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Herpes simplex virus (HSV) type 1 is a frequent pathogen causing infectious encephalitis (HSVE). Early treatment with intravenous acyclovir has led to a significant decrease in mortality. However, especially in children, deterioration during or after HSVE may occur without any evidence of HSV reactivation or improvement following repeated antiviral therapy. Here, we report 15 patients (age range 3 months to 15 years) who suffered from autoimmune encephalitis with autoantibodies to NMDAR1 following Herpes encephalitis, presenting with movement abnormalities (young children) or neuropsychiatric symptoms (older children) as major complaints, respectively. The diagnosis was based on positive cerebrospinal fluid (CSF) and/or serum anti-NMDAR-antibodies with two children showing only positive CSF antibody findings. The time lag between first symptoms and diagnosis of autoimmune encephalitis was significantly longer than between first symptoms and diagnosis of HSVE (p

Background Aplasia cutis congenita (ACC) is a rare congenital anomaly characterized by localized or widespread absence of skin at birth, mainly affecting the scalp. Most information about ACC exists as individual case reports and medium-sized studies. Objectives This study aimed to investigate the epidemiology of ACC, using data from a large European network of population-based registries for congenital anomalies (EUROCAT). Methods Twenty-eight EUROCAT population-based registries in 16 European countries were involved. Poisson regression models were exploited to estimate the overall and live birth prevalence, to test time trends in prevalence between four 5-year periods and to evaluate the impact of the change of coding for ACC from the unspecific ICD9-BPA code to the specific ICD10 code. Proportions of ACC cases associated with other anomalies were reported. Results Five hundred cases were identified in the period 1998–2017 (prevalence: 5.10 per 100,000 births). Prevalence across 5-year periods did not differ significantly and no significant differences were evident due to the change from ICD9 to ICD10 in ACC coding. Heterogeneity in prevalence was observed across registries. The scalp was the most common site for ACC (96.4%) and associated congenital anomalies were present in 33.8% of cases. Patau and Adams–Oliver syndromes were the most frequent among the associated chromosomal anomalies (88.3%) and the associated genetic syndromes (57.7%), respectively. 16% of cases were associated with limb anomalies and 15.4% with congenital heart defects. A family history of ACC was found in 2% of cases. Conclusion To our knowledge, this is the only population-based study on ACC. The EUROCAT methodologies provide reliable prevalence estimates and proportions of associated anomalies.

Specifying peri- and postnatal factors in children born very preterm (VPT) that affect later outcome helps to improve long-term treatment.To enhance the predictability of 5-year cognitive outcome by perinatal, 2-year developmental and socio-economic data.92 VPT infants, born 2007-2009, gestational age32 weeks and/or birthweight of 1500 g, were assessed longitudinally including basic neonatal, socio-economic (SES), 2-year Mental Developmental Index (MDI, Bayley Scales II), 5-year Mental Processing Composite (MPC, Kaufman-Assessment Battery for Children), and Language Screening for Preschoolers data. 5-year infants born VPT were compared to 34 term controls.The IQ of 5-year infants born VPT was 10 points lower than that of term controls and influenced independently by preterm birth and SES. MDI, SES, birth weight and birth complications explained 48% of the variance of the MPC. The MDI proved highly predictive (r=0.6, R2=36%) for MPC but tended to underestimate the cognitive outcome. A total of 61% of the 2-year infants born VPT were already correctly classified (specificity of .93, sensitivity of .54). CHAID decision tree technique identified SES as decisive for the outcome for infants born VPT with medium MDI results (76-91): They benefit from effects associated to a higher SES, while those with a poor MDI outcome and a birth weight≤890 g do not.Developmental follow-up of preterm children enhances the quality of prognosis and later outcome when differentially considering perinatal risks and SES.Spezifisches Identifizieren peri- und postnataler Faktoren verbessert die langfristige Behandlung sehr frühgeborener (VPT) Kinder und damit ihre Entwicklungschancen. ZIEL: Die kognitive Entwicklung 5-jähriger VPT Kinder auf Basis von perinatalen, sozioökonomischen und entwicklungsrelevanten 2-Jahres-Daten optimal vorhersagen. Patienten und Methoden: 92 sehr Frühgeborene, geboren 2007–2009,32 SSW bzw.1500 g wurden längsschnittlich untersucht anhand von neonatalen Daten, sozioökonomischem Status (SES), 2-Jahres Mental Developmental Index (MDI, Bayley Scales II), 5-Jahres IQ (MPC, K-ABC) und des Sprachscreenings für Vorschulkinder. Die 5-jährigen VPT Kinder wurden mit 34 gleichaltrigen Reifgeborenen verglichen.5-jährige VPT Kinder hatten einen 10 Punkte niedrigeren IQ als Reifgeborene, separat beeinflusst durch die Faktoren Frühgeburt und SES. MDI; SES, Geburtsgewicht und -komplikationen erklärten 48% der Varianz des MPC. Der MDI erwies sich als starker Prädiktor (r=0.6, R2=36%), 61% der Frühgeborenen wurden bereits mit 2 Jahren richtig eingestuft (Spezifität .93, Sensitivität .54). Ein CHAID Entscheidungsbaum identifizierte den SES als entscheidende Variable bei mittlerem MDI (76–91). Diese VPT Kinder profitieren von einem höheren SES; jene mit schlechtem MDI und einem Geburtsgewicht ≤ 890 g tun dies nicht.Die differenzierte Berücksichtigung von perinatalen Risikofaktoren und SES verbessert die entwicklungsdiagnostische Nachsorge sehr frühgeborener Kinder in der Qualität der Prognose und damit ein besseres späteres Outcome.

