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Non-motor aspects in dystonia are now well recognized. The sense of agency, which refers to the experience of controlling one's own actions, has been scarcely studied in dystonia, even though its disturbances can contribute to movement disorders. Among various brain structures, the cerebral cortex, the cerebellum, and the basal ganglia are involved in shaping the sense of agency. In myoclonus dystonia, resulting from a dysfunction of the motor network, an altered sense of agency may contribute to the clinical phenotype of the condition. In this study, we compared the explicit and implicit sense of agency in patients with myoclonus dystonia caused by a pathogenic variant of SGCE (DYT-SGCE) and control participants. We utilized behavioural tasks to assess the sense of agency and performed neuroimaging analyses, including structural, resting-state functional connectivity, and dynamic causal modelling, to explore the relevant brain regions involved in the sense of agency. Additionally, we examined the relationship between behavioural performance, symptom severity, and neuroimaging findings. We compared 19 patients with DYT-SGCE and 24 healthy volunteers. Our findings revealed that patients with myoclonus-dystonia exhibited a specific impairment in explicit sense of agency, particularly when implicit motor learning was involved. However, their implicit sense of agency remained intact. These patients also displayed grey-matter abnormalities in the motor cerebellum, as well as increased functional connectivity between the cerebellum and pre-supplementary motor area. Dynamic causal modelling analysis further identified reduced inhibitory effects of the cerebellum on the pre-supplementary motor area, decreased excitatory effects of the pre-supplementary motor area on the cerebellum, and increased self-inhibition within the pre-supplementary motor area. Importantly, both cerebellar grey-matter alterations and functional connectivity abnormalities between the cerebellum and pre-supplementary motor area were found to correlate with explicit sense of agency impairment. Increased self-inhibition within the pre-supplementary motor area was associated with less severe myoclonus symptoms. These findings highlight the disruption of higher-level cognitive processes in patients with myoclonus-dystonia, further expanding the spectrum of neurological and psychiatric dysfunction already identified in this disorder.
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INTRODUCTION: Pathogenic variants in ATP1A3 cause various phenotypes of neurological disorders, including alternating hemiplegia of childhood 2, CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) and rapid-onset dystonia-parkinsonism (RDP). Early developmental and epileptic encephalopathy has also been reported. Polymicrogyria has recently been added to the phenotypic spectrum of ATP1A3-related disorders. CASE REPORT: We report here a male patient with early developmental delay who at 12 months presented dystonia of the right arm which evolved into hemidystonia at the age of 2. A cerebral MRI showed bilateral perisylvian polymicrogyria with intact basal ganglia. Whole-exome and whole-genome sequencing analyses identified a de novo new ATP1A3 missense variant (p.Arg914Lys) predicted pathogenic. Hemidystonia was thought not to be due to polymicrogyria, but rather a consequence of this variant. CONCLUSION: This case expands the phenotypic spectrum of ATP1A3-related disorders with a new variant associated with hemidystonia and polymicrogyria and thereby, suggests a clinical continuum between the different phenotypes of this condition.
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Distonia , Distúrbios Distônicos , Polimicrogiria , Distúrbios Distônicos/genética , Humanos , Masculino , Mutação/genética , Fenótipo , Polimicrogiria/diagnóstico por imagem , Polimicrogiria/genética , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
OBJECTIVE: To perform genotype-phenotype, clinical and molecular analysis in a large 3-generation family with autosomal dominant congenital spinal muscular atrophy. METHODS: Using a combined genetic approach including whole genome scanning, next generation sequencing-based multigene panel, whole genome sequencing, and targeted variant Sanger sequencing, we studied the proband and multiple affected individuals of this family who presented bilateral proximal lower limb muscle weakness and atrophy. RESULTS: We identified a novel heterozygous variant, c.1826T > C; p.Ile609Thr, in the DYNC1H1 gene localized within the common haplotype in the 14q32.3 chromosomal region which cosegregated with disease in this large family. Within the family, affected individuals were found to have a wide array of clinical variability. Although some individuals presented the typical lower motor neuron phenotype with areflexia and denervation, others presented with muscle weakness and atrophy, hyperreflexia, and absence of denervation suggesting a predominant upper motor neuron disease. In addition, some affected individuals presented with an intermediate phenotype characterized by hyperreflexia and denervation, expressing a combination of lower and upper motor neuron defects. CONCLUSION: Our study demonstrates the wide clinical variability associated with a single disease causing variant in DYNC1H1 gene and this variant demonstrated a high penetrance within this large family.
