variants result in a milder phenotype with epilepsy, developmental delay, and autism spectrum disorder. CONCLUSION: De novo heterozygous SP9 variants are responsible for a neurodevelopmental disease. Interestingly, variants located in conserved DNA-binding domains of KLF/SP family transcription factors may lead to neomorphic DNA-binding functions resulting in a combination of loss- and gain-of-function effects.
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Trastorno del Espectro Autista , Epilepsia , Discapacidad Intelectual , Interneuronas , Factores de Transcripción Sp , Factores de Transcripción , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Epilepsia/genética , Epilepsia/patología , Heterocigoto , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Interneuronas/metabolismo , Interneuronas/patología , Mutación Missense/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Fenotipo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Transcripción Sp/genéticaRESUMEN
Epilepsy is a neurological disorder characterized by recurring seizures, detected by electroencephalography (EEG). EEG signals can be detected by manual time-consuming analysis and recently by automatic detection. The latter poses a significant challenge due to the high dimensional and non-stationary nature of EEG signals. Recently, deep learning (DL) techniques have emerged as valuable tools for seizure detection. In this study, a novel data-driven model based on DL, incorporating a self-attention mechanism (SAT), is proposed. One notable advantage of the proposed method is its simplicity in application, as the raw signal data is directly fed into the suggested network without requiring expertise in signal processing. The model leverages a one-dimensional convolutional neural network (CNN) to extract relevant features from EEG signals. These features are then passed through a long short-term memory (LSTM) module to benefit from its memory capabilities, along with a SAT mechanism. The key contribution of this paper lies in the addition of the SAT layer to the LSTM encoder, enabling enhanced exploration of the latent mapping during the encoding step. Cross-subject experiments revealed good performance of this approach with F1-score of 97.8% and 92.7% for binary and five-class epileptic seizure recognition tasks, respectively, on the public UCI dataset, and 97.9% on the CHB-MIT database, surpassing state-of-the-art DL performance. Besides, the proposed method exhibits robustness to inter-subject variability.
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Electroencefalografía , Convulsiones , Humanos , Convulsiones/diagnóstico , Bases de Datos Factuales , Redes Neurales de la Computación , Procesamiento de Señales Asistido por ComputadorRESUMEN
BACKGROUND: Periventricular cysts are one of the most extensively documented antenatal brain lesions found through fetal ultrasound at the University Hospital of Angers. The main purpose of our study was to determine the contribution of fetal magnetic resonance imaging (MRI) and postnatal transfontanellar ultrasound (TFU) in the assessment of isolated periventricular cysts found on antenatal ultrasound at the University Hospital of Angers. METHODS: This retrospective, descriptive study was carried out over a 10-year period. Overall, 82 cases were included, divided into two groups according to the type of cysts found on the ultrasound: 13 cases of subependymal pseudocysts (SEPC) and 69 cases of frontal horn cysts (FHC). In all, 43 children underwent a postnatal TFU: seven in the SEPC group and 36 in the FHC group. RESULTS: Our study found excellent agreement between antenatal ultrasound and fetal MRI in the FHC group concerning classification of the cysts (approval rate [TA]: 98.60%; kappa coefficient [κ]: 0.85), their location (TA: 98.80%; κ: 0.91), their number (TA: 78.20%; κ: 0.73), and the detection of FHC (TA: 81.10%; κ: 0.74), as well as a good agreement concerning the detection of SEPC and temporal horn cysts (THC; TA: 99.40% and 95.60%, respectively). Fetal MRI proved to be better in the SEPC group for cyst classification (TA: 66.70%; κ: 0.33), their location (TA: 60%; κ: 0.41), and their number (TA: 53, 30%; κ: 0.45) and the detection of SEPC (TA: 23.10%; κ: 0.14). In both groups, postnatal TFU did not provide additional information compared to MRI. CONCLUSION: The finding of periventricular cysts in antenatal ultrasound should lead to a reference ultrasound, a key procedure for distinguishing between SEPC and FHC. In our study, no additional benefit from MRI and TFU was established for the evaluation of FHC. These findings should be considered as normal variants, thus limiting pre- and postnatal investigations. The visualization of SEPC, THC, or a parenchymal abnormality on the reference ultrasound should lead to an additional MRI being performed and a personalized follow-up of the child.
