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In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). fAChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicenter cohort (n = 46 cases) associated with maternal fAChR antibodies, 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established MG diagnosis. All mothers (n = 30) had AChR antibodies, and where tested, against the fAChR (binding to fAChR was often much greater than that to the adAChR). Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%) or, during early infancy mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/IVIG/PLEX) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognised and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose Fetal Acetylcholine Receptor Antibody-related Disorder (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognise, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.

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.

Zusammenfassung Hintergrund Durch die Optimierung medizinischer Versorgungsstrukturen und die gravierenden Fortschritte bei der Entwicklung neuer Therapieverfahren wird ein Anstieg der Lebenserwartung bei Patienten mit neuromuskulären Erkrankungen beobachtet. Dies führt zu einer Erweiterung des phänotypischen Spektrums, wodurch neue bzw. bislang wenig relevante Krankheitsmanifestationen in unterschiedlichen Organsystemen an Bedeutung gewinnen. Die Betreuung jugendlicher und junger Erwachsener mit neuromuskulären Erkrankungen verlangt daher eine zunehmend enge interdisziplinäre Zusammenarbeit. Fragestellung Wie kann der Transitionsprozess von der Pädiatrie in die Erwachsenenmedizin so strukturiert werden, dass die einzelnen Fachdisziplinen effizient in den komplexen Behandlungs- und Versorgungsprozess eingebunden und die Lebensqualität der Patienten verbessert werden? Material und Methode An der Universitätsmedizin Essen wurde ein strukturierter Transitionsprozess etabliert. Exemplarisch wurde anhand des Morbus Pompe („late onset M. Pompe“ [LOPD]), der Duchenne-Muskeldystrophie (DMD) und der juvenilen Myasthenia gravis (jMG) ein entsprechendes Versorgungskonzept entwickelt. Dies umfasst vier Elemente: 1) Mit der Einführung klinikübergreifender SOPs („standard operating procedure“) werden die logistischen Abläufe sowie die diagnostischen und therapeutischen Maßnahmen einheitlich abgestimmt und der Transitionsprozess verbindlich festgelegt. 2) Um einen nahtlosen Übergang zu gewährleisten, werden junge Patienten vor Erreichen des 17. Geburtstages mit ihren Eltern im Zuge gemeinsamer Transitionssprechstunden betreut. Dies schafft die Möglichkeit des gegenseitigen Kennenlernens und der Bildung eines nachhaltigen Vertrauensverhältnisses. 3) Ein quartalsweise stattfindendes „Transitionsboard“ bringt die beteiligten Fachdisziplinen aus Kinder- und Erwachsenenmedizin für einen fallbezogenen interdisziplinären Austausch und eine stetige Optimierung des Transitionsprozesses regelmäßig zusammen. 4) Als gemeinsame Informationsplattform und Datengrundlage wurde eine klinikübergreifende „Transitionsdatenbank“, in der medizinische Befunde und Verlaufsparameter erfasst werden, implementiert. Schlussfolgerung Mit dem Essener Transitionsmodell soll die Versorgungslücke junger Patienten mit neuromuskulären Erkrankungen während der kritischen Übergangsphase von der Kinder- zur Erwachsenenmedizin geschlossen und die Grundlage für eine erfolgreiche Weiterbehandlung im Erwachsenenalter geschaffen werden.

