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Unilateral facial palsy in a newborn is rarely caused by a developmental defect. It occurs either isolated or in the context of a syndrome. This article describes a multidisciplinary approach towards unilateral, isolated congenital facial palsy along with a literature review. We report six patients, three boys and three girls, who presented with a unilateral facial palsy at birth. Clinical assessment was performed by an ear-nose-throat (ENT) surgeon, a pediatric neurologist, and an ophthalmologist. Magnetic resonance imaging (MRI) of the posterior fossa and computerized tomography (CT) of the temporal bone were requested to exclude structural anomalies of the facial nerve. Imaging revealed the underlying cause in five patients out of six (80%), showing an ipsilateral facial nerve aplasia or hypoplasia. These findings point towards an underlying developmental defect and underscore the importance of MRI in the diagnostic work-up. Surgical and non-surgical therapies were discussed with the parents.Conclusion: Congenital unilateral facial palsy caused by a developmental defect outside the context of a syndrome is rare. A multidisciplinary approach is recommended to differentiate between various causes and to initiate timely treatment.What is Known:• Congenital facial palsy is mostly caused by environmental/external fcators.• However in rare cases it can be developmental defect.What is New:• This paper describes 6 cases of isolated congenital facial palsy related to a developmental defect and presents the largest case series in the literature caused by aplasia/hypoplasia of the facial nerve.• MRI and CT-imaging allow for an assessment of the facial nerve at the root entry zone of the brainstem and along its course through the middle ear or the face. Moreover, they proved to be helpful in differentiating between several causes of congenital facial palsy.

Dravet syndrome (DS) is one of the most pharmacoresistant and devastating forms of childhood epilepsy syndromes. Distinct de novo mutations in the SCN1A gene are responsible for over 80% of DS cases. While DS is largely resistant to treatment with existing anti-epileptic drugs, promising results have been obtained in clinical trials with human patients treated with the serotonin agonist fenfluramine as an add-on therapeutic. We developed a zebrafish model of DS using morpholino antisense oligomers (MOs) targeting scn1Lab, the zebrafish ortholog of SCN1A. Zebrafish larvae with an antisense knockdown of scn1Lab (scn1Lab morphants) were characterized by automated behavioral tracking and high-resolution video imaging, in addition to measuring brain activity through local field potential recordings. Our findings reveal that scn1Lab morphants display hyperactivity, convulsive seizure-like behavior, loss of posture, repetitive jerking and a myoclonic seizure-like pattern. The occurrence of spontaneous seizures was confirmed by local field potential recordings of the forebrain, measuring epileptiform discharges. Furthermore, we show that these larvae are remarkably sensitive to hyperthermia, similar to what has been described for mouse models of DS, as well as for human DS patients. Pharmacological evaluation revealed that sodium valproate and fenfluramine significantly reduce epileptiform discharges in scn1Lab morphants. Our findings for this zebrafish model of DS are in accordance with clinical data for human DS patients. To our knowledge, this is the first study demonstrating effective seizure inhibition of fenfluramine in an animal model of Dravet syndrome. Moreover, these results provide a basis for identifying novel analogs with improved activity and significantly milder or no side effects.

Background Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABA A receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS. Methods This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6–17 years. Results Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo. Conclusions While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects. Trial registration ClinicalTrials.gov, NCT01725152

ADP ribosylation is a reversible posttranslational modification mediated by poly(ADP-ribose)transferases (e.g., PARP1) and (ADP-ribosyl)hydrolases (e.g., ARH3 and PARG), ensuring synthesis and removal of mono-ADP-ribose or poly-ADP-ribose chains on protein substrates. Dysregulation of ADP ribosylation signaling has been associated with several neurodegenerative diseases, including Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Recessive ADPRHL2/ ARH3 mutations are described to cause a stress-induced epileptic ataxia syndrome with developmental delay and axonal neuropathy (CONDSIAS). Here, we present two families with a neuropathy predominant disorder and homozygous mutations in ADPRHL2 . We characterized a novel C26F mutation, demonstrating protein instability and reduced protein function. Characterization of the recurrent V335G mutant demonstrated mild loss of expression with retained enzymatic activity. Although the V335G mutation retains its mitochondrial localization, it has altered cytosolic/nuclear localization. This minimally affects basal ADP ribosylation but results in elevated nuclear ADP ribosylation during stress, demonstrating the vital role of ADP ribosylation reversal by ARH3 in DNA damage control.

Objective Patients with Early Infantile Epileptic Encephalopathy (EIEE) 52 have inherited, homozygous variants in the gene SCN1B, encoding the voltage‐gated sodium channel (VGSC) β1 and β1B non‐pore‐forming subunits. Methods Here, we describe the detailed electroclinical features of a biallelic SCN1B patient with a previously unreported variant, p.Arg85Cys. Results The female proband showed hypotonia from birth, multifocal myoclonus at 2.5 months, then focal seizures and myoclonic status epilepticus (SE) at 3 months, triggered by fever. Auditory brainstem response (ABR) showed bilateral hearing loss. Epilepsy was refractory and the patient had virtually no development. Administration of fenfluramine resulted in a significant reduction in seizure frequency and resolution of SE episodes that persisted after a 2‐year follow‐up. The patient phenotype is more compatible with early infantile developmental and epileptic encephalopathy (DEE) than with typical Dravet syndrome (DS), as previously diagnosed for other patients with homozygous SCN1B variants. Biochemical and electrophysiological analyses of the SCN1B variant expressed in heterologous cells showed cell surface expression of the mutant β1 subunit, similar to wild‐type (WT), but with loss of normal β1‐mediated modification of human Nav1.1‐generated sodium current, suggesting that SCN1B‐p.Arg85Cys is a loss‐of‐function (LOF) variant. Interpretation Importantly, a review of the literature in light of our results suggests that the term, early infantile developmental and epileptic encephalopathy, is more appropriate than either EIEE or DS to describe biallelic SCN1B patients.

