NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain.

The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.

The Origin of the Cerebral Palsies: Contribution of Population-Based Neuroimaging Data.

BACKGROUND: Surveillance of cerebral palsy in Europe (SCPE) presents the first population-based results on neuroimaging findings in children with cerebral palsy (CP) using a magnetic resonance imaging classification system (MRICS). METHOD: MRIs of children with CP born between 1999 and 2009 from 18 European countries were analyzed. MRICS identifies patterns of brain pathology according to timing during brain development which was analyzed with respect to CP subtypes and gestational age. RESULTS: MRIs or written reports from 3,818 children were available. The main clinical characteristics were similar to the 5,415 without such data. Most frequent was predominant white matter injury (49%), followed by predominant gray matter injury (21%). Maldevelopments were found in 11% of cases. Miscellaneous findings were present in 8.5% and normal findings in 10.6%. MRI patterns of children with unilateral spastic, bilateral spastic, and dyskinetic CP were mainly lesional (77, 71, and 59%, respectively), whereas children with ataxic CP had more maldevelopments, miscellaneous, and normal findings (25, 21, and 32%, respectively). In children born preterm, predominant white matter injury was most prevalent (80% in children born <32 weeks of gestation). CONCLUSION: Analysis of MRI in the European CP database identified CP as a mainly lesional condition on a large population basis, maldevelopments were relatively uncommon. An exception was ataxic CP. Children born preterm mostly presented with a lesion typical for their gestational age (GA) at birth. The decreasing prevalence of CP in this group suggests that progress in perinatal and neonatal medicine may lead to a reduction of these lesions.

Ocular flutter as presenting manifestation of pediatric MOG antibody-associated demyelination: A case report.

A 13-year-old girl presented with a 5-day history of oscillopsia. On examination, ocular flutter and mild cerebellar signs were found. Brain magnetic resonance imaging (MRI) revealed four periventricular and subcortical non-enhancing lesions. Cerebrospinal fluid (CSF) oligoclonal bands were negative. Neuroblastoma or other malignancies were not found. She responded well to a corticosteroid-intravenous immunoglobulin (IVIG) combination and remained symptom-free for 3 years until presenting again with isolated ocular flutter. Brain MRI at this time remained atypical for classic multiple sclerosis (MS) with a predominance of juxtacortical demyelinating lesions. CSF was positive for oligoclonal bands. Serum myelin oligodendrocyte glycoprotein (MOG) antibodies were present. Ocular flutter can be the presenting feature of MOG antibody-associated pediatric demyelination.

Pediatric Headache and Epilepsy Comorbidity in the Pragmatic Clinical Setting.

INTRODUCTION: Demographic and clinical data were collected from three cross-sectional samples, from the headache and epilepsy clinics according to respective protocols. During structured interviews, we examined the co-occurrence of headaches and epilepsy in children and their families: (1) 172 children from the headache clinic, were questioned for the number and type of epileptic seizures and epilepsy diagnosis. (2) Around 70 children from the epilepsy clinic for the frequency and type of headaches and headache syndrome diagnosis. (3) A total of 149 parents of children with benign childhood epilepsy with centro-temporal spikes (BCECTS) and childhood absence epilepsy (CAE), for the relative frequency of headaches in first- and second-degree relatives. RESULTS: Out of 172, 84 (48.8%) children with headache had a migraine and 60 (34.9%) had tension headaches; 3 children (1.7%) had epilepsy or unprovoked seizures. Migraine and epilepsy, co-occurred in 2/84 (2.3%). Eight out of 70 patients with epilepsy had headaches (11.4%); none had migraine. Around 43% of patients with BCECTS or CAE had a family history of headache, more prevalent in first-degree relatives of children with BCECTS than CAE. CONCLUSION: Contrary to existing literature, migraine and epilepsy, co-occurred infrequently in these highly selected samples. Family history of headache was frequent in patients with BCECTS and CAE, without any significant difference between the two.

Illness perceptions determine psychological distress and quality of life in youngsters with epilepsy.

