Novel Genetic and Biochemical Insights into the Spectrum of NEFL-Associated Phenotypes.

Background: NEFL encodes for the neurofilament light chain protein. Pathogenic variants in NEFL cause demyelinating, axonal and intermediate forms of Charcot-Marie-Tooth disease (CMT) which present with a varying degree of severity and somatic mutations have not been described yet. Currently, 34 different CMT-causing pathogenic variants in NEFL in 174 patients have been reported. Muscular involvement was also described in CMT2E patients mostly as a secondary effect. Also, there are a few descriptions of a primary muscle vulnerability upon pathogenic NEFL variants. Objectives: To expand the current knowledge on the genetic landscape, clinical presentation and muscle involvement in NEFL-related neurological diseases by retrospective case study and literature review. Methods: We applied in-depth phenotyping of new and already reported cases, molecular genetic testing, light-, electron- and Coherent Anti-Stokes Raman Scattering-microscopic studies and proteomic profiling in addition to in silico modelling of NEFL-variants. Results: We report on a boy with a muscular phenotype (weakness, myalgia and cramps, Z-band alterations and mini-cores in some myofibers) associated with the heterozygous p.(Phe104Val) NEFL-variant, which was previously described in a neuropathy case. Skeletal muscle proteomics findings indicated affection of cytoskeletal proteins. Moreover, we report on two further neuropathic patients (16 years old girl and her father) both carrying the heterozygous p.(Pro8Ser) variant, which has been identified as 15% somatic mosaic in the father. While the daughter presented with altered neurophysiology,neurogenic clump feet and gait disturbances, the father showed clinically only feet deformities. As missense variants affecting proline at amino acid position 8 are leading to neuropathic manifestations of different severities, in silico modelling of these different amino acid substitutions indicated variable pathogenic impact correlating with disease onset. Conclusions: Our findings provide new morphological and biochemical insights into the vulnerability of denervated muscle (upon NEFL-associated neuropathy) as well as novel genetic findings expanding the current knowledge on NEFL-related neuromuscular phenotypes and their clinical manifestations. Along this line, our data show that even subtle expression of somatic NEFL variants can lead to neuromuscular symptoms.

Pediatric Community-Acquired Brain Abscesses: A Single-center Retrospective Study.

The European Society for Clinical Microbiology and Infectious Diseases recommends 3rd generation cephalosporins and metronidazole for empirical treatment of community-acquired brain abscesses. In 53 retrospectively analyzed pediatric patients with community-acquired brain abscesses at a German University Hospital Staphylococcus aureus was identified as a relevant pathogen (21%). Therefore, it may be reasonable to cover S. aureus when selecting empirical therapy.

Mutations in PTPN11 could lead to a congenital myasthenic syndrome phenotype: a Noonan syndrome case series.

The RASopathies are a group of genetic rare diseases caused by mutations affecting genes involved in the RAS/MAPK (RAS-mitogen activated protein kinase) pathway. Among them, PTPN11 pathogenic variants are responsible for approximately 50% of Noonan syndrome (NS) cases and, albeit to a lesser extent, of Leopard syndrome (LPRD1), which present a few overlapping clinical features, such as facial dysmorphism, developmental delay, cardiac defects, and skeletal deformities. Motor impairment and decreased muscle strength have been recently reported. The etiology of the muscle involvement in these disorders is still not clear but probably multifactorial, considering the role of the RAS/MAPK pathway in skeletal muscle development and Acetylcholine Receptors (AChR) clustering at the neuromuscular junction (NMJ). We report, herein, four unrelated children carrying three different heterozygous mutations in the PTPN11 gene. Intriguingly, their phenotypic features first led to a clinical suspicion of congenital myasthenic syndrome (CMS), due to exercise-induced fatigability with a variable degree of muscle weakness, and serum proteomic profiling compatible with a NMJ defect. Moreover, muscle fatigue improved after treatment with CMS-specific medication. Although the link between PTPN11 gene and neuromuscular transmission is unconfirmed, an increasing number of patients with RASopathies are affected by muscle weakness and fatigability. Hence, NS or LPDR1 should be considered in children with suspected CMS but negative genetic workup for known CMS genes or additional symptoms indicative of NS, such as facial dysmorphism or intellectual disability.