The galactosyltransferase T-synthase exclusively synthesizes the T-antigen, a ubiquitous Oglycan core structure. Its function is dependent on its specific molecular chaperone, Cosmc (C1GALT1C1). In two maternal half-brothers with developmental delay, immunodeficiency, short stature, thrombocytopenia and acute kidney injury (AKI) resembling atypical hemolytic uremic syndrome, we identified the hemizygous variant c.59C > A (p.Ala20Asp) in Xchromosomal C1GALT1C1. Their heterozygous mother and maternal grandmother show an attenuated phenotype with skewed X-inactivation in blood. AKI in the male patients proved fully responsive to treatment with the complement inhibitor Eculizumab. This germline variant within the transmembrane domain of Cosmc causes dramatically reduced expression of the Cosmc chaperone with a significant reduction of Tsynthase enzyme activity, resulting in incomplete O-glycosylation. Transfection of patient cells with wildtype C1GALT1C1 partially rescued this glycosylation defect. We also detected very high levels of galactose-deficient IgA1 in all four affected individuals.

CONTEXT Equine-assisted therapy in different facets aims to improve the clinical condition of children with cerebral palsy. A more comprehensive overview on the overall effects and on the differences between different treatment modalities seems desirable. OBJECTIVE We compared the effectiveness of various equine-assisted treatments on motor capabilities and quality of life of children with cerebral palsy. DATA SOURCES We conducted systematic searches of PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. STUDY SELECTION Randomized and nonrandomized controlled parallel-group or crossover studies on equine-assisted therapies in comparison with standard of care were included. DATA EXTRACTION Data on motor function assessed by different instruments were considered as the primary outcome. Secondary outcomes included global, social, physical, and emotional scores of quality of life. RESULTS Strong evidence for a positive effect of equine-assisted therapies, particularly hippotherapy, on global gross motor function and motor capabilities during walking in children with cerebral palsy was identified (SMD 0.24, 95% CI 0.05 to 0.43, P = .01, t2 = 0.00, I2 = 15%; SMD 2.68, 95% CI 1.02 to 4.34, P = .002, t2 = 0.0, I2 = 0%). No evidence for the improvement in quality of life could be shown in the global assessment, nor in any subscore. CONCLUSIONS Equine-assisted therapy, particularly hippotherapy, can be a therapeutic tool for children who are learning to walk. LIMITATION The heterogeneity of tools used in different studies and the low number of studies addressing quality of life issues limited the number of studies available for distinct analyses.