The aim of this cross-sectional study was to explore the extent to which gender, epilepsy severity, and self-regulation concepts (illness perceptions, autonomous treatment regulation, perceived autonomy support by parents) predict psychological distress and quality of life (QoL) in young patients with epilepsy. Structured interviews were conducted in 100 patients (Mage=13.9, SD=2.21, 41% girls), and data were analyzed by means of multiple hierarchical regression analyses. Seizures of most patients (91%) were well controlled by antiepileptics, 3% of the patients had infrequent seizures, and seizures in 6% were pharmacoresistant. At a multivariate level, it appeared that youngsters with epilepsy who expect that their disease will last for a long time, who believe that they have less personal control over their illness, and who expect the illness to have a high emotional impact reported higher levels of distress. In addition, a better QoL was reported by youngsters who believed that treatment did not control their illness and who thought that their epilepsy would not affect them emotionally. Findings indicate the importance of illness perceptions, and it is suggested that they should be targeted in future interventions in youngsters with epilepsy.

Current approach to cerebral palsy.

This teaching review aims to provide an overview of the current approach to children with cerebral palsy (CP), retrieving the best available evidence and summarizing existing knowledge in the field of CP in children. We also highlight areas where more research is needed and novel strategies for diagnosing and treating cerebral palsy. CP includes a group of permanent disorders of movement and posture that cause activity limitation. Multiple risk factors, occurring preconceptionally, prenatally, perinatally, or postneonatally, are involved in the pathogenesis of CP, with the prenatal ones accounting for 80-90 % of cases. Due to its heterogeneity, CP has various classifications, but usually is classified based on clinical findings and motor impairment. Standardized function classification systems have been developed to address inconsistencies in previous classifications. The combination of clinical assessment and validated predictive tools is recommended for an early diagnosis, which is important for early intervention and prevention of secondary impairments. The therapeutic regimen in CP involves prevention and management of the motor and associated problems. It includes the enhancement of motor performance, the enrichment of cognition and communication skills, the prevention of secondary impairments, and the support of parents and caregivers. The care of CP children demands a multidisciplinary approach focused on improving motor skills, reducing comorbidities, enhancing the quality of life, and prolonging survival.

Combined exome analysis and exome depth assessment achieve a high diagnostic yield in an epilepsy case series, revealing significant genomic heterogeneity and novel mechanisms.

OBJECTIVES: Genetics of epilepsy are highly heterogeneous and complex. Lesions detected involve genes encoding various types of channels, transcription factors, and other proteins implicated in numerous cellular processes, such as synaptogenesis. Consequently, a wide spectrum of clinical presentations and overlapping phenotypes hinders differential diagnosis and highlights the need for molecular investigations toward delineation of underlying mechanisms and final diagnosis. Characterization of defects may also contribute valuable data on genetic landscapes and networks implicated in epileptogenesis. METHODS: This study reports on genetic findings from exome sequencing (ES) data of 107 patients with variable types of seizures, with or without additional symptoms, in the context of neurodevelopmental disorders. RESULTS: Multidisciplinary evaluation of ES, including ancillary detection of copy number variants (CNVs) with the ExomeDepth tool, supported a definite diagnosis in 59.8% of the patients, reflecting one of the highest diagnostic yields in epilepsy. CONCLUSION: Emerging advances of next-generation technologies and 'in silico' analysis tools offer the possibility to simultaneously detect several types of variations. Wide assessment of variable findings, specifically those found to be novel and least expected, reflects the ever-evolving genetic landscape of seizure development, potentially beneficial for increased opportunities for trial recruitment and enrollment, and optimized, even personalized, medical management.

Prevalence, Clinical Features, Neuroimaging, and Genetic Findings in Children With Ataxic Cerebral Palsy in Europe.

