Search

Introduction: In one third of all patients with epilepsy, seizure freedom is not achieved through anti-seizure medication (ASM). These patients have an increased risk of earlier death, poorer cognitive development, and reduced quality of life. Cenobamate (CNB) has recently been approved as a promising novel ASM drug for the treatment of adults with focal-onset epilepsy. However, there is little experience for its application in pediatric patients., Methods: In a multicenter study we evaluated retrospectively the outcome of 16 pediatric patients treated "off label" with CNB., Results: In 16 patients with a mean age of 15.38 years, CNB was started at an age of 15.05 years due to DRE. Prior to initiation of therapy, an average of 10.56 (range 3-20) ASM were prescribed. At initiation, patients were taking 2.63 (range 1-4) ASM. CNB was increased by 0.47 ± 0.27mg/kg/d every 2 weeks with a mean maximum dosage of 3.1 mg/kg/d (range 0.89-7) and total daily dose of 182.81 mg (range 50-400 mg). Seizure freedom was achieved in 31.3% and a significant seizure reduction of >50% in 37.5%. Adverse events occurred in 10 patients with fatigue/somnolence as the most common. CNB is taken with high adherence in all but three patients with a median follow-up of 168.5 days., Conclusion: Cenobamate is an effective ASM for pediatric patients suffering from drug-resistant epilepsy. In addition to excellent seizure reduction or freedom, it is well-tolerated. Cenobamate should be considered as a novel treatment for DRE in pediatric patients., Competing Interests: TK-P and TM were employed by Epilepsiezentrum Kleinwachau gemeinnützige GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Makridis, Bast, Prager, Kovacevic-Preradovic, Bittigau, Mayer, Breuer and Kaindl.)

Neurodevelopmental diseases are often associated with other comorbidities, especially inflammatory processes. The disease may affect the trace element (TE) status, which in turn may affect disease severity and progression. Selenium (Se) is an essential TE required for the biosynthesis of selenoproteins including the transporter selenoprotein P (SELENOP) and extracellular glutathione peroxidase (GPX3). SELENOP deficiency in transgenic mice resulted in a Se status-dependent phenotype characterized by impaired growth and disturbed neuronal development, with epileptic seizures on a Se-deficient diet. Therefore, we hypothesized that Se and SELENOP deficiencies may be prevalent in paediatric patients with a neurodevelopmental disease. In an exploratory cross-sectional study, serum samples from children with neurodevelopmental diseases ( n = 147) were analysed for total serum Se, copper (Cu), and zinc (Zn) concentrations as well as for the TE biomarkers SELENOP, ceruloplasmin (CP), and GPX3 activity. Children with epilepsy displayed elevated Cu and Zn concentrations but no dysregulation of serum Se status. Significantly reduced SELENOP concentrations were found in association with intellectual disability (mean ± SD (standard deviation); 3.9 ± 0.9 mg/L vs. 4.4 ± 1.2 mg/L, p = 0.015). A particularly low GPX3 activity (mean ± SD; 172.4 ± 36.5 vs. 192.6 ± 46.8 U/L, p = 0.012) was observed in phacomatoses. Autoantibodies to SELENOP, known to impair Se transport, were not detected in any of the children. In conclusion, there was no general association between Se deficiency and epilepsy in this observational analysis, which does not exclude its relevance to individual cases. Sufficiently high SELENOP concentrations seem to be of relevance to the support of normal mental development. Decreased GPX3 activity in phacomatoses may be relevant to the characteristic skin lesions and merits further analysis. Longitudinal studies are needed to determine whether the observed differences are relevant to disease progression and whether correcting a diagnosed TE deficiency may confer health benefits to affected children.