Background and Purpose: The purpose of this study was to investigate the natural course of cerebral cavernous malformations (CCM) in the pediatric population, with special emphasis on the risk of first and recurrent bleeding over a 5-year period. Methods: Our institutional database was screened for patients with CCM treated between 2003 and 2020. Patients ≤18 years of age with complete magnetic resonance imaging data set, clinical baseline characteristics, and ≥1 follow-up examination were included. Surgically treated individuals were censored after CCM removal. We assessed the impact of various parameters on first or recurrent intracerebral hemorrhage (ICH) at diagnosis using univariate and multivariate logistic regression adjusted for age and sex. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative 5-year risk for (re)hemorrhage. Results: One hundred twenty-nine pediatric patients with CCM were analyzed. Univariate logistic regression identified brain stem CCM (odds ratio, 3.15 [95% CI, 1.15−8.63]; P =0.026) and familial history of CCM (odds ratio, 2.47 [95% CI, 1.04−5.86]; P =0.041) as statistically significant predictors of ICH at diagnosis. Multivariate logistic regression confirmed this correlation (odds ratio, 3.62 [95% CI, 1.18−8.99]; P =0.022 and odds ratio, 2.53 [95% CI, 1.07−5.98]; P =0.035, respectively). Cox regression analysis identified ICH as mode of presentation (hazard ratio, 14.01 [95% CI, 1.80−110.39]; P =0.012) as an independent predictor for rehemorrhage during the 5-year follow-up. The cumulative 5-year risk of (re)bleeding was 15.9% (95% CI, 10.2%−23.6%) for the entire cohort, 30.2% (20.2%−42.3%) for pediatric patients with ICH at diagnosis, and 29.5% (95% CI, 13.9%−51.1%) for children with brain stem CCM. Conclusions: Pediatric patients with brain stem CCM and familial history of CCM have a higher risk of ICH as mode of presentation. During untreated 5-year follow-up, they revealed a similar risk of (re)hemorrhage compared to adult patients. The probability of (re)bleeding increases over time, especially in cases with ICH at presentation or brain stem localization.

AimAmplitude-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.MethodsNormal 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 (ResultsAmplitude 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.ConclusionsaEEG interpretation must account for age and electrode positions but not for sex in infants and children.

Contains fulltext : 287938.pdf (Publisher’s version ) (Closed access) 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.

Background and ObjectiveThe 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.MethodsIn 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.ResultsOne 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.DiscussionIn 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.

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.

Aims Variable degrees of inflammation, necrosis, regeneration and fibrofatty replacement are part of the pathological spectrum of the dystrophic process in alpha dystroglycanopathy LGMDR9 (FKRP-related, OMIM #607155), one of the most prevailing types of LGMDs worldwide. Inflammatory processes and their complex interplay with vascular, myogenic and mesenchymal cells may have a major impact on disease development. The purpose of our study is to describe the specific immune morphological features in muscle tissue of patients with LGMDR9 in order to enable a better understanding of the phenotype of muscle damage leading to disease progression. Methods We have analysed skeletal muscle biopsies of 17 patients genetically confirmed as having LGMDR9 by histopathological and molecular techniques. Results We identified CD206+ MHC class II+ and STAT6+ immune-repressed macrophages dominating the endomysial infiltrate in areas of myofibre regeneration and fibrosis. Additionally, PDGFRβ+ pericytes were located around MHC class II+ activated capillaries residing in close proximity to areas of fibrosis and regenerating fibres. Expression of VEGF was found on many regenerating neonatal myosin+ fibres myofibres and CD206+ macrophages also co-expressed VEGF. Conclusion Our results show characteristic immune inflammatory features in LGMDR9 and more specifically shed light on the predominant role of macrophages and their function in vascular organization, fibrosis and myogenesis. Understanding disease-specific immune phenomena potentially inform about possibilities for anti-fibrotic and anti-inflammatory therapeutic strategies, which may complement Ribitol replacement and gene therapies for LGMDR9 that may be available in the future.

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.

Bilateral optic neuritis (bilON) is a rare clinical presentation often thought to be associated with relapsing disorders such as neuromyelitis optica spectrum disorders (NMOSD) or multiple sclerosis (MS).To characterize the clinical, radiological phenotype and antibody status of children presenting with bilON.Retrospective multicenter study on children with bilON age18 years with a first episode aquired demyelinating syndrome (ADS), cMRI, AQP4- and serum MOG-antibody status and follow-up data were collected.30 patients (f:m = 15:15, median age 8.0y) with bilON met the inclusion criteria. 22/30 (73%) were MOG-positive (median: 1:1280, range: 1:160-1:1520). No patient showed AQP4-abs. 4/30 patients (13%), all with high MOG-abs titers, had recurrent episodes. No patient developed MS. Improvement after IVMP was observed in most patients (26/30; 87%). Outcome was favorable with no sequelae in 22/30 patients. Serial MOG-abs titers tested in 15/22 patients decreased to a median of 1:160 (range: 0-1:640) over a period of 31 months (range: 2-141 months) in 14/15 (93%) patients. MR imaging showed a predominantly anterior affection of the visual system in seropositive patients with bilateral intraorbital lesions in 68% (15/22), compared to 25% in MOG-negative patients (2/8).Pediatric bilON is associated with high MOG-abs titers in combination with anterior involvement of the visual system. Despite severe loss of vision, the majority of patients shows distinct recovery after IVMP.