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Dineínas do Citoplasma/genética , Atrofia Muscular Espinal/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neurônios Motores/fisiologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular Espinal/patologia , Linhagem , Fenótipo , Reflexo , Extremidade Superior/fisiopatologiaRESUMO
Objective: To assess adverse events (AEs) and efficacy of add-on cannabidiol (CBD) with a slower titration protocol in pediatric clinical practice. Methods: We conducted a prospective, open-label, multicenter study in seven French reference centers for rare epilepsies. Patients had slow titration to reach a target dose of 10 mg/kg/day within at least 1 month and then gradually increased to a maximum dose of 20 mg/kg/day. We analyzed AEs and efficacy at M1 (month 1), M2, and M6, comparing two sets of subgroups: Dravet syndrome (DS) vs. Lennox-Gastaut (LGS) and patients with clobazam (CLB+) vs. patients without (CLB-). Results: One hundred and twenty-five patients were enrolled (62 LGS, 48 DS, 5 Tuberous sclerosis, and 10 other etiologies). Median concomitant antiepileptic drugs (AEDs) was three (25th percentile: 3, 75th percentile: 4). Patients received a dose of 10 (10-12), 14 (10-20), and 15.5 mg/kg/day (10-20) at M1, M2, and M6, respectively. Twenty-six patients discontinued CBD, 19 due to lack of efficacy, 2 due to AEs, 4 for both, and 1 had a sudden unexpected death in epilepsy. AEs were reported in 61 patients (48.8%), mainly somnolence (n = 26), asthenia (n = 20), and behavior disorders (n = 16). Abnormal transaminases (≥3 times) were reported in 11 patients receiving both valproate and clobazam. AEs were significantly higher at M2 (p = 0.03) and increased with the number of AEDs (p = 0.03). At M6, total seizure frequency change from baseline was -41% ± 37.5% (mean ± standard deviation), and 28 patients (37.8%) had a reduction ≥50%. AE and efficacy did not differ between DS vs. LGS and CLB+ vs. CLB- patients. Significance: A slower titration of CBD dose delivered better tolerance with comparable efficacy to previous trials. Concomitant CLB did not increase efficacy rates but in a few cases increased AEs. This slow titration scheme should help guide clinicians prescribing CBD and allow patients to benefit from its potential efficacy.
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Myoclonus-dystonia (MD) is a syndrome characterized by myoclonus of subcortical origin and dystonia, frequently associated with psychiatric comorbidities. The motor and psychiatric phenotypes of this syndrome likely result from cortico-striato-thamalo-cerebellar-cortical pathway dysfunction. We hypothesized that reactive and proactive inhibitory control may be altered in these patients. Using the Stop Signal Task, we assessed reactive and proactive inhibitory control in MD patients with (n = 12) and without (n = 21) deep brain stimulation of the globus pallidus interna and compared their performance to matched healthy controls (n = 24). Reactive inhibition was considered as the ability to stop an already initiated action and measured using the stop signal reaction time. Proactive inhibition was assessed through the influence of several consecutive GO or STOP trials on decreased response time or inhibitory process facilitation. The proactive inhibition was solely impaired in unoperated MD patients. Patients with deep brain stimulation showed impairment in reactive inhibition, independent of presence of obsessive-compulsive disorders. This impairment in reactive inhibitory control correlated with intrinsic severity of myoclonus (i.e. pre-operative score). The results point to a dissociation in reactive and proactive inhibitory control in MD patients with and without deep brain stimulation of the globus pallidus interna.
