SCN2A gene-related early-infantile developmental and epileptic encephalopathy (EI-DEE) is a rare and severe disorder that manifests in early infancy. SCN2A mutations affecting the fast inactivation gating mechanism can result in altered voltage dependence and incomplete inactivation of the encoded neuronal Nav1.2 channel and lead to abnormal neuronal excitability. In this study, we evaluated clinical data of seven missense Nav1.2 variants associated with DEE and performed molecular dynamics simulations, patch-clamp electrophysiology, and dynamic clamp real-time neuronal modelling to elucidate the molecular and neuron-scale phenotypic consequences of the mutations. The N1662D mutation almost completely prevented fast inactivation without affecting activation. The comparison of wild-type and N1662D channel structures suggested that the ambifunctional hydrogen bond formation between residues N1662 and Q1494 is essential for fast inactivation. Fast inactivation could also be prevented with engineered Q1494A or Q1494L Nav1.2 channel variants, whereas Q1494E or Q1494 K variants resulted in incomplete inactivation and persistent current. Molecular dynamics simulations revealed a reduced affinity of the hydrophobic IFM-motif to its receptor site with N1662D and Q1494L variants relative to wild-type. These results demonstrate that the interactions between N1662 and Q1494 underpin the stability and the orientation of the inactivation gate and are essential for the development of fast inactivation. Six DEE-associated Nav1.2 variants, with mutations mapped to channel segments known to be implicated in fast inactivation were also evaluated. Remarkably, the L1657P variant also prevented fast inactivation and produced biophysical characteristics that were similar to those of N1662D, whereas the M1501 V, M1501T, F1651C, P1658S, and A1659 V variants resulted in biophysical properties that were consistent with gain-of-function and enhanced action potential firing of hybrid neurons in dynamic action potential clamp experiments. Paradoxically, low densities of N1662D or L1657P currents potentiated action potential firing, whereas increased densities resulted in sustained depolarization. Our results provide novel structural insights into the molecular mechanism of Nav1.2 channel fast inactivation and inform treatment strategies for SCN2A-related EI-DEE. The contribution of non-inactivating Nav1.2 channels to neuronal excitability may constitute a distinct cellular mechanism in the pathogenesis of SCN2A-related DEE.

– Barré syndrome (GBS) is an immune-mediated disorder of the peripheral nervous system (PNS) with subtypes including demyelinating and axonal forms. The optic nerves are almost invariably spared by GBS as they are part of the central nervous system (CNS). The combination of optic neuritis (ON) and GBS has only rarely been described, and only once in a child with the demyelinating form. 1 We present two paediatric cases of severe axonal GBS and ON following Mycoplasma pneumoniae infection.

BackgroundUBA5 is the activating enzyme of UFM1 in the ufmylation post-translational modification system. Different neurological phenotypes have been associated with UBA5 pathogenic variants including epilepsy, intellectual disability, movement disorders and ataxia.Methods and resultsWe describe a large multigenerational consanguineous family presenting with a severe congenital neuropathy causing early death in infancy. Whole exome sequencing and linkage analysis identified a novel homozygous UBA5 NM_024818.3 c.31C>T (p.Arg11Trp) mutation. Protein expression assays in mouse tissue showed similar levels of UBA5 in peripheral nerves to the central nervous system. CRISPR-Cas9 edited HEK (human embrionic kidney) cells homozygous for the UBA5 p.Arg11Trp mutation showed reduced levels of UBA5 protein compared with the wild-type. The mutant p.Arg11Trp UBA5 protein shows reduced ability to activate UFM1.ConclusionThis report expands the phenotypical spectrum of UBA5 mutations to include fatal peripheral neuropathy.

Background and purposeClusters of acute limb weakness in paediatric patients have been linked to outbreaks of non-polio enteroviruses, termed acute flaccid myelitis (AFM). Outside these clusters, in countries where polio is not endemic, this poliomyelitic-like illness is rare in childhood and its natural history is not well defined. We describe presenting features, investigation findings and long-term outcome of a series of children with AFM.MethodsThis was a retrospective cohort study.ResultsEight children (six females) aged 3 months to 8 years (median age 5 years) met case criteria. Initial symptoms were pain (n = 7) followed by limb weakness with hypotonia (n = 8). Flaccid paralysis occurred in only three patients. Two had cranial nerve dysfunction. Magnetic resonance imaging of the spinal cord demonstrated grey matter involvement particularly affecting the anterior cord, with longitudinally extensive changes in three children. Cerebrospinal fluid examination showed pleocytosis in six children with raised cerebrospinal fluid protein in five. Nerve conduction and electromyography findings were consistent with a motor neuronopathy. Residual deficits were common, with moderate to severe weakness seen in five patients. Median follow-up was 28 months (range 17-108 months, 30.4 patient years in total).ConclusionsAcute flaccid myelitis is an uncommon condition in childhood with a high rate of significant long-term morbidity. AFM should be considered in children presenting with acute limb pain and weakness.