Guideline for the management of myasthenic syndromes.

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.

Bi-allelic variants of FILIP1 cause congenital myopathy, dysmorphism and neurological defects.

Filamin-A-interacting protein 1 (FILIP1) is a structural protein that is involved in neuronal and muscle function and integrity and interacts with FLNa and FLNc. Pathogenic variants in filamin-encoding genes have been linked to neurological disorders (FLNA) and muscle diseases characterized by myofibrillar perturbations (FLNC), but human diseases associated with FILIP1 variants have not yet been described. Here, we report on five patients from four unrelated consanguineous families with homozygous FILIP1 variants (two nonsense and two missense). Functional studies indicated altered stability of the FILIP1 protein carrying the p.[Pro1133Leu] variant. Patients exhibit a broad spectrum of neurological symptoms including brain malformations, neurodevelopmental delay, muscle weakness and pathology and dysmorphic features. Electron and immunofluorescence microscopy on the muscle biopsy derived from the patient harbouring the homozygous p.[Pro1133Leu] missense variant revealed core-like zones of myofibrillar disintegration, autophagic vacuoles and accumulation of FLNc. Proteomic studies on the fibroblasts derived from the same patient showed dysregulation of a variety of proteins including FLNc and alpha-B-crystallin, a finding (confirmed by immunofluorescence) which is in line with the manifestation of symptoms associated with the syndromic phenotype of FILIP1opathy. The combined findings of this study show that the loss of functional FILIP1 leads to a recessive disorder characterized by neurological and muscular manifestations as well as dysmorphic features accompanied by perturbed proteostasis and myopathology.

Giant Cavernous Malformation Mimicking an Infiltrative Intracranial Neoplasm in Children-Case Report and Systematic Review of the Literature.

BACKGROUND: Giant cavernous malformations (GCMs) are rare and poorly characterized neurovascular lesions in adults or children and often misclassified. In this study, we provide a review of pediatric GCM cases to highlight this rare entity as an important differential diagnosis in preoperative assessment. METHODS: We report a pediatric case of GCM that presented as an intracerebral, periventricular, and infiltrative mass lesion. We performed a systematic review of published literature describing cases of GCM in children using the PubMed, Embase, and Cochrane Library databases. Studies describing cerebral or spinal cavernous malformation >4 cm were included. Demographic, clinical, radiographic, and outcome data were extracted. RESULTS: Thirty-eight studies accounting for 61 patients were reviewed. most patients were 1-10 years old and 55.73% were male. Average lesion sizes ranged between 4 and 6 cm (40.98% >6 cm; 8.19% >10 cm). Supratentorial localization was most common (75.40%), with frontal and parieto-occipital regions being frequent localizations. Infratentorial lesions (24.60%) were located within the cerebellum (16.39%) and brainstem (8.19%). One case of spinal cavernoma was found. The main clinical manifestations were seizures (44.26%), focal neurologic deficit (36.06%), and headache (22.95%). Imaging showed contrast enhancement (36.06%), cystic features (27.86%), and infiltrative growth pattern (4.91%). CONCLUSIONS: GCMs show variable clinical and radiologic features, representing a diagnostic challenge for treating surgeons. Imaging may show various tumorlike features such as cystic or infiltrative patterns with contrast enhancement. The existence of GCM should be considered preoperatively. Gross total resection should be attempted whenever possible, because it correlates with a good recovery and long-term outcomes. Also, a clear definition criteria of when a cerebral cavernous malformation is termed giant should be established.

[Myasthenia in adults, children, and adolescents: what's new?] / Myasthenie bei Erwachsenen, Kindern und Jugendlichen ­ was ist neu?