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Distúrbios Distônicos/fisiopatologia , Adulto , Estimulação Encefálica Profunda/métodos , Transtornos Dissociativos/fisiopatologia , Distonia/fisiopatologia , Feminino , Globo Pálido/fisiopatologia , Humanos , Inibição Psicológica , Masculino , Mioclonia/fisiopatologia , Inibição Proativa , Tempo de Reação/fisiologia , Inibição Reativa , Transmissão Sináptica , Adulto JovemRESUMO
The molecular diagnosis of early-onset epileptic encephalopathy (EOEE), an expanding field in child neurology, is becoming increasingly possible thanks to the widespread availability of next-generation sequencing and whole-exome sequencing. In the past 15 years, mutations in STXBP1, KCNQ2, SCN2A, SCN8A and numerous other genes have been reported, giving a more accurate insight for these rare diseases. Among these genes, germline mutations in Phosphatidyl Inositol Glycan A (PIGA) gene were first reported in 2012. Located on Xp22.2, PIGA is involved in the synthesis of GPI (glycosylphosphatidylinositol) which acts as a membrane anchor for different proteins: enzymes, adhesion molecules, regulation of the complement way, and co-receptor in transduction signal. Children suffering from this condition exhibit developmental delay with early-onset epilepsy, severe dysmorphic signs, multi-visceral anomalies and early death in the most severe forms. Here, we report five cases of germline PIGA mutations, with two missense mutations that have not been reported to date. We provide a new insight into the electroclinical phenotype. At the onset, epileptic spasms and focal-onset seizures with upper limbs and ocular involvements were present. Epilepsy proved pharmacoresistant in 4 out of 5 cases. Interictal EEG may be normal at the onset of epilepsy, but abnormalities in electroencephalographic studies were eventually present in all cases. Different types of seizures may be present simultaneously, and epileptic phenotypes evolve with aging.
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Proteínas de Membrana/genética , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , FenótipoRESUMO
BACKGROUND: Subependymal giant cell astrocytomas (SEGAs) arise in 10-26% of tuberous sclerosis complex (TSC) patients. SEGAs cause obstructive hydrocephalus and increase morbi-mortality. It is recommended that TSC patients be followed with contrast enhanced magnetic resonance imaging (CE-MRI), but repetitive use of gadolinium-based contrast-agents (GBCAs) may cause organ deposits. OBJECTIVE: To compare the diagnostic performances of non-CE- and CE-MRI to differentiate SEGAs from subependymal nodules in TSC patients during follow-up. MATERIALS AND METHODS: Thirty-five TSC patients (median age: 2.4 years) were enrolled in this retrospective single-center study from September 2007 to January 2019. Inclusion criteria were a certain diagnosis of TSC and at least three follow-up brain MRIs with GBCA injection. Two consecutive MRI scans per patient were selected and anonymized. Three radiologists performed a blinded review of non-enhanced and enhanced MRI sequences during different sessions. The diagnostic performances were compared (sensitivity, specificity, positive/negative predictive values, accuracy, inter/intra-observer agreements). RESULTS: The accuracies for detecting SEGAs were good and similar between the non-enhanced and enhanced MRI sequences. The sensitivity and specificity of non-CE-MRI to diagnose SEGA ranged from 75% to 100% and from 94% to 100%, respectively. The differences in numbers of false-positive and false-negative patients between non-CE- and CE-MRI never exceeded one case. Nodules size >10 mm, location near the Monro foramen, hydrocephalus and modifications between two consecutive MRI scans were significantly associated with the diagnosis of SEGA for the three readers (all P-values <0.05). Inter- and intra-observer agreements were also excellent for non-enhanced and enhanced MRI sequences (kappa=0.85-1 and 0.81-0.93, respectively). CONCLUSION: The performances of non-enhanced and enhanced MRI sequences are comparable for detecting SEGAs, questioning the need for systematic GBCA injections for TSC patients.
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Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Imageamento por Ressonância Magnética/métodos , Meglumina/administração & dosagem , Compostos Organometálicos/administração & dosagem , Esclerose Tuberosa/complicações , Astrocitoma/etiologia , Neoplasias Encefálicas/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.
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Cútis Laxa/fisiopatologia , Aldeído Desidrogenase/genética , Consanguinidade , Cútis Laxa/classificação , Cútis Laxa/genética , Humanos , Lactente , MasculinoRESUMO
BACKGROUND: The molecular anomalies causing moyamoya disease (MMD) and moyamoya syndromes (MMS) are unknown in most patients. OBJECTIVE: This study aimed to identify de novo candidate copy number variants (CNVs) in patients with moyamoya. METHODS: Rare de novo CNVs screening was performed in 13 moyamoya angiopathy trios using whole exome sequencing (WES) reads depth data and whole genome high density SNP array data. WES and SNP array data from an additional cohort of 115 unrelated moyamoya probands were used to search for recurrence of these rare de novo CNVs. RESULTS: Two de novo CNVs were identified in two unrelated probands by both methods and confirmed by qPCR. One of these CNVs, located on Xq28, was detected in two additional families. This interstitial Xq28 CNV gain is absent from curated gold standard database of control genomic variants and gnomAD databases. The critical region contains five genes, including MAMLD1, a major NOTCH coactivator. Typical MMD was observed in the two families with a duplication, whereas in the triplicated patients of the third family, a novel MMS associating moyamoya and various systemic venous anomalies was evidenced. CONCLUSION: The recurrence of this novel Xq28 CNV, its de novo occurrence in one patient and its familial segregation with the affected phenotype in two additional families strongly suggest that it is pathogenic. In addition to genetic counselling application, its association with pulmonary hypertension is of major importance for clinical care. These data also provide new insights into the genomic architecture of this emblematic, non-atherosclerotic, large vessel disease.