Disturbed mitochondrial fusion and fission have been linked to various neurodegenerative disorders. In siblings from two unrelated families who died soon after birth with a profound neurodevelopmental disorder characterized by pontocerebellar hypoplasia and apnoea, we discovered a missense mutation and an exonic deletion in the SLC25A46 gene encoding a mitochondrial protein recently implicated in optic atrophy spectrum disorder. We performed functional studies that confirmed the mitochondrial localization and pro-fission properties of SLC25A46. Knockdown of slc24a46 expression in zebrafish embryos caused brain malformation, spinal motor neuron loss, and poor motility. At the cellular level, we observed abnormally elongated mitochondria, which was rescued by co-injection of the wild-type but not the mutant slc25a46 mRNA. Conversely, overexpression of the wild-type protein led to mitochondrial fragmentation and disruption of the mitochondrial network. In contrast to mutations causing non-lethal optic atrophy, missense mutations causing lethal congenital pontocerebellar hypoplasia markedly destabilize the protein. Indeed, the clinical severity appears inversely correlated with the relative stability of the mutant protein. This genotype-phenotype correlation underscores the importance of SLC25A46 and fine tuning of mitochondrial fission and fusion in pontocerebellar hypoplasia and central neurodevelopment in addition to optic and peripheral neuropathy across the life span.

Acute flaccid paralysis is associated with inflammation, infection, or tumors in the spinal cord or peripheral nerves. Melioidosis (Burkholderia pseudomallei infection) can rarely cause this presentation. We describe a case of spinal melioidosis in a 4-year-old boy presenting with flaccid paralysis, and review the literature on this rare disease.

Journal of Paediatrics and Child HealthVolume 52, Issue 8 p. 842-846 Instructive Case Fixed dilated pupils: Clues to an ACTA2 mutation allowing early stroke prevention Omega Leong, Omega Leong Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorErik Andersen, Erik Andersen Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorEppie M Yiu, Eppie M Yiu Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia Murdoch Children's Research Institute, Melbourne, Victoria, AustraliaSearch for more papers by this authorDavid Green, David Green Department of Paediatrics, Alice Springs Hospital, Alice Springs, Northern Territory, AustraliaSearch for more papers by this authorMark T Mackay, Mark T Mackay Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia Murdoch Children's Research Institute, Melbourne, Victoria, AustraliaSearch for more papers by this authorJames E Elder, James E Elder Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia Department of Ophthalmology, Royal Children's Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorKatherine B Howell, Corresponding Author Katherine B Howell Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia Murdoch Children's Research Institute, Melbourne, Victoria, AustraliaCorrespondence: Dr Katherine Howell, Department of Neurology, Royal Children's Hospital Melbourne, Flemington Road, Melbourne, Vic. 3052, Australia. Fax: +61 39345 5977; email: katherine.howell@rch.org.auSearch for more papers by this author Omega Leong, Omega Leong Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorErik Andersen, Erik Andersen Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorEppie M Yiu, Eppie M Yiu Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia Murdoch Children's Research Institute, Melbourne, Victoria, AustraliaSearch for more papers by this authorDavid Green, David Green Department of Paediatrics, Alice Springs Hospital, Alice Springs, Northern Territory, AustraliaSearch for more papers by this authorMark T Mackay, Mark T Mackay Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia Murdoch Children's Research Institute, Melbourne, Victoria, AustraliaSearch for more papers by this authorJames E Elder, James E Elder Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia Department of Ophthalmology, Royal Children's Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorKatherine B Howell, Corresponding Author Katherine B Howell Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia Murdoch Children's Research Institute, Melbourne, Victoria, AustraliaCorrespondence: Dr Katherine Howell, Department of Neurology, Royal Children's Hospital Melbourne, Flemington Road, Melbourne, Vic. 3052, Australia. Fax: +61 39345 5977; email: katherine.howell@rch.org.auSearch for more papers by this author First published: 31 May 2016 https://doi.org/10.1111/jpc.13251Citations: 2 Conflict of interest: None declared. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume52, Issue8August 2016Pages 842-846 RelatedInformation