Therapy of myasthenia gravis (MG) is increasingly oriented to the patient's antibody status. In addition to symptomatic therapy, steroids, classic long-term immunosuppressive therapies and thymectomy are regularly used. In recent years, new therapeutic approaches have been developed that particularly benefit acetylcholine receptor (AChR) antibody (Abs) positive patients with highly active disease. While the C5 complement inhibitor eculizumab was reserved for treatment-refractory generalized courses of AChR-Abs positive MG, two new drugs, the neonatal Fc receptor inhibitor efgartigimod and the more advanced C5 complement inhibitor ravulizumab, have recently been approved as add-on therapy for AChR-Abs positive generalized MG (gMG). In highly active courses of MG with Abs against the muscle-specific receptor tyrosine kinase (MuSK), the use of rituximab should be considered early in the course of the disease. The efficacy of the new drugs in children and adolescents with juvenile MG (JMG) is currently being tested in clinical trials. The new guideline recommends the use of modern immunomodulators based on a step-by-step approach depending on disease activity. With the German Myasthenia Register (MyaReg), the changing therapeutic landscape and quality of life of patients with myasthenic syndromes can be assessed, thus providing real-world data on the care of MG patients. Despite treatment based on the previous guideline, many MG patients suffer considerable impairment to their quality of life. With the new immunomodulators, there is the possibility of early intensified immunotherapy, which, in contrast to long-term immunosuppressants, can lead to a rapid improvement in the course of the disease.

High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID-A Single Center Cohort Study.

BACKGROUND: Long COVID (LC) is a diagnosis that requires exclusion of alternative somatic and mental diseases. The aim of this study was to examine the prevalence of differential diagnoses in suspected pediatric LC patients and assess whether adult LC symptom clusters are applicable to pediatric patients. MATERIALS AND METHODS: Pediatric presentations at the Pediatric Infectious Diseases Department of the University Hospital Essen (Germany) were assessed retrospectively. The correlation of initial symptoms and final diagnoses (LC versus other diseases or unclarified) was assessed. The sensitivity, specificity, negative and positive predictive values of adult LC symptom clusters were calculated. RESULTS: Of 110 patients, 32 (29%) suffered from LC, 52 (47%) were diagnosed with alternative somatic/mental diseases, and 26 (23%) remained unclarified. Combined neurological and respiratory clusters displayed a sensitivity of 0.97 (95% CI 0.91-1.00) and a negative predictive value of 0.97 (0.92-1.00) for LC. DISCUSSION/CONCLUSIONS: The prevalence of alternative somatic and mental diseases in pediatric patients with suspected LC is high. The range of underlying diseases is wide, including chronic and potentially life-threatening conditions. Neurological and respiratory symptom clusters may help to identify patients that are unlikely to be suffering from LC.

Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.

PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

[Essen transition model for neuromuscular diseases]. / "Essener Transitionsmodell" bei neuromuskulären Erkrankungen.

BACKGROUND: Advances in healthcare systems with new therapeutic options improve the life expectancy of patients with neuromuscular diseases. With this, a shift in the phenotype of the diseases from the neuromuscular system towards other organs is more frequently observed, requiring closer interdisciplinary cooperation in caring for these young adults. Therefore, the transition to the adult caring system is nowadays a multilayered transfer with the need for complex care of these patients. OBJECTIVE: How can the transitional process be efficiently structured to combine the therapeutic effort of each specialist discipline involved and improve the healthcare process and quality of life in young adults with neuromuscular diseases? MATERIAL AND METHOD: The Departments of Neuropediatrics and Neurology of the University Medicine Essen established the Essen transition model for a structured transitional process. A concept of care was developed for the late onset Pompe's disease, Duchenne muscular dystrophy and juvenile myasthenia gravis representatively for neuromuscular diseases. It consists of four components: 1) In a standardized operational procedure (SOP), general processes, clinical diagnostic steps and guidance of treatment between the two departments are harmonized and specified. 2) The young adults and their relatives are seen in a joint consultation of both disciplines allowing a comprehensive handover for healthcare professionals. 3) In a quarterly meeting, transition conference representatives from the different specialized disciplines from pediatric and adult medicine get together for a case-related interdisciplinary exchange. 4) An interdepartmental transitional database was created to integrate all diagnostic results and parameters as a common information platform and data basis. CONCLUSION: The Essen transition model aims to close a gap in the transition of patients with neuromuscular diseases and improve healthcare in these patients with their complex needs.