Background: Minichromosomal maintenance (MCM) complex components 2, 4, 5 and 6 have been linked to human disease with phenotypes including microcephaly and intellectual disability. The MCM complex has DNA helicase activity and is thereby important for the initiation and elongation of the replication fork and highly expressed in proliferating neural stem cells., Methods: Whole-exome sequencing was applied to identify the genetic cause underlying the neurodevelopmental disease of the index family. The expression pattern of Mcm7 was characterised by performing quantitative real-time PCR, in situ hybridisation and immunostaining. To prove the disease-causative nature of identified MCM7 , a proof-of-principle experiment was performed., Results: We reported that the homozygous missense variant c.793G>A/p.A265T (g.7:99695841C>T, NM_005916.4) in MCM7 was associated with autosomal recessive primary microcephaly (MCPH), severe intellectual disability and behavioural abnormalities in a consanguineous pedigree with three affected individuals. We found concordance between the spatiotemporal expression pattern of Mcm7 in mice and a proliferative state: Mcm7 expression was higher in early mouse developmental stages and in proliferative zones of the brain. Accordingly, Mcm7/MCM7 levels were detectable particularly in undifferentiated mouse embryonal stem cells and human induced pluripotent stem cells compared with differentiated neurons. We further demonstrate that the downregulation of Mcm7 in mouse neuroblastoma cells reduces cell viability and proliferation, and, as a proof-of-concept, that this is counterbalanced by the overexpression of wild-type but not mutant MCM7 ., Conclusion: We report mutations of MCM7 as a novel cause of autosomal recessive MCPH and intellectual disability and highlight the crucial function of MCM7 in nervous system development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Brain structures in the infant brain are investigated reliably using cranial magnetic resonance imaging. However, the lack of quantitative standard values for various brain regions results in data interpretation that is often subjective or based on small patient cohorts. The aim of this study was to create simple linear measurements to assess brain structures in infancy., Methods: We assessed cranial magnetic resonance imaging sessions of 131 children without intracerebral pathology retrospectively for size of various brain structures throughout the first year of life., Results: Standard values for the size and the growth rate of 14 brain structures including lateral ventricles, frontal subarachnoid space, pons, medulla oblongata, cerebellar vermis, pituitary gland, optical nerve, corpus callosum and the tegmentovermian angle were defined., Conclusion: Our study offers reference values for the biometric assessment of the infant brain. Especially in children with multiple brain malformations, it is essential to know the normal absolute and relative size of brain structures., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Cerebral palsy is the most prevalent physical disability in children; however, its inherent molecular mechanisms remain unclear. In the present study, we performed in-depth clinical and molecular analysis on 120 idiopathic cerebral palsy families, and identified underlying detrimental genetic variants in 45% of these patients. In addition to germline variants, we found disease-related postzygotic mutations in ∼6.7% of cerebral palsy patients. We found that patients with more severe motor impairments or a comorbidity of intellectual disability had a significantly higher chance of harbouring disease-related variants. By a compilation of 114 known cerebral-palsy-related genes, we identified characteristic features in terms of inheritance and function, from which we proposed a dichotomous classification system according to the expression patterns of these genes and associated cognitive impairments. In two patients with both cerebral palsy and intellectual disability, we revealed that the defective TYW1, a tRNA hypermodification enzyme, caused primary microcephaly and problems in motion and cognition by hindering neuronal proliferation and migration. Furthermore, we developed an algorithm and demonstrated in mouse brains that this malfunctioning hypermodification specifically perturbed the translation of a subset of proteins involved in cell cycling. This finding provided a novel and interesting mechanism for congenital microcephaly. In another cerebral palsy patient with normal intelligence, we identified a mitochondrial enzyme GPAM, the hypomorphic form of which led to hypomyelination of the corticospinal tract in both human and mouse models. In addition, we confirmed that the aberrant Gpam in mice perturbed the lipid metabolism in astrocytes, resulting in suppressed astrocytic proliferation and a shortage of lipid contents supplied for oligodendrocytic myelination. Taken together, our findings elucidate novel aspects of the aetiology of cerebral palsy and provide insights for future therapeutic strategies., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Facioscapulohumeral muscular dystrophy type 2 (FSHD2) and arhinia are 2 distinct disorders caused by pathogenic variants in the same gene: SMCHD1 . The mechanism underlying this phenotypic divergence remains unclear. In this study, we characterize the neuromuscular phenotype of individuals with arhinia caused by SMCHD1 variants and analyze their complex genetic and epigenetic criteria to assess their risk for FSHD2., Methods: Eleven individuals with congenital nasal anomalies, including arhinia, nasal hypoplasia, or anosmia, underwent a neuromuscular examination, genetic