Background Equine-assisted treatments of the motor system appear to have an effect on the neuromuscular system and aim to improve the pathological condition of children with cerebral palsy. Hippotherapy is a distinct form of equine-assisted therapy where certified physiotherapists use the horse as a dynamic tool in a medical treatment setting. The objective of the proposed review is to summarize and critically appraise the evidence on the effect of equine-assisted treatments on motor capabilities of children with cerebral palsy. Methods We will identify trials through systematic searches of PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL). Quality assessment of retrieved articles will be conducted using the criteria outlined in the revised tool to assess risk of bias in randomized trials (RoB 2.0) or the ROBINS-I tool (Risk Of Bias In Non-randomized Studies - of interventions), respectively. Quantitative data synthesis will be performed if treatments, participants, and the underlying clinical question are homogenous and provide adequate outcome data for meta-analysis. Otherwise, data will be synthesized, using the narrative synthesis approach. Conclusion This review will provide a critical summary of the evidence regarding the impact of equine-assisted treatments on motor capabilities of children with cerebral palsy. The result from this review will help to inform healthcare practitioners and policymakers on the additional effect of equine-assisted treatments on reducing the burden of cerebral palsy among children. Systematic review registration This systematic review protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO). Registration number: CRD42018096403. This protocol was prepared using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols checklist (PRISMA-P).

Background Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay. Methods We report eight children with PTU; six of them also exhibiting symptoms of ataxia and/or developmental delay. Treatment with carbonic anhydrase inhibition was offered to children with persisting and/or severe forms. Results Whole-exome sequencing and genome-wide array analysis (n = 7) did not reveal mutations in the three known genes associated with PTU (CACNA1A, GRID2, SEPSECS), whereas by MLPA a heterozygous deletion of exon 31 of the CACNA1A gene could be detected in one patient, her mother and two further family members. Further exome and array analysis showed no recurrent variants in potentially novel PTU-related genes in more than one patient. A de novo variant at a highly conserved position in the SIM1 gene was detected in one patient, for which a pathogenic effect could be speculated. Carbonic anhydrase inhibition was started in five children and proved at least partially effective in all of them. Conclusion Irrespective of the clinical background and the molecular basic mechanism of PTU, therapeutic carbonic anhydrase inhibition was effective in all five children (acetazolamide, n = 3; sultiame, n = 2) who received this treatment.

Seizure 96, 18-21 (2022). doi:10.1016/j.seizure.2022.01.006, Published by Elsevier, Oxford [u.a.]

Journal of medical virology 94(7), 3087-3095 (2022). doi:10.1002/jmv.27682, Published by Wiley, Bognor Regis [u.a.]

Funder: Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein‐Westfalen; Id: http://dx.doi.org/10.13039/501100009591, Funder: Bundesministerium für Bildung und Forschung; Id: http://dx.doi.org/10.13039/501100002347, AIMS: MICU1 encodes the gatekeeper of the mitochondrial Ca2+ uniporter, MICU1 and biallelic loss-of-function mutations cause a complex, neuromuscular disorder in children. Although the role of the protein is well understood, the precise molecular pathophysiology leading to this neuropaediatric phenotype has not been fully elucidated. Here we aimed to obtain novel insights into MICU1 pathophysiology. METHODS: Molecular genetic studies along with proteomic profiling, electron-, light- and Coherent anti-Stokes Raman scattering microscopy and immuno-based studies of protein abundances and Ca2+ transport studies were employed to examine the pathophysiology of MICU1 deficiency in humans. RESULTS: We describe two patients carrying MICU1 mutations, two nonsense (c.52C>T; p.(Arg18*) and c.553C>T; p.(Arg185*)) and an intragenic exon 2-deletion presenting with ataxia, developmental delay and early onset myopathy, clinodactyly, attention deficits, insomnia and impaired cognitive pain perception. Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis. Comparative mitochondrial Ca2+ transport and proteomic studies on lymphoblastoid cells revealed that the [Ca2+ ] threshold and the cooperative activation of mitochondrial Ca2+ uptake were lost in MICU1-deficient cells and that 39 proteins were altered in abundance. Several of those proteins are linked to mitochondrial dysfunction and/or perturbed Ca2+ homeostasis, also impacting on regular cytoskeleton (affecting Spectrin) and Golgi architecture, as well as cellular survival mechanisms. CONCLUSIONS: Our findings (i) link dysregulation of mitochondrial Ca2+ uptake with muscle pathology (including perturbed lipid homeostasis and ER-Golgi morphology), (ii) support the concept of a functional interplay of ER-Golgi and mitochondria in lipid homeostasis and (iii) reveal the vulnerability of the cellular proteome as part of the MICU1-related pathophysiology.