Risk and course of COVID-19 in immunosuppressed patients with myasthenia gravis.

BACKGROUND: Patients with myasthenia gravis (MG) are potentially prone for a severe COVID-19 course, but there are limited real-world data available on the risk associated with COVID-19 for patients with MG. Here, we investigate whether current immunosuppressive therapy (IST) influences the risk of SARS-CoV-2 infection and COVID-19 severity. METHODS: Data from the German myasthenia gravis registry were analyzed from May 2020 until June 2021 and included patient demographics, MG disease duration, comorbidities, current IST use, COVID-19 characteristics, and outcomes. Propensity score matching was employed to match MG patients with IST to those without, and multivariable binary logistic regression models were used to determine associations between IST with (1) symptomatic SARS-CoV-2 infection and (2) severe COVID-19 course, as measured by hospitalization or death. RESULTS: Of 1379 patients with MG, 95 (7%) patients (mean age 58 (standard deviation [SD] 18) presented with COVID-19, of which 76 (80%) received IST at time of infection. 32 patients (34%) were hospitalized due to COVID-19; a total of 11 patients (12%) died. IST was a risk factor for hospitalization or death in the group of COVID-19-affected MG patients (odds ratio [OR] 3.04, 95% confidence interval [CI] = 1.02-9.06, p = 0.046), but current IST was not associated with a higher risk for SARS-CoV-2 infection itself. DISCUSSION: In this national MG cohort study, current IST use was a risk factor for a severe disease course of COVID-19 but not for SARS-CoV-2 infection itself. These data support the consequent implementation of effective strategies to prevent COVID-19 in this high-risk group. TRIAL REGISTRATION INFORMATION: German clinical trial registry ( https://www.drks.de ), DRKS00024099, first patient enrolled: February 4th, 2019.

Development of restrictive eating disorders in children and adolescents with long-COVID-associated smell and taste dysfunction.

Background: Absent or abnormal senses of smell and taste have been frequently reported during both acute and long COVID in adult patients. In contrast, pediatric patients who test positive for SARS-CoV-2 are often asymptomatic and the loss of smell and/or taste has been infrequently reported. After observing several young patients with COVID-associated anosmia and ageusia at our clinic, we decided to investigate the incidence of subsequent eating disorders in these patients and in SARS-CoV-2 positive patients who did not experience anosmia and ageusia during the same period. Material and methods: A single-site retrospective cohort study of 84 pediatric patients with suspected long COVID who were treated in the Pediatric Infectious Diseases Outpatient Clinic at the University Hospital Essen were evaluated for persistent symptoms of COVID-19. Smell and taste dysfunction as well as eating behaviors were among the signs and symptoms analyzed in this study. Results: 24 out of 84 children and adolescents described smell and taste dysfunction after confirmed or suspected SARS-CoV-2 infections. A large number of these patients (6 out of 24) demonstrated increased fixation on their eating behavior post-COVID and over time these patients developed anorexia nervosa. Discussion/Conclusion: In this study we saw a possible association of long-lasting post-COVID smell and taste dysfunction with subsequent development of eating disorders. This observation is worrisome and merits further investigation by healthcare providers at multiple clinical sites.

Temporal Dynamics of MOG Antibodies in Children With Acquired Demyelinating Syndrome.

BACKGROUND AND OBJECTIVE: The spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG-IgG titers in children with MOGAD in correlation with clinical presentation and disease course. METHODS: In this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG-positive. RESULTS: One hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG-negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG-negative. DISCUSSION: In this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG-negative, are shown to have a significantly reduced relapse risk.

Essen transition model for neuromuscular diseases.