testing, muscle ultrasound, and muscle MRI. Risk for FSHD2 was determined by combined genetic and epigenetic analysis of 4q35 haplotype, D4Z4 repeat length, and methylation profile. We also compared expression levels of pathogenic DUX4 mRNA in primary myoblasts or dermal fibroblasts (upon myogenic differentiation or epigenetic transdifferentiation, respectively) in these individuals vs those with confirmed FSHD2., Results: Among the 11 individuals with rare, pathogenic, heterozygous missense variants in exons 3-11 of SMCHD1, only a subset (n = 3/11; 1 male, 2 female; age 25-51 years) met the strict genetic and epigenetic criteria for FSHD2 (D4Z4 repeat unit length <21 in cis with a 4qA haplotype and D4Z4 methylation <30%). None of the 3 individuals had typical clinical manifestations or muscle imaging findings consistent with FSHD2. However, the patients with arhinia meeting the permissive genetic and epigenetic criteria for FSHD2 displayed some DUX4 expression in dermal fibroblasts under the epigenetic de-repression by drug treatment and in the primary myoblasts undergoing myogenic differentiation., Discussion: In this cross-sectional study, we identified patients with arhinia who meet the full genetic and epigenetic criteria for FSHD2 and display the molecular hallmark of FSHD- DUX4 de-repression and expression in vitro-but who do not manifest with the typical clinicopathologic phenotype of FSHD2. The distinct dichotomy between FSHD2 and arhinia phenotypes despite an otherwise poised DUX4 locus implies the presence of novel disease-modifying factors that seem to operate as a switch, resulting in one phenotype and not the other. Identification and further understanding of these disease-modifying factors will provide valuable insight with therapeutic implications for both diseases., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

We report 3 patients (age 8, 13 and 14 years) with drug-resistant epilepsy due to Rasmussen encephalitis treated with cannabidiol in addition to their current antiseizure medication (ASM). In all three patients we observed a positive effect, which seemed to surpass the efficacy that would be expected from a different fourth or fifth antiseizure drug used during the course of the disease., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Nearly one-third of all infants with epilepsy develop drug-resistant epilepsy. Although epilepsy surgery is a well-established therapy across all age groups, there might be a reluctance to operate on infants in the first six months of life due to unique surgical and anesthesiologic difficulties., Methods: We performed a meta-analysis and systematic review to assess the outcome and complication rate of epilepsy surgery in infants operated on ≤ six months of life., Results: 158 infants underwent epilepsy surgery, most frequently a hemispherotomy rather than focal surgery. Overall seizure freedom after surgery was 65.6% [CI: 0.5785; 0.7261], with higher seizure-free rates following hemispherotomy (71%) than after focal surgery (58%). Complications occurred in 27.7% [0.1794; 0.4004] of patients. Most prevalently, a hydrocephalus developed in 20 out of 136 cases (14.71%). Anti-seizure medication (ASM) was discontinued in 21.5% [0.1431; 0.3100] and reduced in 85.9% [0.515; 0.9721] of 93 patients postoperatively. 84.6% of infants displayed cognitive impairment (development quotient (DQ) <85) preoperatively. After surgery, there was a trend toward a cognitive gain. However, cognitive gain was seen almost exclusively in seizure-free patients., Discussion: Excellent seizure control can be achieved with epilepsy surgery in the first six months of life, a large proportion of patients are able to reduce or discontinue ASM. Data regarding cognitive outcome are promising, but also show that the primary goal should be to achieve seizure freedom. Given the more difficult surgical conditions, epilepsy surgery in the first six months of life should only be performed in specialized epilepsy centers., (Copyright © 2022 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Cerebral palsy (CP) refers to a non-progressive permanent lesion of the developing brain, which can manifest with motor function disability and various comorbidities and complications. However, there is little data on the correlation between motor and mental function in CP, as cognitive assessments are rarely the main focus of studies on children with CP., Methods: We studied a large cohort of 381 children and adolescents with CP. We analyzed the relationship between severity of CP and the presence of developmental disturbances (motor, motor-linguistic, global) including cognition, the number of aids and education., Results: We found a strong correlation between the severity of CP according to the Gross Motor Function Classification System (GMFCS) and developmental disturbances. In line with this finding, the number of aids per individual also correlated significantly with CP severity and the extent of developmental disturbance. Going beyond the number of aids most patients already received special education in kindergarten. Later, the type of schooling correlated significantly with severity of CP and developmental disturbance. While developmental disturbance and cognition correlated, this was not the case for CP severity and cognition. The latter indicates a wide range in individual manifestation and resources., Conclusions: Our data underline that cognition does not necessarily correlate with CP severity. Thus, in addition to the evaluation and treatment of motor deficits, cognitive assessment should be offered early-on to improve patient-centered counselling and support with respect to appropriate education.

