Karine Pelc

Epilepsy in Angelman syndrome.

Angelman syndrome is a neurogenetic disorder caused by lack of UBE3A gene expression from the maternally inherited chromosome 15 due to various 15q11-q13 abnormalities. In addition to severe developmental delay, virtual absence of speech, motor impairment, a behavioural phenotype that includes happy demeanor, and distinctive rhythmic electroencephalographic features, over 90% of patients have epilepsy. Many different seizure types may occur, atypical absences and myoclonic seizures being particularly prevalent. Non-convulsive status epilepticus is common, sometimes in the context of the epileptic syndrome referred to as myoclonic status in non-progressive encephalopathies. Epilepsy predominates in childhood, but may persist or reappear in adulthood. Management is difficult in a proportion of patients. It might be improved by better understanding of pathophysiology. Current hypotheses involve abnormal inhibitory transmission due to impaired regulation of GABAA receptors related to functional absence of UBE3A and abnormal hippocampal CaMKII activity.

Behavior and neuropsychiatric manifestations in Angelman syndrome

Angelman syndrome has been suggested as a disease model of neurogenetic developmental condition with a specific behavioral phenotype. It is due to lack of expression of the UBE3A gene, an imprinted gene located on chromosome 15q. Here we review the main features of this phenotype, characterized by happy demeanor with prominent smiling, poorly specific laughing and general exuberance, associated with hypermotor behavior, stereotypies, and reduced behavioral adaptive skills despite proactive social contact. All these phenotypic characteristics are currently difficult to quantify and have been subject to some differences in interpretation. For example, prevalence of autistic disorder is still debated. Many of these features may occur in other syndromic or nonsyndromic forms of severe intellectual disability, but their combination, with particularly prominent laughter and smiling may be specific of Angelman syndrome. Management of problematic behaviors is primarily based on behavioral approaches, though psychoactive medication (eg, neuroleptics or antidepressants) may be required.

Effect of ankle-foot orthoses on trunk sway and lower limb intersegmental coordination in children with bilateral cerebral palsy.

INTRODUCTION Ankle-foot orthoses may significantly improve lower limb kinematics in the gait of children with cerebral palsy. Here we aimed to analyze the effect of ankle-foot orthoses on trunk postural control and lower limb intersegmental coordination in children with mild spastic diplegia (GMFCS I or II). METHODS We recorded tridimensional trunk kinematics and thigh, shank, and foot elevation angles in 20 4-12 year-old children born preterm with spastic diplegia and 20 typically developing children while walking either barefoot or with ankle-foot orthoses. RESULTS We found significantly greater trunk excursions in children with cerebral palsy compared to typically developing children in both conditions. When wearing ankle-foot orthoses cerebral palsy children showed increased trunk frontal angular velocity. No significant changes in trunk displacement and angular velocity were recorded in the sagittal plane in either group. Typically developing children wearing orthoses showed increased trunk frontal displacement. Wearing orthoses induced significant changes in shank and foot elevation in both groups. CONCLUSION Ankle-foot orthoses affect postural control and intersegmental coordination in children with cerebral palsy. This should be taken into account when planning therapeutic management.

What would the brain look like in Angelman syndrome

Scientific knowledge relies on sound evidence. In many domains the latter is still erratic, so that the former is provisionally replaced by inference based on scant data provided unsatisfactorily answered questions remain critically open for scrutiny. Neuroimaging and pathology of Angelman syndrome provide an illustration of this process. Although this condition is primarily characterised by various aspects of brain dysfunction and despite the relatively good availability of neuroimaging techniques in centres where the syndrome has been extensively studied for several dozens of years, there have been surprisingly few neuroimaging studies. Harry Angelman described the skull X-ray and pneumoencephalogram of his three patients when he first characterised the syndrome in 1965. Skull X-rays were normal, excluding craniosynostosis as a cause for the patients’ microcephaly; air encephalograms showed slight ventricular dilatation in all children and increased presence of air around the cortex, suggesting mild cortical–subcortical atrophy. These techniques have become obsolete with the advent of computed tomography and of course magnetic resonance imaging (MRI). In their aetiolological work-up for developmental delay or epilepsy, many patients undergo MRI before the diagnosis of Angelman syndrome is established, allowing for at least retrospective studies but even those have been extremely limited. The general, largely uncontrolled experience with structural imaging techniques has been a lack of abnormalities except for eventual, mild to moderate non-specific cerebral atrophy and more rarely cerebellar atrophy. In this issue of the European Journal of Paediatric Neurology, Harting and her colleagues present a retrospective MRI study involving nine children with Angelman syndrome, i.e. the largest group studied to date in this way although several hundreds of patients have been reported and many more diagnosed over more than 40 years. Interestingly, they report white matter changes in most of these patients and