BACKGROUND AND OBJECTIVES: To report on prevalence, associated impairments, severity, and neuroimaging findings in children with ataxic cerebral palsy (CP). METHODS: In children coded as having ataxic CP in the Central database of Joint Research Center-Surveillance of Cerebral Palsy in Europe (JRC-SCPE) and born during 1980-2010, birth characteristics, severity profiles including associated impairments, neuroimaging patterns, and the presence of syndromes were analyzed. Definitions were according to validated SCPE guidelines. Prevalence over time was estimated using Poisson regression. RESULTS: In total, 679 children with ataxic CP were identified in 20 European CP registers. The proportion with ataxic CP was 3.8% and varied from 0% to 12.9%. Prevalence over time showed no significant trend. Approximately 70% of children with ataxic CP were able to walk, and 40% had severe intellectual impairment and a high impairment index. Children with ataxic CP were mostly born at term (79%) and with normal birth weight (77%). Neuroimaging patterns revealed normal findings in 29%, brain maldevelopments in 28.5%, miscellaneous findings in 23.5%, and brain injuries in 19%, according to the SCPE classification. Genetic syndromes were described in 9%. DISCUSSION: This register-based multicenter study on children with ataxic CP provides a large sample size for the analysis of prevalence, severity, and origin of this rare CP subtype. Even with strict inclusion and classification criteria, there is variation between registers on how to deal with this subtype, and diagnosis of ataxic CP remains a challenge. Ataxic cerebral palsy differs from other CP subtypes: children with ataxic CP have a disability profile that is more pronounced in terms of cognitive than gross motor dysfunction. They are mostly term born and the origin rarely suggests acquired injuries. In addition to neuroimaging, a comprehensive genetic workup is particularly recommended for children with this CP type.

Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition.

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SNF2H (SMARCA5) or SNF2L (SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.

Development of Lower Extremity Strength in Ambulatory Children With Bilateral Spastic Cerebral Palsy in Comparison With Typically Developing Controls Using Absolute and Normalized to Body Weight Force Values.

This cross-sectional study aimed to examine the development of lower limb voluntary strength in 160 ambulatory patients with bilateral spastic cerebral palsy (CP) (106 diplegics/54 quadriplegics) and 86 typically developing (TD) controls, aged 7-16 years. Handheld dynamometry was used to measure isometric strength of seven muscle groups (hip adductors and abductors, hip extensors and flexors, knee extensors and flexors, and ankle dorsiflexors); absolute force (AF) values in pounds were collected, which were then normalized to body weight (NF). AF values increased with increasing age (p < 0.001 for all muscle groups), whereas NF values decreased through adolescence (p < 0.001 for all muscle groups except for hip abduction where p = 0.022), indicating that increases in weight through adolescence led to decreases in relative force. Both AF and NF values were significantly greater in TD subjects when compared with children with CP in all muscle and all age groups (p < 0.001). Diplegics and quadriplegics demonstrated consistently lower force values than TD subjects for all muscle groups, except for the hip extensors where TD children had similar values with diplegics (p = 0.726) but higher than quadriplegics (p = 0.001). Diplegic patients also exhibited higher values than quadriplegics in all muscles, except for the knee extensors where their difference was only indicative (p = 0.056). The conversion of CP subjects' force values as a percentage of the TD subjects' mean value revealed a pattern of significant muscle strength imbalance between the CP antagonist muscles, documented from the following deficit differences for the CP muscle couples: (hip extensors 13%) / (hip flexors 32%), (adductors 27%) / (abductors 52%), and (knee extensors 37%) / (knee flexors 53%). This pattern was evident in all age groups. Similarly, significant force deficiencies were identified in GMFCS III/IV patients when compared with TD children and GMFCS I/II patients. In this study, we demonstrated that children and adolescents with bilateral CP exhibited lower strength values in lower limb muscles when compared with their TD counterparts. This difference was more prevalent in quadriplegic patients and those with a more severe impairment. An important pattern of muscle strength imbalance between the antagonist muscles of the CP subjects was revealed.

Moderately and Late Preterm Infants: Short- and Long-Term Outcomes From a Registry-Based Cohort.