Microcephaly or reduced head circumference results from a multitude of abnormal developmental processes affecting brain growth and/or leading to brain atrophy. Autosomal recessive primary microcephaly (MCPH) is the prototype of isolated primary (congenital) microcephaly, affecting predominantly the cerebral cortex. For MCPH, an accelerating number of mutated genes emerge annually, and they are involved in crucial steps of neurogenesis. In this review article, we provide a deeper look into the microcephalic MCPH brain. We explore cytoarchitecture focusing on the cerebral cortex and discuss diverse processes occurring at the level of neural progenitors, early generated and mature neurons, and glial cells. We aim to thereby give an overview of current knowledge in MCPH phenotype and normal brain growth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zaqout and Kaindl.)

Background: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups., Methods: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity., Findings: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8-59·0, IQR 9-23) and a mean weight of 9·1 kg (range 4·0-15·0, IQR 7·4-10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9-19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings., Interpretation: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored., Funding: None., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests No author received financial support for the present manuscript. CW declares consulting fees from Novartis and Biogen (paid personally) and Roche (paid to institution); honoraria from Novartis and Biogen; and travel support from Biogen. AZ declares grants and travel support from Biogen; consulting fees and honoraria from Novartis, Roche, and Biogen; and advisory board participation for Novartis and Roche. JJ declares honoraria for review writing from Biogen; and travel support and personal fees for advisory board participation from Biogen, Roche, Novartis/Avexis, Sarepta Therapeutics, and PTC. GS declares payment for consulting from Novartis. MF-B declares consulting fees from Novartis Gene Therapy, Biogen, and Roche. CS declares training support from Biogen. HH declares support from the SMArtCARE registry (paid to institution) and payment for participation on advisory board from Novartis; and is a board member of the International Child Neurology Association. SI declares support from SMArtCARE (paid to institution) and payments for advisory board participation from Novartis. AP declares financial support from Biogen for the SMArtCARE registry; compensation for training activities from Biogen; and advisory board participation for Novartis Gene Therapy. WM-F declares consulting fees and honoraria from Novartis and Roche; honoraria from Biogen; and advisory board participation for Novartis and Roche. KV declares speaker's honoraria from Biogen and travel fees from Biogen and Santhera. AB declares speaker's honoraria from Biogen and Genzyme; travel support from Merck group; and advisory board participation for Novartis. MS declares payments for lectures from Novartis, Biogen, and Genzyme. BW declares honoraria for lectures, interviews, and workshops from Novartis, Biogen, and Pfizer; travel support for meetings from Novartis and Biogen; and advisory board participation for Novartis and Biogen. BP declares support for advisory board participation from Novartis, Biogen, Roche, Zogenix, and PCT; payment for manuscript writing from Novartis; and payment for workshop from Biogen. GB declares consulting fee from PTC; honoraria for lectures and information events; payment for participation on advisory boards from PTC, Roche, Novartis, Pfizer, and Biogen; and being an unpaid consultant for Wiener Gesundheitsverbund (WiGeV), Austrian Social Insurance, and Austrian Department of Pharmaceutical Affairs. RAF declares consulting fees, payment for lecture, and travel support from Biogen; and payment for advisory board participation from AveXis/Novartis. CR declares consulting fees from Biogen, EISAI, Novartis, PTC, Roche, and UCB; and payment for participation on advisory boards from Biogen, Novartis, and Roche. MvdH declares payment for lecture from Avexis/Novartis, Biogen, and PTC; payment for manuscript writing from Biogen; and advisory board participation for Avexis/Novartis, Biogen, Roche, and Sarepta. AMK declares grants from the German Research Foundation; consulting fees from Covance; payment for lecture from Ethypharm; and advisory board participation from Novartis, GW Pharma, and Ethypharm. