Purpose With an incidence of 2-5 per million adults, cerebral venous and sinus thrombosis (CVST) is a rarity in the spectrum of cerebrovascular diseases. The etiology and symptomatic presentation are heterogeneous and diverse. CSVT is, therefore, often underdiagnosed. In addition to therapeutic anticoagulation, venous thrombectomy is a last-resort therapy in individual cases. Case Description A 42-year-old woman was admitted to the hospital with postural headache following an unsuccessful lumbar puncture. On suspicion of post-puncture syndrome, analgesic therapy with adjuvant caffeine tablets was initially chosen, leading to rapid improvement and short-term discharge. However, only one day later, the patient presented with a significant worsening of her symptoms and new onset of paresthesia. Since distally accentuated paresis of the left arm also occurred within a very short period of time, a cerebral MRI examination was performed. This revealed an extensive CVST. Due to the extensive CVST and progressive worsening of symptoms, mechanical venous thrombectomy was discussed and performed on an interdisciplinary basis. Mechanical thrombectomy was successful and resulted in complete improvement of symptoms. Discussion The pathophysiological diagnosis is cerebrospinal fluid leak syndrome after unsuccessful lumbar puncture. According to the Monroe-Kellie doctrine, the loss of CSF leads to compensatory dilatation and venous stasis, which in combination can lead to venous insufficiency and promote prothrombotic conditions. Although the available data on the performance of venous thrombectomy suggest caution, there should always be sufficient discretion for individual decision making. As our experience shows, there is a chance of successful venous thrombectomy in the early phase of CVST.

SNURPORTIN-1, encoded by SNUPN , plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients’ primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.

Background In 2017, the German Academy for Rare Neurological Diseases (Deutsche Akademie für Seltene Neurologische Erkrankungen; DASNE) was founded to pave the way for an optimized personalized management of patients with rare neurological diseases (RND) in all age groups. Since then a dynamic national network for rare neurological disorders has been established comprising renowned experts in neurology, pediatric neurology, (neuro-) genetics and neuroradiology. DASNE has successfully implemented case presentations and multidisciplinary discussions both at yearly symposia and monthly virtual case conferences, as well as further educational activities covering a broad spectrum of interdisciplinary expertise associated with RND. Here, we present recommendation statements for optimized personalized management of patients with RND, which have been developed and reviewed in a structured Delphi process by a group of experts. Methods An interdisciplinary group of 37 RND experts comprising DASNE experts, patient representatives, as well as healthcare professionals and managers was involved in the Delphi process. First, an online collection was performed of topics considered relevant for optimal patient care by the expert group. Second, a two-step Delphi process was carried out to rank the importance of the selected topics. Small interdisciplinary working groups then drafted recommendations. In two consensus meetings and one online review round these recommendations were finally consented. Results 38 statements were consented and grouped into 11 topics: health care structure, core neurological expertise and core mission, interdisciplinary team composition, diagnostics, continuous care and therapy development, case conferences, exchange / cooperation between Centers for Rare Diseases and other healthcare partners, patient advocacy group, databases, translation and health policy. Conclusions This German interdisciplinary Delphi expert panel developed consented recommendations for optimal care of patients with RND in a structured Delphi process. These represent a basis for further developments and adjustments in the health care system to improve care for patients with RND and their families.

The purpose of this study was to develop a fully automated and reliable volumetry of the cerebellum of children during infancy and childhood using deep learning algorithms in comparison to manual segmentation. In addition, the clinical usefulness of measuring the cerebellar volume is shown. One hundred patients (0 to 16.3 years old) without infratentorial signal abnormalities on conventional MRI were retrospectively selected from our pool of pediatric MRI examinations. Based on a routinely acquired 3D T1-weighted magnetization prepared rapid gradient echo (MPRAGE) sequence, the cerebella were manually segmented using ITK-SNAP. The data set of all 100 cases was divided into four splits (four-fold cross-validation) to train the network (NN) to delineate the boundaries of the cerebellum. First, the accuracy of the newly created neural network was compared with the manual segmentation. Secondly, age-related volume changes were investigated. Our trained NN achieved an excellent Spearman correlation coefficient of 0.99, a Dice Coefficient of 95.0 ± 2.1%, and an intersection over union (IoU) of 90.6 ± 3.8%. Cerebellar volume increased continuously with age, showing an exponentially rapid growth within the first year of life. Using a convolutional neural network, it was possible to achieve reliable, fully automated cerebellar volume measurements in childhood and infancy, even when based on a relatively small cohort. In this preliminary study, age-dependent cerebellar volume changes could be acquired.

Zielsetzung Studien zur Bestimmung des Kleinhirnvolumens wurden hauptsächlich bei Erwachsenen durchgeführt. Die Segmentierung zerebellärer Strukturen bei Kindern, insbesondere bei Neugeborenen und Kleinkindern, ist aufgrund der geringen Größe und reduzierten Bildkontraste eine Herausforderung. Außerdem sind MR-Untersuchungen von gesunden Kindern oft nicht verfügbar. Ziel dieser Studie war die Entwicklung einer zuverlässigen vollautomatischen Volumetrie des Kleinhirns während der physiologischen postnatalen Hirnentwicklung auf Basis von routinemäßig akquirierten 3D-T1-gewichteten MPRage-Datensätzen und Deep-Learning-Algorithmen.