Background: While most studies on the association of preterm birth and cerebral palsy (CP) have focused on very preterm infants, lately, attention has been paid to moderately preterm [32 to <34 weeks gestational age (GA)] and late preterm infants (34 to <37 weeks GA). Methods: In order to report on the outcomes of a cohort of moderately and late preterm infants, derived from a population-based CP Registry, a comparative analysis of data on 95 moderately preterm infants and 96 late preterm infants out of 1,016 with CP, was performed. Results: Moderately preterm neonates with CP were more likely to have a history of N-ICU admission (p = 0.001) and require respiratory support (p < 0.001) than late preterm neonates. Birth weight was significantly related to early neonatal outcome with children with lower birth weight being more likely to have a history of N-ICU admission [moderately preterm infants (p = 0.006)/late preterm infants (p < 0.001)], to require ventilator support [moderately preterm infants (p = 0.025)/late preterm infants (p = 0.014)] and not to have neonatal seizures [moderately preterm infants (p = 0.044)/late preterm infants (p = 0.263)]. In both subgroups, the majority of children had bilateral spastic CP with moderately preterm infants being more likely to have bilateral spastic CP and less likely to have ataxic CP as compared to late preterm infants (p = 0.006). The prevailing imaging findings were white matter lesions in both subgroups, with statistically significant difference between moderately preterm infants who required ventilator support and mainly presented with this type of lesion vs. those who did not and presented with gray matter lesions, maldevelopments or miscellaneous findings. Gross motor function was also assessed in both subgroups without significant difference. Among late preterm infants, those who needed N-ICU admission and ventilator support as neonates achieved worse fine motor outcomes than those who did not. Conclusions: Low birth weight is associated with early neonatal problems in both moderately and late preterm infants with CP. The majority of children had bilateral spastic CP and white matter lesions in neuroimaging. GMFCS levels were comparable in both subgroups while BFMF was worse in late preterm infants with a history of N-ICU admission and ventilator support.

Trends in Prevalence and Severity of Pre/Perinatal Cerebral Palsy Among Children Born Preterm From 2004 to 2010: A SCPE Collaboration Study.

Aim: To report on prevalence of cerebral palsy (CP), severity rates, and types of brain lesions in children born preterm 2004 to 2010 by gestational age groups. Methods: Data from 12 population-based registries of the Surveillance of Cerebral Palsy in Europe network were used. Children with CP were eligible if they were born preterm (<37 weeks of gestational age) between 2004 and 2010, and were at least 4 years at time of registration. Severity was assessed using the impairment index. The findings of postnatal brain imaging were classified according to the predominant pathogenic pattern. Prevalences were estimated per 1,000 live births with exact 95% confidence intervals within each stratum of gestational age: ≤27, 28-31, 32-36 weeks. Time trends of both overall prevalence and prevalence of severe CP were investigated using multilevel negative binomial regression models. Results: The sample comprised 2,273 children. 25.8% were born from multiple pregnancies. About 2-thirds had a bilateral spastic CP. 43.5% of children born ≤27 weeks had a high impairment index compared to 37.0 and 38.5% in the two other groups. Overall prevalence significantly decreased (incidence rate ratio per year: 0.96 [0.92-1.00[) in children born 32-36 weeks. We showed a decrease until 2009 for children born 28-31 weeks but an increase in 2010 again, and a steady prevalence (incidence rate ratio per year = 0.97 [0.92-1.02] for those born ≤27 weeks. The prevalence of the most severely affected children with CP revealed a similar but not significant trend to the overall prevalence in the corresponding GA groups. Predominant white matter injuries were more frequent in children born <32 weeks: 81.5% (≤27 weeks) and 86.4% (28-31 weeks), compared to 63.6% for children born 32-36 weeks. Conclusion: Prevalence of CP in preterm born children continues to decrease in Europe excepting the extremely immature children, with the most severely affected children showing a similar trend.

Neuroimaging Patterns and Function in Cerebral Palsy-Application of an MRI Classification.

Background: Cerebral palsy (CP) is a disorder of movement and posture and every child with CP has a unique composition of neurological symptoms, motor severity, and associated impairments, constituting the functional profile. Although not part of the CP definition, magnetic resonance imaging (MRI) sheds light on the localization, nature, and severity of brain compromise. The MRI classification system (MRICS), developed by the Surveillance of Cerebral Palsy in Europe (SCPE), describes typical MRI patterns associated with specific timing of vulnerability in different areas of the brain. The classification has proven to be reliable and easy to use. Aims: The aim of this study is to apply the MRICS on a large dataset and describe the functional profile associated with the different MRI patterns of the MRICS. Materials and Methods: Data on children with CP born in 1999-2009 with a post-neonatal MRI from 20 European registers in the JRC-SCPE Central Registry was included. The CP classification and the MRICS was applied, and The Gross Motor Function Classification (GMFCS) and the Bimanual Fine Motor Function (BFMF) classification were used. The following associated impairments were documented: intellectual impairment, active epilepsy, visual impairment, and hearing impairment. An impairment index was used to characterize severity of impairment load. Results: The study included 3,818 children with post-neonatal MRI. Distribution of CP type, motor, and associated impairments differed by neuroimaging patterns. Functional profiles associated with neuroimaging patterns were described, and the impairment index showed that bilateral findings were associated with a more severe outcome both regarding motor impairment and associated impairments than unilateral compromise. The results from this study, particularly the differences in functional severity regarding uni- and bilateral brain compromise, may support counseling and service planning of support of children with CP.