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS) include a heterogeneous group of autosomal recessive inherited diseases characterized by primary (congenital) microcephaly, the absence of visceral abnormalities, and a variable degree of cognitive impairment, short stature and facial dysmorphism. Recently, biallelic variants in the nuclear pore complex (NPC) component nucleoporin 85 gene (NUP85) were reported to cause steroid-resistant nephrotic syndrome (SRNS). Here, we report biallelic variants in NUP85 in two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS, thereby expanding the phenotypic spectrum of NUP85-linked diseases. Structural analysis predicts the identified NUP85 variants cause conformational changes that could have an effect on NPC architecture or on its interaction with other NUPs. We show that mutant NUP85 is, however, associated with a reduced number of NPCs but unaltered nucleocytoplasmic compartmentalization, abnormal mitotic spindle morphology, and decreased cell viability and proliferation in one patient's cells. Our results also indicate the link of common cellular mechanisms involved in MCPH-SCKS spectrum disorders and NUP85-associated diseases. In addition to the previous studies, our results broaden the phenotypic spectrum of NUP85-linked human disease and propose a role for NUP85 in nervous system development., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: In Germany, so far the COVID-19 pandemic evolved in two distinct waves, the first beginning in February and the second in July, 2020. The Berlin University Children's Hospital at Charité (BCH) had to ensure treatment for children not infected and infected with SARS-CoV-2. Prevention of nosocomial SARS-CoV-2 infection of patients and staff was a paramount goal. Pediatric hospitals worldwide discontinued elective treatments and established a centralized admission process. Methods: The response of BCH to the pandemic adapted to emerging evidence. This resulted in centralized admission via one ward exclusively dedicated to children with unclear SARS-CoV-2 status and discontinuation of elective treatment during the first wave, but maintenance of elective care and decentralized admissions during the second wave. We report numbers of patients treated and of nosocomial SARS-CoV-2 infections during the two waves of the pandemic. Results: During the first wave, weekly numbers of inpatient and outpatient cases declined by 37% ( p < 0.001) and 29% ( p = 0.003), respectively. During the second wave, however, inpatient case numbers were 7% higher ( p = 0.06) and outpatient case numbers only 6% lower ( p = 0.25), compared to the previous year. Only a minority of inpatients were tested positive for SARS-CoV-2 by RT-PCR (0.47% during the first, 0.63% during the second wave). No nosocomial infection of pediatric patients by SARS-CoV-2 occurred. Conclusion: In contrast to centralized admission via a ward exclusively dedicated to children with unclear SARS-CoV-2 status and discontinuation of elective treatments, maintenance of elective care and decentralized admission allowed the almost normal use of hospital resources, yet without increased risk of nosocomial infections with SARS-CoV-2. By this approach unwanted sequelae of withheld specialized pediatric non-emergency treatment to child and adolescent health may be avoided., Competing Interests: HB was employed by Labor Berlin GmbH, a joint subsidiary of the public hospitals Charité Universitätsmedizin Berlin and Vivantes—Netzwerk für Gesundheit GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Terliesner, Rosen, Kaindl, Reuter, Lippold, Mall, Bernuth and Gratopp.)