BACKGROUND. Deciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell’s function and its pathophysiology. METHODS. Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene. RESULTS. We identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, the patients showed signs of respiratory chain defects, and a CRISPR/Cas9-KO cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of periodic acid–Schiff–positive (PAS-positive) material in tissues from affected individuals, together with decreased glycogen branching enzyme 1 (GBE1) activity, indicated an additional impact of C2orf69 on glycogen metabolism. CONCLUSIONS. Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on other metabolic pathways.

We report a 9-year-old girl homozygous for a loss-of-function mutation in the PIEZO-2 gene. She showed generalized muscular hypotonia with severe scoliosis, joint deformities, deficient proprioceptive function and selective atrophy and signal alterations of both gastrocnemii on whole body MRI scan. Light microscopic and ultrastructural examination showed few atrophic fibres, abnormal mitochondria, focal myofibrillar disruption and endomysial capillary microangiopathy.

Monatsschrift Kinderheilkunde 169(2), 151-158 (2021). doi:10.1007/s00112-020-01076-7 special issue: "Pädiatrische Dermatologie", Published by Springer, Berlin

Neurology: Neuroimmunology & Neuroinflammation ; official journal of the American Academy of Neurology 8(6), e1062 (2021). doi:10.1212/NXI.0000000000001062, Published by Lippincott Williams & Wilkins, Philadelphia, Pa.

EBioMedicine 72, 103588 (2021). doi:10.1016/j.ebiom.2021.103588, Published by Elsevier, Amsterdam [u.a.]

Neurology: Neuroimmunology & Neuroinflammation ; official journal 8(6), 1-15 (2021). doi:10.1212/NXI.0000000000001086, Published by Wolters Kluwer, Philadelphia, Pa.

Knowledge on the mechanisms of viral spread, of time-related changes, and age-specific factors of severe acute respiratory syndrome coronavirus 2 infections is important to develop recommendations aimed at controlling the pandemic. In this context, longitudinal data on proportions of positive results in different age groups are rare. Data on total positive counts and on shares of positive counts deriving from a private (MVZ) and a University (RWTH) laboratory were analyzed retrospectively and compared with public data on total positive counts of the Robert Koch Institute (RKI). Data were covered for Weeks 9-24 of the year 2020 and all patient ages. Total positive counts were lower in children compared to adults. Proportions of children and adults tested positive were 3%-5% and 5%-7%, respectively. RKI and MVZ data showed similar time-related patterns. Patients of 20-60 years of age did account for the initial virus spread (maximum infection rates at Weeks 9-11). Thereafter, infection rates decreased in older patients whereas children did not show a comparable time-related decrease. Pediatric data generated in outpatient settings and hospitals differed markedly which should be considered in further studies. In summary, compared with adults children are less affected by severe acute respiratory syndrome coronavirus 2 infections and are unlikely to account for the initial viral spread. However, children show sustained viral activity and may serve as a viral reservoir.

ObjectiveTo describe the presentations, radiologic features, and outcomes of children with autoimmune encephalitis associated with myelin oligodendrocyte glycoprotein antibodies (MOG abs).MethodsIdentification of children fulfilling the diagnostic criteria for possible autoimmune encephalitis (AE) and testing positive for serum MOG abs. Chart review and comprehensive analysis of serum MOG abs using live cell assays and rat brain immunohistochemistry.ResultsTen children (4 girls, 6 boys) with AE and serum MOG abs were identified. The median age at onset was 8.0 years (range: 4–16 years). Children presented with a combination of encephalopathy (10/10), headache (7/10), focal neurologic signs (7/10), or seizures (6/10). CSF pleocytosis was common (9/10, median 80 white cell count/μL, range: 21–256). Imaging showed cortical and deep gray matter involvement in all in addition to juxtacortical signal alterations in 6/10 children. No involvement of other white matter structures or contrast enhancement was noted. MOG abs were detected in all children (median titer 1:640; range: 1:320–1:10,540). Nine children had a favorable outcome at discharge (modified Rankin scale of < 2). Five of 10 children had up to 3 additional demyelinating relapses associated with persisting MOG abs. One child had NMDA receptor (NMDAR) abs at initial presentation. A second child had a third demyelinating episode with MOG abs with overlapping NMDAR encephalitis.DiscussionAE associated with serum MOG abs represents a distinct form of autoantibody-mediated encephalitis in children. We therefore recommend including MOG abs testing in the workup of children with suspected AE.