Intravenous midazolam in convulsive status epilepticus in children with pharmacoresistant epilepsy.

Although the efficacy of midazolam in refractory status epilepticus and as a first-line agent in children with established status epilepticus has been reported, differences in starting doses, continuation method, timing of efficacy assessment, and discontinuation pose limitations in deriving a specific protocol for midazolam use. An audit of clinical experience with a protocol of midazolam as first-line agent for impending status epilepticus (defined as a continuous, generalized, convulsive seizure lasting >5 minutes) in 76 episodes of unprovoked convulsive status epilepticus in children 1-15 years old with treatment-refractory epilepsy demonstrated that: (1) repeated bolus midazolam 0.1mg/kg (every 5 minutes, maximum 5) controlled 91% of events; (2) three bolus doses controlled 89% of the episodes, with minimal chance of response beyond that; (3) treating impending status resulted in lower doses (mean 0.17 mg/kg) than reported and infrequent utilization of additional anticonvulsants (9%); and (4) adverse events were infrequent (respiratory depression 13%, assisted ventilation 3%).

Management of epilepsy associated with tuberous sclerosis complex: Updated clinical recommendations.

Patients with tuberous sclerosis complex (TSC) are at very high risk for developing epilepsy, and the majority experience seizure onset during the first year of life. Early targeted interventions increase the probability of seizure-freedom and may protect neurodevelopment. In 2012, clinical recommendations for the management of epilepsy in patients with TSC were published by a panel of European experts. Since that time novel studies, reports, and expert opinions in preclinical and clinical TSC-related sciences prompted the need for updated recommendations, including epileptogenesis in TSC, the potential role of predictive biomarkers, the possible benefits of presymptomatic diagnosis and preventive treatment, and new treatment options including mTOR inhibitors. A reconvened panel reviewed the current literature to answer specific questions and five panelists discussed the findings, followed by a general discussion during which all issues were debated to achieve consensus regarding recommendations. A draft manuscript based on these discussions and recommendations was then circulated several times among the panelists, who added their own comments. All the panelists/authors agreed with the final manuscript, which was then submitted for publication. The panel concluded that the need for early diagnosis of TSC-associated seizures is now established, electroencephalographic monitoring has good predictive value for epilepsy before seizure onset in TSC, and, until conclusive data from the EPISTOP trial are available, administration of vigabatrin may be considered in children with subclinical epileptiform EEG discharges. The panel also supported the role of adjunctive everolimus for TSC-associated drug-refractory seizures and emphasized the necessity of early surgical evaluation.

Familial Moyamoya disease in two European children.

We present familial Moyamoya disease in two European children and emphasize the importance of familial factors in the pathogenesis of this disease and its appearance not only in Asians but in the Western population as well. The first patient, a Greek female infant, also has coagulation disorders. Her mother, also suffering from Moyamoya and other family members, have similar coagulation disorders (Factor V Leiden, Methylene-tetrahydrofolic reductase and Factor II 20210A mutations). The second patient, a Scottish boy, is unique in that familial Moyamoya affects five members of three consecutive generations of his maternal family. Genetic analysis in the Greek family demonstrated no abnormality on chromosome 3p26, as in other cases. However, the mitochondrial DNA and Y chromosomal genotype showed that affected members had the same sequence of the Mitochondrial 3 portion of D-loop with Japanese patients. These findings suggest that the pathogenesis of Moyamoya may vary across races and ethnic groups.