Background and Objective: Rasmussen encephalitis (RE) is characterized by its unilateral cerebral involvement. However, both ipsi- and contralesional cerebellar atrophy have been anecdotally reported raising questions about the nature and extent of infratentorial findings. Using MRI, we morphometrically investigated the cerebellum and hypothesized abnormalities beyond the effects of secondary atrophy, implicating a primary involvement of the cerebellum by RE., Methods: Voxel-based morphometry of the cerebellum and brainstem was conducted in 57 patients with RE and in 57 matched controls. Furthermore, patient-specific asymmetry indices (AIs) of cerebellar morphometry and fluid-attenuated inversion recovery (FLAIR) intensity were calculated. Using diffusion tensor imaging, the integrity of the cortico-ponto-cerebellar (CPC) tract was assessed. Finally, a spatial independent component analysis (ICA) was used to compare atrophy patterns between groups., Results: Patients with RE showed bilateral cerebellar and predominantly ipsilesional mesencephalic atrophy ( p < 0.01). Morphometric AIs revealed ipsilesional < contralesional asymmetry in 27 and ipsilesional > contralesional asymmetry in 30 patients. In patients with predominant ipsilesional atrophy, morphometric AIs strongly correlated with FLAIR intensity AIs ( r = 0.86, p < 0.0001). Fractional anisotropy was lower for ipsilesional-to-contralesional CPC tracts than opposite tracts ( T = 2.30, p < 0.05). ICA revealed bilateral and strictly ipsi- and contralesional atrophy components in patients with RE ( p < 0.05)., Discussion: We demonstrated atrophy of the ipsilesional-to-contralesional CPC pathway and, consequently, interpret the loss of contralesional gray matter as secondary crossed cerebellar atrophy. The ipsilesional cerebellar atrophy, however, defies this explanation. Based on FLAIR hyperintensities, we interpret ipsilesional atrophy to be due to inflammation in the scope of a primary involvement of the cerebellum by RE., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

N -methyladenosine (m 6 -methyladenosine (m 6 , a novel cause of a neurodevelopmental disorder we identified recently, impairs neurogenesis, neurite outgrowth, and synaptic formation by regulating m Arhgef2 , a novel cause of a neurodevelopmental disorder we identified recently, impairs neurogenesis, neurite outgrowth, and synaptic formation by regulating m 6 A methylation. Arhgef2 and total m Mettl14 A level significantly in the cerebral cortex. m 6 A level significantly in the cerebral cortex. m 6 reduces m Arhgef2 reduces m 6 A methylation of 1,622 mRNAs, including Npdc1 and Cend1, deficiency decreases m Arhgef2 deficiency decreases m 6 A methylations of the Npdc1 and Cend1 mRNAs via down-regulation of Mettl14, and thereby inhibits the translation of Npdc1 and nuclear export of Cend1 mRNAs. Overexpression of Mettl14, Npdc1, and Cend1 rescue the abnormal phenotypes in Arhgef2 mediates m Arhgef2 mediates m 6 A-tagged target mRNAs to impair neural differentiation., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Spina bifida (SB) is an umbrella term for multiple conditions characterized by misclosure of vertebral arches. Neuropathologic findings in SB cases are often reported with imprecise and overlapping terminology. In view of the increasing identification of SB-associated genes and pathomechanisms, the precise description of SB subtypes is highly important. In particular, the term "myelomeningocele" is applied to various and divergent SB subtypes. We reevaluated 90 cases with SB (58 prenatal; 32 postnatal). The most frequent SB phenotype in our cohort was myeloschisis, which is characterized by an open neural plate with exposed ependyma (n = 28; 31.1%). An open neural plate was initially described in only in two-thirds of the myeloschisis cases. An additional 21 cases (23.3%) had myelomeningocele; 2 cases (2.2%) had a meningocele; and 21 cases (23.3%) had an unspecified SB aperta (SBA) subtype. Overall, the SB phenotype was corrected in about one-third of the cases. Our findings highlight that "myelomeningocele" and "SB aperta" cannot be used as synonymous terms and that myeloschisis is an underreported SB phenotype. Based on our findings and a review of literature we propose a classification of SB subtypes in SB occulta and the 3 SBA subtypes, meningocele, myelomeningocele, and myeloschisis., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13). Phenotypes and genotypes of ten pediatric patients with pathogenic DYNC1H1 variants were analyzed in a multi-center study. Data mining of large-scale genomic variant databases was used to investigate domain-specific vulnerability and conservation of DYNC1H1. We identified ten patients with nine novel mutations in the DYNC1H1 gene. These patients exhibit a broad spectrum of clinical findings, suggesting an overlapping disease manifestation with intermixed phenotypes ranging from neuropathy (peripheral nervous system, PNS) to severe intellectual disability (central nervous system, CNS). Genomic profiling of healthy and patient variant datasets underlines the domain-specific effects of genetic variation in DYNC1H1, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype-phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength in DYNC1H1-NMD and motor domain with cerebral malformations in DYNC1H1-NDD. We highlight that the current classification into distinct disease entities does not sufficiently reflect the clinical disease manifestation that clinicians face in the diagnostic work-up of DYNC1H1-related disorders. We propose a novel clinical classification for DYNC1H1-related disorders encompassing a spectrum from DYNC1H1-NMD with an exclusive PNS phenotype to DYNC1H1-NDD with concomitant CNS involvement.