Journal of Paediatrics and Child HealthVolume 52, Issue 6 p. 669-671 Instructive Case Cerebral palsy is not a diagnosis: A case report of a novel atlastin-1 mutation Erik W Andersen, Erik W Andersen Children's Neurosciences Centre, The Royal Children's Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorRichard J Leventer, Richard J Leventer Children's Neurosciences Centre, The Royal Children's Hospital, Melbourne, Victoria, Australia Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, VictoriaSearch for more papers by this authorDinah S Reddihough, Dinah S Reddihough Department of Developmental Medicine, The Royal Children's Hospital, Melbourne, Victoria, Australia Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, VictoriaSearch for more papers by this authorMark R Davis, Mark R Davis Department of Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Western Australia, AustraliaSearch for more papers by this authorMonique M Ryan, Corresponding Author Monique M Ryan [email protected] Children's Neurosciences Centre, The Royal Children's Hospital, Melbourne, Victoria, Australia Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, VictoriaCorrespondence: Prof Monique M Ryan, Department of Neurology, Royal Children's Hospital Melbourne, 50 Flemington Road, Parkville, Vic. 3052, Australia. Fax: +61 39345 5977; email: [email protected]Search for more papers by this author Erik W Andersen, Erik W Andersen Children's Neurosciences Centre, The Royal Children's Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorRichard J Leventer, Richard J Leventer Children's Neurosciences Centre, The Royal Children's Hospital, Melbourne, Victoria, Australia Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, VictoriaSearch for more papers by this authorDinah S Reddihough, Dinah S Reddihough Department of Developmental Medicine, The Royal Children's Hospital, Melbourne, Victoria, Australia Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, VictoriaSearch for more papers by this authorMark R Davis, Mark R Davis Department of Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Western Australia, AustraliaSearch for more papers by this authorMonique M Ryan, Corresponding Author Monique M Ryan [email protected] Children's Neurosciences Centre, The Royal Children's Hospital, Melbourne, Victoria, Australia Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, VictoriaCorrespondence: Prof Monique M Ryan, Department of Neurology, Royal Children's Hospital Melbourne, 50 Flemington Road, Parkville, Vic. 3052, Australia. Fax: +61 39345 5977; email: [email protected]Search for more papers by this author First published: 22 June 2016 https://doi.org/10.1111/jpc.13200Citations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume52, Issue6June 2016Pages 669-671 RelatedInformation

A large multi-consanguineous Australian family originally from Lebanon was studied after four children from different generations died between 19 days and 16 weeks of age. The affected babies presented with irritability, severe weakness including facial weakness, hypotonia, poor feeding, soft cry, and severe motor delay. Two had tongue fasciculations and two reduced fetal movements and foot deformities. Brain and spine MRI and EEG in one patient were normal. EMG performed in one of the patients at age 6 weeks showed absent CMAPS and active denervation on EMG with essentially normal sensory responses. A follow-up study 2 weeks later showed no responses from sensory or motor nerves. EMGs in two other subjects also showed absent motor and sensory responses. Nerve biopsies in two infants showed active demyelination with occasional unmyelinated large fibres and moderate axonal loss. Teased nerve preparations confirmed near-absence of myelin. All affected family members died from respiratory failure. Mutations in genes associated with congenital neuropathies were excluded by exome sequencing. Linkage analysis performed in four affected and five unaffected relatives pointed at a homozygous region in chromosome 3. Within this region reside three rare homozygous missense changes, one in each of three genes, in all affected family members. Functional studies to determine the pathogenic role of the most likely candidate variant are being performed. A new form of fatal congenital hypomyelinating neuropathy is presented. Its molecular cause is currently under further investigation. The identification of subsequent families is necessary for a better clinical and molecular characterization of the condition.

Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS. Methods: Multicenter retrospective study. Results: A total of 144 children and adolescents (median age 8 years, range 0.7–17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05–9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1–8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0–2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0–2 was greater in patients given rituximab early in their disease course compared to those treated later. Conclusion: While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. Classification of evidence: This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.