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Quistes , Embarazo , Niño , Femenino , Humanos , Estudios Retrospectivos , Quistes/diagnóstico por imagen , Ira , Hospitales Universitarios , Imagen por Resonancia Magnética , Ultrasonografía PrenatalRESUMEN
Background: Mitochondrial disorders (MD) are metabolic diseases related to genetic mutations in mitochondrial DNA and nuclear DNA that cause dysfunction of the mitochondrial respiratory chain. Cognitive impairment and psychiatric symptoms are frequently associated with MD in the adult population. The aim of this study is to describe the neuropsychological profile in children and adolescents with MD. Methods: We prospectively recruited a sample of 12 children and adolescents between February 2019 and February 2020 in the Reference Center for Mitochondrial Disorders of Angers (France). Participants and their parents completed an anamnestic form describing socio-demographic data and completed the WISC-V (Wechsler Intelligence Scale for Children, 5th edition) and the Parent and Teacher forms of the BRIEF (Behavior Rating Inventory of Executive Function). Results: In our sample, the mean IQ (Intellectual Quotient) score was 87.3 ± 25.3. The score ranged from 52 to 120. Concerning executive functions, a significant global clinical complaint was found for parents (six times more than normal) and to a lesser extent, for teachers (among 3 to 4 times more). Levels of intelligence and executive functioning were globally linked in our cohort but dissociation remains a possibility. Conclusion: The results of this study show that MD can be associated to neuropsychological disorders in children and adolescents, especially regarding the intelligence quotient and the executive function. Our study also highlights the need for regular neuropsychological assessments in individuals with MD and developing brains, such as children and adolescents.
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Autosomal dominant and recessive mutations in COL12A1 cause the Ehlers-Danlos/myopathy overlap syndrome. Here, we describe a boy with fetal hypokinesia, severe neonatal weakness, striking hyperlaxity, high arched palate, retrognathia, club feet, and pectus excavatum. His motor development was initially delayed but muscle strength improved with time while hyperlaxity remained very severe causing recurrent joint dislocations. Using trio exome sequencing and a copy number variation (CNV) analysis tool, we identified an in-frame de novo heterozygous deletion of the exons 45 to 54 in the COL12A1 gene. Collagen XII immunostaining on cultured skin fibroblasts demonstrated intracellular retention of collagen XII, supporting the pathogenicity of the deletion. The phenotype of our patient is slightly more severe than other cases with dominantly acting mutations, notably with the presence of fetal hypokinesia. This case highlights the importance of CNVs analysis in the COL12A1 gene in patients with a phenotype suggesting Ehlers-Danlos/myopathy overlap syndrome.
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Síndrome de Ehlers-Danlos , Enfermedades Musculares , Colágeno Tipo XII/genética , Variaciones en el Número de Copia de ADN , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Exones , Humanos , Hipocinesia/genética , Masculino , Enfermedades Musculares/genética , MutaciónRESUMEN
OBJECTIVE: To develop an electrophysiological marker of proprioceptive spino-cortical tracts integrity based on corticokinematic coherence (CKC) in young children with unilateral cerebral palsy (UCP), in whom behavioral measures are not applicable. METHODS: Electroencephalography (EEG) signals from 12 children with UCP aged 19 to 57 months were recorded using 128-channel EEG caps while their fingers were moved at 2â¯Hz by an experimenter, in separate sessions for the affected and non-affected hands. The coherence between movement kinematics and EEG signals (i.e., CKC) was computed at the sensor and source (using a realistic head model) levels. Peaks of CKC obtained for the affected and non-affected hands were compared for location and strength. The relation between CKC strength on the lesion-side, the lesion-type (cortico-subcortical vs. subcortical) and the level of manual ability were studied with 2-way repeated-measures ANOVA. RESULTS: At the individual level, a significant CKC peak at the central area contralateral to the moved hand was found in all young children with their non-affected hand and in 8 out of 12 children with their affected hand. At the group level, CKC to the affected hand movements was weaker than CKC to the non-affected hand movements. This difference was influenced by the type of lesion, the effect being predominant in the subgroup (nâ¯=â¯5) with cortico-subcortical lesions. CONCLUSION: CKC is measurable with EEG in young children with UCP and provides electrophysiological evidence for altered proprioceptive spino-cortical tracts on the lesioned brain hemisphere, particularly in children with cortico-subcortical lesions.