Phenotypic plasticity and the perception-action-cognition- environment paradigm in neurodevelopmental genetic disorders

Careful study of the phenotype can have implications at several levels, namely clinical diagnosis, pathophysiological reasoning, management planning, and outcome measurement. Behavioural phenotypes involve cognition, communication, social skills, and motor control. They can be documented in a host of neurodevelopmental conditions and approached with the recently refined perception–action–cognition–environment (PACE) paradigm, which focuses on the neurodevelopmental processes that underlie learning and adaption to the environment through perception, action, and cognitive processing. Although this paradigm was originally developed in the context of cerebral palsy, it can be applied along developmental trajectories in several neurogenetic conditions, including Down syndrome, fragile X syndrome, Rett syndrome, Angelman syndrome, and Williams syndrome, to name but a few. It must be recognized, however, that relevant, valid tools for assessment and management strategies still need to be developed.

The ADHD Tetragrammaton taken in vain in neurogenetic disorders

School teachers and parents often refer children to medical attention for ‘ADHD’ (for attention-deficit/hyperactivity disorder) rather than for qualified complaints or symptoms. In our experience, this trend also seems to increasingly affect parents of children with diagnosed severe neurogenetic disorders (e.g. Angelman syndrome), who are tempted to single out their children’s cognitive and behavioural features as being consistent with ADHD. It is as if a diagnosis of ADHD renders the symptoms less outlandish and more acceptable to parents. More consequentially, it often calls for prescription of ‘ADHD drugs’. It may also bring about a fair amount of confusion, including for research. We offer the view that a diagnosis of ADHD in people with neurogenetic disorders is currently not helpful.

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems.

We report the case of a 7‐year‐old male of Western European origin presenting with moderate intellectual disability, severe childhood apraxia of speech in the presence of oral and manual dyspraxia, and hypotonia across motor systems including the oral and speech motor systems. Exome sequencing revealed a de novo frameshift protein truncating mutation in the fourth exon of BCL11A, a gene recently demonstrated as being involved in cognition and language development. Making parallels with a previously described patient with a 200 kb 2p15p16.1 deletion encompassing the entire BCL11A gene and displaying a similar phenotype, we characterize in depth how BCL11A is involved in clinical aspects of language development and oral praxis.

Early intervention and environmental factors: optimizing the development of infants born preterm