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Proteínas de Ligação a DNA/genética , Dosagem de Genes/genética , Predisposição Genética para Doença , Doença de Moyamoya/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos X/genética , Feminino , Duplicação Gênica/genética , Genoma Humano/genética , Humanos , Lactente , Masculino , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/patologia , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento do ExomaRESUMO
AIM: We aimed to evaluate the contribution of early magnetic resonance imaging (MRI) for the presymptomatic diagnosis of Sturge-Weber syndrome (SWS) in infants with a facial port-wine birthmark (PWB). METHOD: Asymptomatic infants with a facial PWB who performed a first MRI scan before 3 months and a second MRI scan after 9 months were included in this study. Leptomeningeal enhancement on T1-weighted imaging and four indirect signs of leptomeningeal angioma (choroid plexus enlargement, cerebral atrophy, signal inversion of the white matter with T2 hyposignal, and T1 hypersignal) were screened on the first MRI scan and correlated with clinical and/or radiological diagnosis of SWS. RESULTS: Thirteen of 30 included patients had SWS with leptomeningeal angioma. Eleven had a leptomeningeal enhancement on the first MRI scan and 10 had associated indirect signs. The presence of a direct or at least one indirect sign of leptomeningeal angioma on the first MRI scan confirmed the diagnosis of SWS with a sensitivity of 100 per cent (95% confidence interval 75-100%) and a specificity of 94 per cent (71-100%). INTERPRETATION: Early diagnosis of SWS is possible on contrast-enhanced MRI performed in asymptomatic infants with a facial PWB before the age of 3 months. This early detection would help to select patients who may benefit from early neuroprotective intervention. WHAT THIS PAPER ADDS: Specific magnetic resonance imaging markers provide early diagnosis of leptomeningeal angioma in Sturge-Weber syndrome (SWS). Presymptomatic diagnosis of SWS should help to select patients for early therapy intervention.
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Hemangioma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neoplasias Meníngeas/diagnóstico por imagem , Mancha Vinho do Porto/diagnóstico por imagem , Síndrome de Sturge-Weber/diagnóstico por imagem , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Humanos , Lactente , Masculino , Mancha Vinho do Porto/etiologia , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Abnormal sensory processing, including temporal discrimination threshold, has been described in various dystonic syndromes. OBJECTIVE: To investigate visual sensory processing in DYT-SGCE and identify its structural correlates. METHODS: DYT-SGCE patients without DBS (DYT-SGCE-non-DBS) and with DBS (DYT-SGCE-DBS) were compared to healthy volunteers in three tasks: a temporal discrimination threshold, a movement orientation discrimination, and movement speed discrimination. Response times attributed to accumulation of sensory visual information were computationally modelized, with µ parameter indicating sensory mean growth rate. We also identified the structural correlates of behavioral performance for temporal discrimination threshold. RESULTS: Twenty-four DYT-SGCE-non-DBS, 13 DYT-SGCE-DBS, and 25 healthy volunteers were included in the study. In DYT-SGCE-DBS, the discrimination threshold was higher in the temporal discrimination threshold (P = 0.024), with no difference among the groups in other tasks. The sensory mean growth rate (µ) was lower in DYT-SGCE in all three tasks (P < 0.01), reflecting a slower rate of sensory accumulation for the visual information in these patients independent of DBS. Structural imaging analysis showed a thicker left primary visual cortex (P = 0.001) in DYT-SGCE-non-DBS compared to healthy volunteers, which also correlated with lower µ in temporal discrimination threshold (P = 0.029). In DYT-SGCE-non-DBS, myoclonus severity also correlated with a lower µ in the temporal discrimination threshold task (P = 0.048) and with thicker V1 on the left (P = 0.022). CONCLUSION: In DYT-SGCE, we showed an alteration of the visual sensory processing in the temporal discrimination threshold that correlated with myoclonus severity and structural changes in the primary visual cortex. © 2019 International Parkinson and Movement Disorder Society.