BACKGROUND: With the optimization of medical care structures and the rapid progress in the development of new therapeutic methods, an increase in life expectancy is observed in patients with neuromuscular diseases. This leads to an expansion of the phenotypic spectrum, whereby new or previously less relevant disease manifestations in different organ systems gain more importance. The care of adolescents and young adults with neuromuscular diseases, therefore, requires increasingly close interdisciplinary collaboration within neuromuscular centers. RESEARCH QUESTION: How can the transition process from pediatric to adult care be structured so that the individual disciplines are efficiently integrated into the complex treatment and care process, and the patients' quality of life is improved? MATERIAL AND METHODS: A structured transition process was established at the University Hospital in Essen, Germany. Exemplarily, a comparable care concept was developed based on Pompe disease, Duchenne muscular dystrophy, and juvenile myasthenia gravis comprising four elements: (1) With the introduction of cross-department standard operating procedures, the logistical processes, as well as the diagnostic and therapeutic measures, are uniformly coordinated, and the transition process is bindingly defined. (2) To ensure a seamless transition, young patients are seen with their parents during joint consultations before they reach their 17th birthday. This creates an opportunity for patients to get to know the subsequent department structure and build a lasting relationship of trust. (3) A quarterly "transition board" regularly brings together the participating disciplines from pediatric and adult care systems for a case-related interdisciplinary exchange and continuous optimization of the transition process. (4) A cross-department "Transition Database", in which medical findings and parameters are recorded, was implemented as a common information platform and database. CONCLUSION: The Essen Transition Model aims to close the gap in care for young patients with neuromuscular diseases during the critical transition from pediatric to adult medicine and to create a successful continuation of treatment in adulthood.

Mitochondrial diseases mimicking autoimmune diseases of the CNS and good response to steroids initially.

INTRODUCTION: Neuroimmunological diseases such as autoimmune encephalitis (AE) or acquired demyelinating syndromes (ADS), can present with neurological symptoms and imaging features that are indistinguishable from mitochondrial diseases (MD) in particular at initial presentation. METHODS: Retrospective analysis of the clinical, laboratory and neuroimaging features of five patients who presented with signs of a neuroimmunological disease but all had pathological pathogenic variants in genes related to mitochondrial energy metabolism. RESULTS: Four patients presented with an acute neurological episode reminiscent of a possible AE and one patient with a suspected ADS at initial presentation. MRI findings were compatible with neuroimmunological diseases in all patients. In two children cerebrospinal fluid (CSF) studies revealed a mildly elevated cell count, two had elevated CSF lactate, none had oligoclonal bands (OCBs). All patients improved rapidly with intravenous steroids or immunoglobulins. Four patients had one or more relapses. Three patients showed worsening of their neurological symptoms with subsequent episodes and one patient died. Relapses in conjunction with new and progressive neurological symptoms, led to additional work-up which finally resulted in different genetic diagnosis of MD in all patients (MT-TL1, MT-ND5, APOA1-BP, HPDL, POLG). DISCUSSION: We would like to draw attention to a subset of patients with MD initially presenting with signs and symptoms mimicking neuroimmunological. Absence of CSF pleocytosis, elevated CSF lactate and progressive, relapsing course should trigger further (genetic) investigations in search of a MD even in patients with good response initially to immunomodulating therapies.

The impact of age and electrode position on amplitude-integrated EEGs in children from 1 month to 17 years of age.

Aim: Amplitude-integrated electroencephalography (aEEG) is used to monitor electrocortical activity in critically ill children but age-specific reference values are lacking. We aimed to assess the impact of age and electrode position on aEEG amplitudes and derive normal values for pediatric aEEGs from neurologically healthy children. Methods: Normal EEGs from awake children aged 1 month to 17 years (213 female, 237 male) without neurological disease or neuroactive medication were retrospectively converted into aEEGs. Two observers manually measured the upper and lower amplitude borders of the C3 - P3, C4 - P4, C3 - C4, P3 - P4, and Fp1 - Fp2 channels of the 10-20 system. Percentiles (10th, 25th, 50th, 75th, 90th) were calculated for each age group (<1 year, 1 year, 2-5 years, 6-9 years, 10-13 years, 14-17 years). Results: Amplitude heights and curves differed between channels without sex-specific differences. During the first 2 years of life, upper and lower amplitudes of all but the Fp1-Fp2 channel increased and then declined until 17 years. The decline of the upper Fp1-Fp2 amplitude began at 4 years, while the lower amplitude declined from the 1st year of life. Conclusions: aEEG interpretation must account for age and electrode positions but not for sex in infants and children.