Background: Anti-neuronal autoantibodies have been reported as the cause of several neurologic disorders other than encephalitis. Unfortunately, data are mostly based on serum analysis. Predictions about pathogenicity are thus limited. To determine the presence of so far unidentified autoantibody-derived neuroreactivity we analyzed cerebrospinal fluid (CSF) of children with neurological disorders other than encephalitis., Patients and Methods: We did a retrospective analysis of CSF from 254 children with various neurologic diseases other than encephalitis and searched for reactivity against neuronal surface antigens by immunofluorescence on unfixed murine brain sections (tissue-based assay, TBA) and by commercial cell-based assays (CBA). A semi-quantitative fluorescence score classified our results and we described the clinical course of all positive patients with strong neuroreactivity., Results: Strong anti-neuronal IgG immunoreactivity of unknown antigen specificity was detected in CSF samples of 10 pediatric patients (4%, n = 10/254) with unsolved neurological disorders. CSF inflammatory markers were elevated. Most patients did not or only partly recover. Five screening-positive patients presented with a combination of headache and visual impairment due to optic nerve atrophy. Our data suggest to consider inflammatory, autoantibody-related etiologies, especially in cases without definite diagnoses., Conclusions: We present an overview of CSF neuroreactivity in children with neurological disorders other than encephalitis, indicating the presence of unidentified anti-neuronal autoantibodies. As TBA enables screening for unknown autoantibodies, we suggest this method as a second step if commercial CBAs do not yield a result. Further studies are necessary to characterize such antibodies, evaluate pathogenicity, and answer the question whether positive CSF neuroreactivity should prompt an immunotherapeutic approach., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Epilepsy is often associated with psychosocial comorbidity and this can be more disabling than the seizure activity. Still, these associated conditions are often underdiagnosed and therefore not sufficiently treated. We studied a large pediatric cohort of 371 patients with epilepsy to identify factors associated with negative outcome. We found that patients with early-onset epilepsy, epilepsy of known etiology, and polypharmacy were the most likely to display cognitive impairment. Behavioral problems were particularly prevalent in patients with an epilepsy duration ≥ 5 years. Similarly, early-onset epilepsy, long illness duration, epilepsy of known etiology, and polypharmacy had an adverse effect on school placement and/or social contact. With polypharmacy being the only potentially modifiable factor, it is important to balance between benefits and adverse effects of antiepileptic drugs and consider alternative therapy options in selected patients such as epilepsy surgery, vagal nerve stimulation, and ketogenic diet early-on., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

TRAPPC9 gene mutations have been linked recently to autosomal recessive mental retardation 13 (MRT13; MIM#613192) with only eight families reported world-wide. We assessed patients from two consanguineous pedigrees of Pakistani descent with non-syndromic intellectual disability and postnatal microcephaly through whole exome sequencing (WES) and cosegregation analysis. Here we report six further patients from two pedigrees with homozygous TRAPPC9 gene mutations, the novel nonsense mutation c.2065G>T (p.E689*) and the previously identified nonsense mutation c.1423C>T (p.R475*). We provide an overview of previously reported clinical features and highlight common symptoms and variability of MRT13. Common findings are intellectual disability and absent speech, and frequently microcephaly, motor delay and pathological findings on MRI including diminished cerebral white matter volume are present. Mutations in TRAPPC9 should be considered in non-syndromic autosomal recessive intellectual disability with severe speech disorder., (© 2017 Wiley Periodicals, Inc.)