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Distúrbios Distônicos/fisiopatologia , Transtornos dos Movimentos/fisiopatologia , Movimento/fisiologia , Percepção Visual/fisiologia , Adulto , Distúrbios Distônicos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/patologia , Mioclonia/patologia , Mioclonia/fisiopatologiaRESUMO
Nijmegen breakage syndrome caused by biallelic pathogenic variants of the DNA-damage response gene NBN, is characterized by severe microcephaly, cancer proneness, infertility, and karyotype abnormalities. We previously reported NBN variants in siblings suffering from fertility defects. Here, we identify a new founder NBN variant (c.442A>G, p.(Thr148Ala)) in Lebanese patients associated with isolated infertility. Functional analyses explored preserved or altered functions correlated with their remarkably mild phenotype. Transcript and protein analyses supported the use of an alternative transcript with in-frame skipping of exons 4-5, leading to p84-NBN protein with a preserved forkhead-associated (FHA) domain. The level of NBN was dramatically reduced and the MRN complex delocalized to the cytoplasm. Interestingly, ataxia-elangiectasia mutated (ATM) also shifted from the nucleus to the cytoplasm, suggesting some interaction between ATM and the MRN complex at a steady state. The ATM pathway activation, attenuated in typical patients with NBS, appeared normal under camptothecin treatment in these new NBN-related infertile patients. Cell cycle checkpoint defect was present in these atypical patients, although to a lesser extent than in typical patients with NBS. In conclusion, we report three new NBN-related infertile patients and we suggest that preserved FHA domain could be responsible for the mild phenotype and intermediate DNA-damage response defects.
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Proteínas de Ciclo Celular/genética , Reparo do DNA , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Infertilidade/diagnóstico , Infertilidade/genética , Proteínas Nucleares/genética , Adulto , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/metabolismo , Análise Mutacional de DNA , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica , Estudos de Associação Genética/métodos , Humanos , Infertilidade/metabolismo , Masculino , Síndrome de Quebra de Nijmegen/diagnóstico , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/metabolismo , Proteínas Nucleares/metabolismo , Ligação Proteica , Transdução de SinaisRESUMO
OBJECTIVE: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. METHODS: We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy-associated missense variant localization over the protein. RESULTS: We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic-clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep-related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases. SIGNIFICANCE: SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.
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Epilepsia/genética , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Idade de Início , Substituição de Aminoácidos , Anticonvulsivantes/uso terapêutico , Diagnóstico Tardio , Diagnóstico Precoce , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Feminino , Movimento Fetal , Humanos , Lactente , Recém-Nascido , Canal de Potássio KCNQ2/genética , Masculino , Proteínas Munc18/genética , Mutação de Sentido Incorreto , Fenótipo , Gravidez , Estudos Prospectivos , Convulsões/genética , Convulsões/fisiopatologia , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
Ataxia-telangiectasia-like disorder (ATLD) is a rare genomic instability syndrome caused by biallelic variants of MRE11 (meiotic recombination 11) characterized by progressive cerebellar ataxia and typical karyotype abnormalities. These symptoms are common to those of ataxia-telangiectasia, which is consistent with the key role of MRE11 in ataxia-telangiectasia mutated (ATM) activation after DNA double-strand breaks. Three unrelated French patients were referred with ataxia. Only one had typical karyotype abnormalities. Unreported biallelic MRE11 variants were found in these three cases. Interestingly, one variant (c.424G>A) was present in two cases and haplotype analysis strongly suggested a French founder variant. Variants c.544G>A and c.314+4_314+7del lead to splice defects. The level of MRE11 in lymphoblastoid cell lines was consistently and dramatically reduced. Functional consequences were evaluated on activation of the ATM pathway via phosphorylation of ATM targets (KAP1 and CHK2), but no consistent defect was observed. However, an S-phase checkpoint activation defect after camptothecin was observed in these patients with ATLD. In conclusion, we report the first three French ATLD patients and a French founder variant, and propose an S-phase checkpoint activation study to evaluate the pathogenicity of MRE11 variants.