De novo pathogenic variants in CNOT3 have recently been reported in a developmental delay disorder (intellectual developmental disorder with speech delay, autism, and dysmorphic facies [IDDSADF, OMIM: #618672]). The patients present with a variable degree of developmental delay and behavioral problems. To date, all reported disease-causing variants occurred de novo and no parent-child transmission was observed. We report for the first time autosomal dominant transmissions of the CNOT3-associated developmental disorder in two unrelated families. The clinical characteristics in our patients match the IDDSADF features reported so far and suggest substantial variability of the phenotype within the same family.

Aims We aimed to analyze the relationship between epilepsy and glutamic acid decarboxylase autoantibodies (GADA) in patients with type 1 diabetes mellitus (T1DM) and the impact of GADA on demographic, clinical, and metabolic data in T1DM patients with epilepsy. Methods We searched for patients with T1DM ≤20 years and GADA measurements, and within this group for patients with epilepsy. We formed groups: T1DM + Epilepsy + GADA positive; T1DM + Epilepsy + GADA negative; T1DM + GADA positive; T1DM + GADA negative. We used logistic regression to analyze the relationship between epilepsy and GADA with odds ratio adjusted for sex, duration of diabetes (DOD), and age at diabetes onset (ADO). We used logistic regression with odds ratio adjusted for DOD and ADO onset using epilepsy as a dependent variable and GADA, HbA1c, ketoacidosis, severe hypoglycemia (SH), sex, celiac disease, and autoimmune thyroiditis as independent variables. We conducted regression analyses adjusted for sex, DOD, and ADO to analyze differences in clinical/metabolic parameters between the groups. Results Epilepsy was not more frequent in GADA-positive patients (GPP). Logistic regression including all patients with GADA measurements showed that hypoglycemia with coma (HC) correlated with epilepsy when compared to no SH. We found no differences in clinical and metabolic data between GPP and GADA-negative patients (GNP) with epilepsy. SH occurred more often in GPP with epilepsy in comparison to GPP without epilepsy. GNP with epilepsy had a higher rate of HC than GPP without epilepsy. Conclusion We found no relationship between epilepsy and GADA. A relationship between T1DM and epilepsy might be explainable by SH.

Unter Enzephalitis versteht man eine Entzundung des Hirnparenchyms und unter Meningitis eine Entzundung der Hirnhaute. Erstere kann direkt erregerbedingt oder infektionsassoziiert sein oder eine nicht erregerbedingte Atiologie haben. Dieser Abschnitt behandelt die viral bedingten Enzephalitiden und die wichtigsten nichtinfektiosen Ursachen sowie die viralen Meningitiden.

Background Mutations in the HECT domain of NEDD4L have recently been identified in a cohort of eight patients with a syndromic form of bilateral periventricular nodular heterotopia (PVNH) in association with neurodevelopmental delay, cleft palate, and toe syndactyly (PVNH7). Methods Case report based on NGS sequencing. Results Here, we describe a girl with a novel heterozygous NEDD4L missense variant, p.Tyr679His, and characteristic clinical findings, including bilateral periventricular nodular heterotopia, cleft palate and mild toe syndactyly. Molecular testing from peripheral blood identified the healthy father to carry the NEDD4L variant in mosaic state. Notably, a previous pregnancy of the couple had been terminated due to a complex fetal developmental disorder, including hypokinesia and flexion contractures. Upon review, this affected fetus was also shown to carry the familial NEDD4L variant. Conclusion Our findings may suggest a broader spectrum of NEDD4L‐associated phenotypes, including severe prenatal neurodevelopmental manifestations, which might represent yet another genetic form of fetal hypokinesia with flexion contractures.