ZusammenfassungDie autoimmune kindliche und juvenile Myasthenia gravis (JMG) ist bedingt durch die Autoantikörper(Ak)-Bildung gegen die postsynaptische Membran der neuromuskulären Endplatte. Die klinischen Symptome können variabel sein, von der milden okulären Symptomatik bis zu generalisierter Schwäche und respiratorischer Insuffizienz. Die klinische Präsentation und der Verlauf der JMG, insbesondere bei präpubertären Patienten, zeigen Unterschiede im Vergleich zur adulten Form. Eine Manifestation ist schon in den ersten beiden Lebensjahren möglich, in diesem Alter kann der Antikörper-Titer auch bei generalisierten Symptomen nur minimal erhöht sein. Bei den Säuglingen und sehr kleinen Kindern ist bei negativen spezifischen Antikörpern das Vorliegen eines kongenitalen myasthenen Syndroms (CMS) eine wichtige Differenzialdiagnose. Eine frühe Diagnosestellung ist bei bestehenden therapeutischen Möglichkeiten in dieser Patientengruppe wichtig. Wir geben eine Übersicht über klinische Symptome, diagnostische Möglichkeiten sowie medikamentöse und operative Therapie bei Kindern mit JMG.

Contains fulltext : 88466.pdf (Publisher’s version ) (Closed access) Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (

Juvenile myasthenia gravis (JMG) is an autoimmune disorder of neuromuscular transmission caused by production of antibodies against components of the postsynaptic membrane of the neuromuscular junction. Ethnicity has influence on incidence, clinical presentation, and the course of the disease. The patients present with a wide range of symptoms-from isolated intermittent ocular symptoms to general muscle weakness with or without respiratory insufficiency. Compared with adults and adolescents, the clinical signs and course of disease in children exhibit differences and occasionally untypical symptoms. Therefore, JMG is often missed and the diagnosis delayed. Isolated ocular symptoms are frequent at onset, spontaneous remission or intermittent symptoms over the longer period of time can occur. Very young children may present with generalized muscle weakness already during the second year of life and in this patient group, specific antibodies can only be slightly increased or even negative. Existing therapeutic options include immunosuppressive therapy and thymectomy but potential long-term side effects on the growing organism and possible influence on immune response in very young children should be considered. Specific clinical symptoms, diagnostic procedures, and a therapeutic approach with consideration of this age group's specificities are discussed.

Congenital myasthenic syndromes (CMS) are rare genetically and clinically heterogeneous disorders characterized by an impaired neuromuscular transmission. Exact prevalence data are not available, approximately 2000 to 3000 patients worldwide have been diagnosed on a molecular level; mutations in 14 different genes are known to date leading to causal defects in presynaptic nerve terminal, synaptic cleft, and postsynaptic apparatus. At last, all known mutations are estimated to cause approximately 50% of all clinically diagnosed CMS. However, phenotypes may vary widely and symptoms can be unspecific, therefore CMS are often missed and their prevalence may be underestimated. But, the exact diagnosis is extremely important to start early appropriate therapy to prevent life-threatening events and to improve the clinical course. Most patients are eligible for drug therapy with esterase inhibitors, 3, 4-diaminopyridine, ephedrine, fluoxetine or quinidine, but the effect of these drugs differs depending on the underlying genetic defect. Moreover, very little is known about the best treatment and care in these patients over a longer period of time.This article provides an overview of specific clinical symptoms, diagnostic work-up, and care including possible pharmacotherapy in case of CMS.