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Parálisis Cerebral , Niño , Preescolar , Mano , Humanos , Lactante , Magnetoencefalografía , Movimiento/fisiología , Propiocepción/fisiologíaRESUMEN
Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition is linked to epilepsy. Gephyrin (Geph) is the principal scaffolding protein at inhibitory synapses and is essential for postsynaptic clustering of glycine (GlyRs) and GABA type A receptors. Consequently, gephyrin is crucial for maintaining the relationship between excitation and inhibition in normal brain function and mutations in the gephyrin gene (GPHN) are associated with neurodevelopmental disorders and epilepsy. We identified bi-allelic variants in the GPHN gene, namely the missense mutation c.1264G > A and splice acceptor variant c.1315-2A > G, in a patient with developmental and epileptic encephalopathy. We demonstrate that the splice acceptor variant leads to nonsense-mediated mRNA decay. Furthermore, the missense variant (D422N) alters gephyrin structure, as examined by analytical size exclusion chromatography and circular dichroism-spectroscopy, thus leading to reduced receptor clustering and sensitivity towards calpain-mediated cleavage. In addition, both alterations contribute to an observed reduction of inhibitory signal transmission in neurons, which likely contributes to the pathological encephalopathy.
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Encefalopatías , Epilepsia , Encefalopatías/metabolismo , Proteínas Portadoras/metabolismo , Epilepsia/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Receptores de GABA-A/metabolismo , Sinapsis/metabolismoRESUMEN
OBJECTIVES: To describe neurological characteristics and CNS involvement on MRI in secondary hemophagocytic lymphohistiocytosis (sHLH) and differentiate it from primary hemophagocytic lymphohistiocytosis (pHLH) and acute disseminated encephalomyelitis (ADEM). METHODS: Nine children with sHLH who had neurological symptoms were retrospectively included. Characteristics of brain MRI were compared to those of 15 children with pHLH and neurological involvement and 44 children with ADEM. RESULTS: Three children (33%) presented with isolated neurological symptoms. Neurological signs occurred within one month following Epstein-Barr virus primary infection or systemic juvenile arthritis exacerbation in 8 patients (89%). Eight children (89%) had MRI lesions. sHLH MRI lesions were distinct of those of pHLH by morphology and signal with more frequent hyposignal intensities on T1-weighted sequences (p = 0.01) and well-defined and less fuzzy lesions (p = 0.03). All patients survived and one patient presented severe motor and cognitive disability. CONCLUSION: Neurological symptoms of sHLH are non-specific and their outcome is favorable in most of the children. MRI at onset may help to differentiate this condition from pHLH.
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Infecciones por Virus de Epstein-Barr , Linfohistiocitosis Hemofagocítica , Niño , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4 , Humanos , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/diagnóstico , Imagen por Resonancia Magnética , Estudios RetrospectivosRESUMEN
BACKGROUND: Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. METHODS: We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients. RESULTS: Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types. CONCLUSION: Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.