MR imaging in children with transverse myelitis and acquired demyelinating syndromes.

BACKGROUND: Transverse myelitis (TM) occurs isolated or within other acquired demyelinating syndromes (ADS) such as neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS) or myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD). OBJECTIVE: To describe and compare clinical and MRI features of children with ADS presenting with TM grouped according to antibody status and diagnosis of MS and NMOSD. PATIENTS AND METHODS: Children with TM, radiological involvement of the myelon, MOG and aquaporin-4 antibody status were elegible. RESULTS: 100 children were identified and divided into MOGAD (n=33), NMOSD (n=7), double seronegative TM (n=34), and MS (n=26). MOGAD children had mainly acute disseminated encephalomyelitis + TM/ longitudinally extensive TM (LETM) (42%) or isolated LETM (30%). In MOGAD, LETM was present in more than half of all children (55%) with predominant involvement of only the grey matter (73%). Leptomeningeal enhancement was highly predictive of MOGAD (16/30; p=0.003). In MS patients spinal MRI showed single (50%) or multiple short lesions (46%) with involvement of grey and white matter (68%). Double seronegative children presented with LETM (74%) and brain lesions were less frequent compared to the other groups (30%). CONCLUSION: Children with ADS presenting with TM reveal important radiological differences such as LETM with predominant involvement of spinal grey matter and leptomeningeal enhancement in MOGAD.

Rituximab in juvenile myasthenia gravis-an international cohort study and literature review.

Juvenile myasthenia gravis (JMG) is a rare, antibody-mediated disorder of the neuromuscular junction. Treatment strategies in JMG are largely informed by adult MG treatments as the pathophysiology is similar. Rituximab is increasingly considered as a treatment option in refractory JMG but has not yet been systematically investigated in this patient group We conducted a retrospective study from five international centres with expertise in paediatric myasthenia. 10 JMG patients treated with rituximab were identified. Following rituximab treatment all patients had a reduction in JMG-related hospital admissions. At 24 month follow up, 6 patients (60%) had achieved complete stable remission or pharmacological remission and 7 patients were able to reduce immunomodulatory treatment(s). The main side-effect was infusion-related reactions (30%) which resolved in all patients with symptomatic treatment. We compared our cohort to previously reported JMG cases treated with rituximab and noted similar response rates but a slightly higher side-effect profile. Rituximab is a safe and effective treatment option in moderate to severe JMG and most patients have an improvement in MG symptoms post treatment.

Identification of a novel homozygous synthesis of cytochrome c oxidase 2 variant in siblings with early-onset axonal Charcot-Marie-Tooth disease.

The synthesis of cytochrome c oxidase 2 (SCO2 ) gene encodes for a mitochondrial located metallochaperone essential for the synthesis of the cytochrome c oxidase (COX) subunit 2. Recessive mutations in SCO2 have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency and in only four cases with axonal neuropathy. Here, we identified a homozygous pathogenic variant (c.361G > C; p.[Gly121Arg]) in SCO2 in two brothers with isolated axonal motor neuropathy. To address pathogenicity of the amino acid substitution, biochemical studies were performed and revealed increased level of the mutant SCO2 -protein and dysregulation of COX subunits in leukocytes and moreover unraveled decrease of proteins involved in the manifestation of neuropathies. Hence, our combined data strengthen the concept of SCO2 being causative for a very rare form of axonal neuropathy, expand its molecular genetic spectrum and provide first biochemical insights into the underlying pathophysiology.