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Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/etiologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Criança , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Lactente , Proteína Homóloga a MRE11/genética , Proteína Homóloga a MRE11/metabolismo , Imageamento por Ressonância Magnética , Mutação , Fenótipo , Splicing de RNA , Pontos de Checagem da Fase S do Ciclo Celular/genética , Transdução de Sinais , TranscriptomaRESUMO
OBJECTIVE: To provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome. METHODS: We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations. RESULTS: A total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of FOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations. CONCLUSIONS: These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe FOXG1 syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that FOXG1 syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Meningite/induzido quimicamente , Meningoencefalite/induzido quimicamente , Adolescente , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/diagnóstico , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Meningite/diagnóstico por imagem , Meningite/fisiopatologia , Meningoencefalite/diagnóstico por imagem , Meningoencefalite/fisiopatologia , Prognóstico , Recidiva , Medição de Risco , Estudos de AmostragemRESUMO
Autoimmune encephalitis with anti-N-methyl-d-aspartate receptor autoantibodies (NMDA-R-Abs) is a recently described disease affecting adult and pediatric patients. Symptoms of the disease are now perfectly described in the adult population but the clinical presentation is less known in young children. The aim of the present study was to describe the clinical presentation and the specificities of symptoms presented by young children with NMDA-R-Abs encephalitis to improve diagnosis of this disease, and to compare these to a series of previously published female adult patients. Fifty cases of children younger than twelve years of age diagnosed with NMDA-R-Abs encephalitis between January 1, 2007 and December 31, 2016 (27 females and 23 males) were retrospectively studied. The first neurological symptoms observed in young children with NMDA-R-Abs encephalitis were characterized by seizure (72%), especially focal seizure (42%), within a median of 15 days before other encephalitis symptoms; other patients mostly had behavioral disorders (26%). The seizures were frequently difficult to diagnose because of the transient unilateral dystonic or tonic posturing presentation or sudden unilateral pain in the absence of clonic movements. A post-ictal motor deficit was also frequently observed. This clinical presentation is different from that observed in adult females with NMDA-R-Abs encephalitis who initially present mainly psychiatric disorders (67%) or cognitive impairment (19%), and less frequently seizures (14%). The diagnosis of NMDA-R-Abs encephalitis should be systematically considered in young children of both sexes who present neurological symptoms suggesting recent seizures (focal or generalized) without obvious other etiology.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Adolescente , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Criança , Transtornos do Comportamento Infantil/etiologia , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Retrospectivos , Convulsões/etiologiaRESUMO
OBJECTIVES: To describe the clinical course, neuroimaging findings and functional outcome of idiopathic spinal cord infarction (SCI) in adolescents. METHODS: Retrospective and descriptive analyses of seven patients with idiopathic SCI and 50 additional cases from the literature were included. Data collected concerned clinical presentation, MRI findings, initial diagnosis, treatments and functional outcome at the last medical visit. RESULTS: Mean age at presentation was 13.2years (range 13-15). All patients presented a sudden and painful acute myelopathy with <24h time to maximal symptoms manifestation. A suspected trigger related to a minor effort was reported in 3/7 cases. Six patients presented with paraplegia, one with paraparesis. All had bladder dysfunction needing catheterization. Three patients had an initial misdiagnosis. Initial MRI was considered as normal in 2 cases. In the 5 other cases, T2-weighted-MR images showed hyperintensity within the thoracolumbar spinal cord, affecting mostly the anterior spinal artery territory. Evidence for associated spinal growth dystrophy were present in 6/7 cases. Mean follow-up time was 27.4months (range 3-46): 2 patients recovered autonomous ambulation, 4 patients regained walking ability with aids and one child (the shortest follow-up) remained wheelchair-dependent. A neurogenic bladder was still reported in 6/7 children at the last visit. Complementary analyses with literature cases were consistent with the findings obtained in our cohort. CONCLUSION: Idiopathic SCI typically occurs in adolescence with a rapid onset and painful acute myelopathy. The MRI shows a T2-hyperintense signal within the spinal cord and provides evidence for an ischemic mechanism. Etiology remains unclear in most cases even though some specific risk factors for this age must play an important role in the pathogenesis, such as mechanical constraints on the immature spine.