Background: Processing speed is frequently reduced in patients suffering from multiple sclerosis (MS). Reduced processing speed can also lead to impaired working memory capacity (WMC) in adult MS patients. Less is known about the interplay of cognitive deficits in paediatric MS patients. Objectives: In the present study, we investigated whether processing speed and WMC are reduced in paediatric MS patients compared with healthy controls and whether reduced processing speed and WMC might explain potential differences in psychometric intelligence between MS patients and healthy controls. Methods: Twenty-one paediatric MS patients and 21 healthy controls completed a reaction time (RT) task, a working memory task, and Cattell’s Culture Fair Test (CFT20-R). Results: Patients with MS had slower RT and lower intelligence scores than healthy controls. We could find no significant differences for WMC. An analysis of covariance revealed that group differences in intelligence could be partially explained by processing speed differences. Conclusion: The results indicate that processing speed is a good marker for MS-related impaired efficiency and increased error-proneness of the central nervous system in higher-order cognition as required by Cattell’s CFT20-R.

Friedreich ataxia (FRDA) is a multisystem autosomal recessive disease with progressive clinical course involving the neuromuscular and endocrine system. Diabetes mellitus (DM) is one typical non-neurological manifestation, caused by beta cell failure and insulin resistance. Because of its rarity, knowledge on DM in FRDA is limited. Based on data from 200,301 patients with DM of the German-Austrian diabetes registry (DPV) and two exemplary patient reports, characteristics of patients with DM and FRDA are compared with classical type 1 or type 2 diabetes. Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 ± 165 and 384 ± 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups. FRDA patients did not show overweight and HbA1c levels were even lower than in T1Dm or T2Dm patients, respectively, indicating good overall diabetes control. FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided.

This study investigated the effect of hippotherapy on gross motor function (Gross Motor Function Measure [GMFM]-66, GMFM dimension E and D) and quality of life (Child Health Questionnaire [CHQ 28], KIDSCREEN-27 parental versions) in children with bilateral spastic cerebral palsy. Seventy-three children (age: 9.1 ± 3.3 years; male = 44; GMFCS levels II = 27; III = 17; IV = 29) were randomized to an early (n = 35) or late (n = 38) treatment group. Data from 66 probands were available for further analysis. Probands received hippotherapy once to twice weekly during a period of 16 to 20 weeks (mean: 17 treatments) in a crossover approach. Whereas no significant changes were found for total GMFM scores and quality of life parameters, a significant increase in GMFM dimension E was found. Children terminating the study early showed lower mean psychosocial quality of life scores than children who completed the whole study (CHQ-28 “psychosocial dimension”; KIDSCREEN-27 “mood and emotional dimension”). Our data are in line with previous reports and suggest that hippotherapy shows distinct therapeutic strengths with regard to promoting upright stand and gait in children with cerebral palsy. Children with higher psychosocial burden of disease may need special support to get access to and benefit from intensified physiotherapy programs.

Background New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD). Objective To describe systematically the CSF profile in children with MOG-EM. Material and methods Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster [MRZ] reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF l-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively. Results Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/μl; range 6–256; mostly lymphocytes and monocytes; > 100/μl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF l-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF l-lactate (p < 0.0003) during acute attacks with age. Conclusion MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

Objective To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients. Methods We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity. Results Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome. Interpretation Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.

Mutations in spectrin beta non-erythrocytic 4 (SPTBN4) have been linked to congenital hypotonia, intellectual disability and motor neuropathy. Here we report on two siblings with a homozygous splice-site mutation in the SPTBN4 gene, lacking previously reported features of the disorder such as seizures, feeding difficulties, respiratory difficulties or profound intellectual disability. Our findings indicate that muscular hypotonia, myopathic facies with ptosis and axonal neuropathy can be the core clinical features in the SPTBN4 disorder and suggest that SPTBN4 mutation analysis should be considered in infants with marked axonal neuropathy.

Industry 4.0 changes the manufacturing industry significantly. In order to stay competitive, companies need to develop new business capabilities and business models that are enabled by Industry 4.0 concepts. However, companies are currently struggling with expensive and risky IT transformation projects that are needed to implement such concepts. We observed a lack of research on the planning and modeling part of IT transformations towards Industry 4.0. Therefore, we conducted a series of expert interviews on the topic of enterprise architecture in the context of modeling and planning Industry 4.0 transformations. As a result, we were able to develop a metamodel that can be used as target model for planning endeavors and a planning process that helps as guideline for such planning projects.