Infants born very preterm have an increased risk of neurodevelopmental disorders including motor, cognitive, and behavioural impairment. This is related in part to medical risk factors, such as brain injury, neurosensory impairment, or respiratory disease. Socio-economic risk factors are also important to consider given that the functioning and disability of an individual inevitably occurs in a context. Environmental factors can act as facilitators or barriers. Low maternal educational background, for example, has been shown to be a strong predictor of long-term cognitive outcomes of extremely low-birthweight infants. Difficult socio-economic conditions have been identified as an independent risk factor for neurological impairment in infancy and early childhood. The question remains whether this can be remediated to some extent by early intervention proposed in a context that supports parentchild interaction; a question currently being explored by Pelc et al. Spittle et al. performed an exploratory study to address this question too. They analysed the influence of social risk factors at term age on the neurological development at 2, 4, and 8 years of age in a group of very preterm infants who underwent an early care programme designed to promote parent-child interaction over the first 12 months of life. They focused on a selection of social items based on a self-designed scale. Interestingly, their findings suggest different effects of intervention according to social risk, most strikingly on cognitive performance and behavioural outcome at 2 years of age. Better results were associated with intervention in children with a high social risk compared to those with a low social risk. This difference in results dependent on social environment presents an intriguing and potentially promising avenue for future research. Upstream prevention of low socio-economic status and very preterm birth, which are linked to some extent, should be primary targets for prevention. Yet, Spittle et al.’s results suggest that an intervention programme that aims to enhance parent-child interaction but not alter the family social risk (as evaluated with the items the authors selected) may still have the potential to improve the child’s development, or at least its early course. This may happen through reducing the stress experienced by the parents. Mothers of very preterm infants experience a high level of stress for multiple reasons including their child’s medical condition, their child’s temperament, and the risk for maternal depression, and this is associated with developmental impairment. Low socioeconomic status is an additional factor. It would be pertinent in future research to consider parenting stress in addition to social risk when studying the effect of early intervention programmes tailored for preterm infants, with the hope of proposing sound recommendations to improve the neurological development of these children.

Multicentre prospective randomised single-blind controlled study protocol of the effect of an additional parent-administered sensorimotor stimulation on neurological development of preterm infants: Primebrain

Introduction Preterm and very low birthweight infants are at increased risk for neurodevelopmental disorders, including cerebral palsy, sensory impairment and intellectual disability. Several early intervention approaches have been designed in the hope of optimising neurological development in this context. It seems important that the intervention takes into account parental mental health, focuses on parent–child interactions and lasts sufficiently long. This study aims to evaluate the effects of a stimulation programme administered by parents until 6 months post-term on motor and neurophysiological development of infants born preterm. Methods and analysis Participants will be infants born <32 weeks’ gestation and/or with a birth weight <1500 g recruited prospectively from two tertiary neonatal intensive care units. They will be randomly assigned to receive nationally recommended follow-up only (control group) or also a stimulation programme between 37 weeks’ gestation and 6 months’ corrected age. Perinatal, clinical neurodevelopmental, socio-demographic and neuroimaging (ultrasonography or MRI) data will be collected. Bayley Scales of Infant Development will be used up to 24 months’ corrected age and Parental Stress Index at 6, 12, 18 and 24 months’ corrected age. High-density (64 or 128 electrodes) EEG, visual, somatosensory and long latency auditory evoked potentials will be recorded at term age, 3, 6, 12, 18 and 24 months’ corrected age. They will be analysed for spatiotemporal frequency bands contents and source localisation. Ethics and dissemination The study was approved by the Ethics Committees of the Hôpital Universitaire des Enfants Reine Fabiola and CHU Saint-Pierre. Results dissemination will be made for stakeholders and families, reports will be written for parents, healthcare providers and policymakers, and scientific papers will be published. Trial registration number NCT02159534; Pre-results.

High-density electroencephalography developmental neurophysiological trajectories.

Efforts to document early changes in the developing brain have resulted in the construction of increasingly accurate structural images based on magnetic resonance imaging (MRI) in newborn infants. Tractography diagrams obtained through diffusion tensor imaging have focused on white matter microstructure, with particular emphasis on neuronal connectivity at the level of fibre tract systems. Electroencephalography (EEG) provides a complementary approach with more direct access to brain electrical activity. Its temporal resolution is excellent, and its spatial resolution can be enhanced to physiologically relevant levels, through the combination of high‐density recordings (e.g. by using 64 channels in newborn infants) and mathematical models (e.g. inverse modelling computation), to identify generators of different oscillation bands and synchrony patterns. The integration of functional and structural topography of the neonatal brain provides insights into typical brain organization, and the deviations seen in particular contexts, for example the effect of hypoxic–ischaemic insult in terms of damage, eventual reorganization, and functional changes. Endophenotypes can then be used for pathophysiolgical reasoning, management planning, and outcome measurements, and allow a longitudinal approach to individual developmental trajectories.