Dravet syndrome, or as it was called in the past ‘severe myoclonic epilepsy in infancy’, is a drug‐resistant epilepsy first described by Charlotte Dravet in 1978. Besides the well‐known and well‐described therapy resistance, Dravet syndrome dramatically impacts the development and behaviour of the affected children. As it is still not a curable disease, families need to be taught how to cope with the disorder and will require assistance from both clinical and non‐clinical structures. At the onset of the disease, many questions arise regarding the diagnosis of Dravet syndrome, the severity of the illness and its deleterious effects, and the management of seizures, especially the long‐lasting status epilepticus. Once the diagnosis has been established, severe convulsions, often unpredictable and long‐lasting, are still a major worry, but developmental and behavioural problems also rapidly become a serious concern. Later on, nearly all parents will have a child who becomes an adult with special needs, requiring specialised attention from professionals.

Monosialotetrahexosylganglioside (GMI) gangliosidosis and Morquio type B (MorB) are two lysosomal storage disorders (LSDs) caused by the same enzyme deficiency, β‐galactosidase (βgal). GMI gangliosidosis, associated with GMI ganglioside accumulation, is a neurodegenerative condition characterized by psychomotor regression, visceromegaly, cherry red spot, and facial and skeletal abnormalities. MorB is characterized by prominent and severe skeletal deformities due to keratan sulfate (KS) accumulation. There are only a few reports on intermediate phenotypes between GMI gangliosidosis and MorB. The presentation of two new patients with this rare intermediate phenotype motivated us to review the literature, to study differences and similarities between GMI gangliosidosis and MorB, and to speculate about the possible mechanisms that may contribute to the differences in clinical presentation. In conclusion, we hypothesize that GMI gangliosidosis and MorB are part of one phenotypic spectrum of the same disease and that the classification of LSDs might need to be revised.

Background Methylphenidate (MPH), the first choice medication for attention-deficit hyperactivity disorder (ADHD), is associated with serious adverse effects like arrhythmia. Evidence on the association of ADHD with immune and oxidant-antioxidant imbalances offers potential for antioxidant and/or immunomodulatory nutritional supplements as ADHD therapy. One small randomised trial in ADHD suggests, despite various limitations, therapeutic benefit from Pycnogenol®, a herbal, polyphenol-rich extract. Methods This phase III trial is a 10-week, randomised, double-blind, placebo and active treatment controlled multicentre trial with three parallel treatment arms to compare the effect of Pycnogenol® to MPH and placebo on the behaviour of 144 paediatric ADHD and attention-deficit disorder (ADD) patients. Evaluations of behaviour (measured by the ADHD-Rating Scale (primary endpoint) and the Social-emotional Questionnaire (SEQ)), immunity (plasma cytokine and antibody levels, white blood cell counts and faecal microbial composition), oxidative stress (erythrocyte glutathione, plasma lipid-soluble vitamins and malondialdehyde and urinary 8-OHdG levels, as well as antioxidant enzyme activity and gene expression), serum zinc and neuropeptide Y level, urinary catecholamines and physical complaints (Physical Complaints Questionnaire) will be performed in week 10 and compared to baseline. Acceptability evaluations will be based on adherence, dropouts and reports of adverse events. Dietary habits will be taken into account. Discussion This trial takes into account comorbid behavioural and physical symptoms, as well as a broad range of innovative immune and oxidative biomarkers, expected to provide fundamental knowledge on ADHD aetiology and therapy. Research on microbiota in ADHD is novel. Moreover, the active control arm is rather unseen in research on nutritional supplements, but of great importance, as patients and parents are often concerned with the side effects of MPH. Trial registration Clinicaltrials.gov number: NCT02700685 . Registered on 18 January 2016. EudraCT 2016-000215-32 . Registered on 4 October 2016.

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. Phenotyping and genetic analyses in 169 probands referred for primary microcephaly produced a molecular diagnosis in 38, with ASPM and WDR62 most prevalent in non‐consanguineous patients, and a total diagnostics rate of 67% in consanguineous patients. Our series includes 11 novel pathogenic variants and reveals epilepsy as a more frequent feature than previously reported.

The tyrosine kinase receptor ErbB4 (erythroblastic leukemia viral oncogene homolog 4) plays a crucial role in numerous neurobiological processes in the developing and adult brain. Moreover, recent molecular genetics studies implicate ErbB4 in the pathophysiology of schizophrenia. However, the phenotypic consequences of haploinsufficiency of ErbB4 are not known, as no coding mutations have been identified until now. Here, we present a patient with early myoclonic encephalopathy and profound psychomotor delay with a de novo reciprocal translocation t(2;6)(q34;p25.3), disrupting the ErbB4 gene. This patient represents the first case of haploinsufficiency for one of the ErbB family members of tyrosine kinase receptors.