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

Introduction Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) is caused by m.8993T>G/C mutations in the mitochondrial adenosine triphosphate synthase subunit 6 gene (MT-ATP6). Traditionally, heteroplasmy levels between 70% and 90% lead to NARP, and >90% result in Leigh syndrome. Methods In this study we report a 30-year-old man with NARP and m.8993T>G in MT-ATP6. Results Although the patient carried the mutation in homoplasmic state in blood with similarly high levels in urine (94%) and buccal swab (92%), he presented with NARP and not the expected, more severe Leigh phenotype. The mutation could not be detected in any of the 3 analyzed tissues of the mother, indicating a large genetic shift between mother and offspring. Nerve biopsy revealed peculiar endoneurial Schwann cell nuclear accumulations, clusters of concentrically arranged Schwann cells devoid of myelinated axons, and degenerated mitochondria. Conclusions We emphasize the phenotypic variability of the m.8993T>G MT-ATP6 mutation and the need for caution in predictive counseling in such patients. Muscle Nerve 54: 328-333, 2016.

The early fetal ultrasound assessment at 11 - 13(+6) weeks of gestation remains the cornerstone of care despite the progress in diagnosing fetal chromosomal defects using cell-free fetal DNA (cffDNA) from the maternal circulation. The measurement of nuchal translucency (NT) allows the risk calculation for the fetal trisomies 21, 18 and 13 but also gives information on those fetal chromosomal defects which are at present unable to be detected using cffDNA. Nuchal translucency is the only auditable parameter at 11 - 13(+6) weeks and gives thus information on the quality of the first trimester anomaly scan. In addition it gives indirect information on the risks for fetal defects and for cardiac anomalies. Also the chances for a healthy live baby can be estimated. As experience with first trimester anomaly scanning increases, and the resolution of the ultrasound equipment has increased substantially, more and more details of the fetal anatomy become accessible at the first trimester scan. Therefore fetal anatomical defects and complex anomalies have become amenable to examination in the first trimester. This guideline describes compulsory and optional parameters for investigation at the first trimester scan and outlines a structured method of examining a first trimester fetus at 11 - 13(+6) weeks of gestation.

Industry 4.0 has become an important concept in the manufacturing industry that increasingly drives change. However, the implementation of this concept is associated to business critical and expensive IT transformation projects, with which companies are currently struggling. We observed a lack of research on the practice of planning IT transformation projects towards Industry 4.0 and its modeling support within currently available EA tools. To investigate this gap, we conducted a series of expert interviews and a tool survey. As a result, we identified several drawbacks of EA tools that need to be addressed in order to be able to efficiently support the modeling and planning of such IT transformations.

Moderate preterm infants (MPI) and late preterm infants (LPI) account for the majority of children born preterm. Up to 5% of MPI and LPI are estimated to manifest neurodevelopmental impairments. However, information about normal early motor development in these patients is lacking.To find characteristic patterns for motor development in the first four months of life among MPI and LPI without risk factors for developmental impairment by using accelerometry of spontaneous movements.Prospective and observational study.Twenty-three MPI and LPI (9 female, 14 male) without known risk factors for neurodevelopmental impairment were included in this study. Spontaneous movements were measured by accelerometry at the time of hospital discharge (mean: 36.6wks postmenstrual age (PMA)) and at the corrected age of three months (mean: 53.0wks PMA).Motor development was described by analyzing 36 parameters calculated from the acceleration signal. Normal neurodevelopmental outcome was confirmed by Bayley Scales of Infant Development at the corrected age of two years.Statistically significant differences (p 0.05) between the two measurements could be shown in 26 out of the 36 parameters. Striking changes in motor development were an increase in acceleration and variability of the spontaneous movements, the main criterion for analyzing spontaneous movements. Furthermore, the regularity of spontaneous movements increased significantly.Characteristic patterns of normal motor development in MPI and LPI can be identified and provide a basis for future investigations aiming at the early detection of abnormal motor development for this specific patient group.