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Consanguinidad , Epilepsia/genética , Genotipo , Microcefalia/genética , Fenotipo , Proteínas de Ciclo Celular/genética , Niño , Epilepsia/epidemiología , Epilepsia/patología , Femenino , Frecuencia de los Genes , Heterogeneidad Genética , Humanos , Incidencia , Masculino , Microcefalia/complicaciones , Microcefalia/patología , Proteínas del Tejido Nervioso/genéticaRESUMEN
Background: Mitochondrial disorders (MD) are a group of clinically heterogeneous genetic disorders resulting from dysfunction of the mitochondrial respiratory chain. Cognitive impairment is a common feature in adults with MD and psychiatric symptoms are associated with MD in up to 70% of the adult population. The aim of this study is to describe the psychiatric profile in children and adolescents with MD by focusing on the description of psychiatric symptoms. Methods: A cohort of 12 children and adolescents was prospectively recruited between February 2019 and February 2020 in the Reference Center for Mitochondrial Disorders of Angers (France). Participants and their parents completed an anamnestic form to provide socio-demographic data and completed the Global Assessment of Functioning scale, the Brief Psychiatric Rating Scale, the Child Depression Inventory, the Revised Children's Manifest Anxiety Scale, and the Conner's Rating Scale to evaluate the inattention/hyperactivity symptoms as well as the Quality of Life scale. Results: Four children (33.3%) were diagnosed with depressive symptoms. With regarding to anxiety, 6 children (50%) reported anxiety issues during the psychiatric interview and 3 children (25%) were suffering from anxiety according to the RCMAS scale. Compared to other children with chronic illnesses, the individuals in our cohort reported a lower overall quality of life score and lower scores in physical and social subscales. Conclusion: Our study shows that MD can lead to psychiatric disorders in children and adolescents, in particular anxiety and depression, as well as poor quality of life. This highlights the need for regular psychiatric assessments in individuals with developing brains, such as children and adolescents. We do not, however, have data regarding the neuropsychological profile of this population.
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PURPOSE: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype. METHODS: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations. RESULTS: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism. CONCLUSION: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.
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Trastorno Autístico , Canales de Calcio Tipo L , Síndrome de QT Prolongado , Sindactilia , Trastorno Autístico/genética , Canales de Calcio Tipo L/genética , Humanos , FenotipoRESUMEN
Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.
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Encefalitis Antirreceptor N-Metil-D-Aspartato/fisiopatología , Ondas Encefálicas/fisiología , Electroencefalografía/métodos , Plasticidad Neuronal , Receptores de N-Metil-D-Aspartato/deficiencia , Fases del Sueño/fisiología , Adolescente , Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Masculino , Receptores de N-Metil-D-Aspartato/inmunología , Estudios Retrospectivos , Adulto JovenRESUMEN
CACNA1A pathogenic mutations are involved in various neurological phenotypes including episodic ataxia (EA2), spinocerebellar ataxia (SCA6), and familial hemiplegic migraine (FHM1). Epilepsy is poorly documented. We studied 18 patients (10 males) carrying de novo or inherited CACNA1A mutations, with median age of 2,5 years at epilepsy onset. Eight mutations were novel. Two variants known leading to gain of function (GOF) were found in 5 patients. Five other patients had non-sense variants leading to loss of function (LOF). Seizures were most often revealed by either status epilepticus (SE) (n = 8), eventually triggered by fever (n = 5), or absences/behavioural arrests (n = 7). Non-epileptic paroxysmal events were frequent and consisted in recurrent hemiplegic accesses (n = 9), jitteriness in the neonatal period (n = 6), and ocular paroxysmal events (n = 9). Most of the patients had early permanent cerebellar dysfunction (n = 16) and early moderate to severe global developmental delay (GDD)/intellectual deficiency (ID) (n = 17). MRI was often abnormal, with cerebellar (n = 8) and/or cerebral (n = 6) atrophy. Stroke-like occurred in 2 cases. Some antiepileptic drugs including topiramate, levetiracetam, lamotrigine and valproate were effective on seizures. Acetazolamide and calcium channel blockers were often effective when used. More than half of the patients had refractory epilepsy. CACNA1A mutation should be evoked in front of 2 main electro-clinical phenotypes that are associated with permanent cerebellar dysfunction and moderate to severe GDD/ID. The first one, found in all 5 patients with GOF variants, is characterized by intractable seizures, early and recurrent SE and hemiplegic accesses. The second, less severe, found in 5 patients with LOF variants, is characterized by refractory early onset absence seizures.