Aim: The aim of this study was to assess the diagnostic approach to microcephaly in childhood and to identify the prevalence of the various underlying causes/disease entities., Method: We conducted a retrospective study on a cohort of 680 children with microcephaly (399 males, 281 females; mean age at presentation 7-8mo, range 1mo-5y) from patients presenting to Charité - University Medicine Berlin (n=474) and University Hospital Dresden (n=206). Patient discharge letters were searched electronically to identify cases of microcephaly, and then the medical records of these patients were used to analyze parameters for distribution., Results: The putative aetiology for microcephaly was ascertained in 59% of all patients, leaving 41% without a definite diagnosis. In the cohort of pathogenetically defined microcephaly, genetic causes were identified in about half of the patients, perinatal brain damage accounted for 45%, and postnatal brain damage for 3% of the cases. Microcephaly was associated with intellectual impairment in 65% of participants, epilepsy was diagnosed in 43%, and ophthalmological disorders were found in 30%. Brain magnetic resonance imaging revealed abnormalities in 76% of participants., Interpretation: Microcephaly remains a poorly defined condition, and a uniform diagnostic approach is urgently needed. A definite aetiological diagnosis is important in order to predict the prognosis and offer genetic counselling. Identifying gene mutations as causes of microcephaly increases our knowledge of brain development and the clinical spectrum of microcephaly. We therefore propose a standardized initial diagnostic approach to microcephaly., (© 2014 Mac Keith Press.)

True microcephaly (head circumference ≤-3SD), either primary (present at birth) or secondary (of postnatal onset) results from an imbalance between progenitor cell production and cell death that lead to a reduced number of neuronal and glial cells within the brain, resulting in reduced brain growth. Primary non-syndromal microcephalies are recessive disorders resulting from abnormal control of mitotic spindle and cell cycle kinetics in progenitor cells. Microcephaly is also a frequent sign of defects in DNA double- and/or single-strand break repair and in nucleotide excision repair, in which it often is associated with general growth impairment. In these etiologies, cognitive functions are reasonably well preserved despite severe reduction in brain volume. Neuronal migration defects are often associated with secondary microcephaly, as are anomalies of telencephalic cleavage. Secondary microcephalies are often associated with increased neuronal death, and can be associated with metabolic disorders such as serine deficiency or thiamine pyrophosphate transporter deficiency. Microcephaly can be associated with hundreds of syndromal congenital anomalies, including many chromosomal disorders. Genetic etiologies of developmental microcephalies are reviewed., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Cyclin dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) has gained attention in the last years following the discovery, in 2005, that recessive mutations cause primary autosomal recessive microcephaly. This disease is seen as an isolated developmental defect of the brain, particularly of the cerebral cortex, and was thus historically also referred to as microcephalia vera. Unraveling the pathomechanisms leading to this human disease is fascinating scientists because it can convey insight into basic mechanisms of physiologic brain development (particularly of cortex formation). It also finds itself in the spotlight because of its implication in trends in mammalian evolution with a massive increase in the size of the cerebral cortex in primates. Here, we provide a timely overview of the current knowledge on the function of CDK5RAP2 and mechanisms that might lead to disease in humans when the function of this protein is disturbed.

Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1), recently referred to as distal spinal muscular atrophy 1 (DSMA1; MIM#604320) and also known as distal hereditary motor neuropathy type 6 (dHMN6 or HMN6), results from mutations in the IGHMBP2 gene on chromosome 11q13.3 encoding the immunoglobulin micro-binding protein 2. In contrast to the infantile spinal muscular atrophy type 1 (SMA1; Werdnig-Hoffmann disease) with weakness predominantly of proximal muscles and bell-shaped thorax deformities due to intercostal muscle atrophy, infants with distal spinal muscular atrophy 1 usually present with distal muscle weakness, foot deformities, and sudden respiratory failure due to diaphragmatic paralysis that often requires urgent intubation. In this article, the authors review the clinical, neuropathological, and genetic aspects of distal spinal muscular atrophy 1 and discuss differential diagnoses.

Traumatic brain injury (TBI) is a major cause of morbidity and mortality among children and adolescents. To gain insight into developmental events influenced by TBI, we analyzed subacute mouse brain proteome changes in a percussion head trauma model at P7 ipsi- and contralateral to the site of injury. The comparison of brain proteomes of trauma mice and controls revealed reproducible changes in the intensity of 28 proteins (30 protein spots) in response to trauma. The changes detected suggest that TBI leads to apoptosis, inflammation, and oxidative stress. These changes were consistent with our results of histological and biochemical evaluation of the brains which revealed widespread apoptotic neurodegeneration, microglia activation, and increased levels of protein carbonyls. Furthermore, we detected changes in proteins involved in neuronal migration as well as axonal and dendritic growth and guidance, suggesting interference of trauma with these developmental events., (Copyright © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)