To evaluate microstructural cerebral changes in children suffering from typical hemolytic uremic syndrome (HUS) based on apparent diffusion coefficient (ADC) maps. For 12 pediatric HUS patients (0.8 - 14.6 years of age) conventional magnetic resonance imaging (cMRI) at 1.5 T was retrospectively analyzed. ADC values were measured in 35 different brain regions and compared with age-related, previously published ADC reference values from a healthy pediatric control group. The HUS cohort was divided into 2 subgroups depending on clinical outcome. Subgroup A showed poor neurological outcome whereas subgroup B demonstrated improvement without lasting neurological deficits. Qualitative analysis revealed lesions by diffusion-weighted imaging (DWI) with hypointense correlate on the ADC map in basal ganglia and/or thalami and corresponding T2 hyperintensities in the majority of patients in Subgroup A (80%). Those in Subgroup B did not show qualitative DWI alterations with ADC correlate even when T2 hyperintense lesions were detected in basal ganglia and/or thalami. Quantitative analysis demonstrated abnormal ADC values in all HUS patients with a trend to a greater number of affected regions in Subgroup A compared to Subgroup B (16 versus 11 median number of regions respectively, p = 0.56). Conclusion : Using DWI qualitative and quantitative differences were found between HUS patients showing poor neurological outcome and those without neurological deficits at discharge. While ADC values indicated more extensive cerebral changes than conventional qualitative findings, both may provide early prognostic indicators for neurological outcome in pediatric HUS patients. What is Known: • In patients with STEC-HUS and neurological symptoms, MRI may show hyperintense signals on T2 and altered diffusivity mostly affecting basal ganglia, thalami and periventricular white matter. What is New: • In such patients, early MRI including quantitative ADC measurements over different brain regions may allow for detection of signal alterations possibly reflecting microstructural changes in such patients.

BACKGROUND AND AIMS:Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant-free survival, extrahepatic manifestations may cause relevant morbidity.METHODS:We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited.RESULTS:Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver-associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT.CONCLUSION:The spectrum of extrahepatic manifestations in PFIC highlights essential, non-redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health-related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.

The cover image is based on the Review Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review by Eva-Doreen Pfi ster et al., https://doi.org/10.1111/liv.15200.

MT-ATP6-associated disease is caused by mutations in the mitochondrial gene MT-ATP6, encoding a subunit of the ATP synthase complex. Clinically, MT-ATP6 mutations were first associated with a syndrome combining neuropathy, ataxia, and retinitis pigmentosa (NARP syndrome) as well as with Leigh syndrome in more than 50% of patients. However, it has recently been shown that the phenotypic spectrum of MT-ATP6-associated disease is much broader, ranging from asymptomatic subjects via rather mild adult-onset CMT-like phenotypes to earlyonset multisystemic neurodegeneration. An 18-year-old female presented with a progressive complex ataxic gait disorder since early childhood. She had learned to walk only at age 3 years with frequent falls persisting and increasing inward rotation of the feet. She lost the ability to walk freely at age 6 years, with full wheelchair-dependency from age 10 years. Neurological examination showed severe distal muscular atrophies, mild tetraparesis, bidirectional gazeevoked and upbeat nystagmus in primary position. Distal loss of vibration sensation and absent deep tendon reflexes were noted. Ataxia was apparent by ataxic-paretic gait, dysmetric heel-shin slide and truncal ataxia, with a Scale for the Assessment and Rating of Ataxia (SARA) score of 17 points at initial examination, worsening to 18.5 points at 1-year-follow-up. Nerve conduction studies showed axonal sensorimotor polyneuropathy. Motorevoked potentials indicated pyramidal tract lesions. Targeted NGS revealed a known pathogenic homoplasmic MT-ATP6 mutation (m.8993T > C; p.L156P) that has been associated with a Leigh syndrome clinically and on MRI. Sequential neuroimaging at age 15 revealed development of T2-hyperintensities (Fig A,B) and corresponding T1-hypointense signal (Fig C,D) at the bottom of cerebellar fissures compared to initial MRI 10 years earlier at age 5 years (Fig E,F). Ethical approval was granted by the local ethics committee (#598/2011BO1) and written informed consent from the patient and her legal guardian were obtained prior to study inclusion. MRI signal alterations are frequent findings in mitochondrial disorders, e.g. necrotic, T2-hyperintense lesions of the basal ganglia in Leigh syndrome. In MT-ATP6-

TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava) is a rare genetic condition, caused by developmental defects during embryogenesis. The phenotypic spectrum of TARP shows high clinical variability with patients either missing cardinal features or having additional clinical traits. Initially, TARP was considered a lethal syndrome, but patients with milder symptoms were recently described. The TARP-locus was mapped to the gene RNA-binding motif protein 10 (RBM10) on the human X-chromosome. We clinically and genetically described a six-year-old boy with a TARP-phenotype. Clinical heterogeneity of symptoms prompted us to sequence the entire exome of this patient. We identified a novel splice variant (NM_005676: c.17+1G>C, p.?) in RBM10. A patient-derived cell line was used to verify the pathogenicity of the RBM10 splice variant by RNA analyses, Western blotting, and immunofluorescence staining. Our molecular genetic findings together with the analyses of progressing clinical symptoms confirmed the diagnosis of TARP. It seems essential to analyze correlations between genotype, phenotype, and molecular/cellular data to better understand RBM10-associated pathomechanisms, assist genetic counseling, and support development of therapeutic approaches.

Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated in autosomal dominant and autosomal recessive human disorders. Autosomal dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1) has rarely been implicated in an autosomal recessive developmental disorder. Here, we report five individuals with biallelic missense variants in WARS1 or SARS1, who presented with an overlapping phenotype of microcephaly, developmental delay, intellectual disability, and brain anomalies. Structural mapping showed that the SARS1 variant is located directly within the enzyme's active site, most likely diminishing activity, while the WARS1 variant is located in the N-terminal domain. We further characterize the identified WARS1 variant by showing that it negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal recessive syndromes caused by variants in WARS1 and SARS1, present functional insights into the pathogenesis of the WARS1-related syndrome and define an emerging disease spectrum: ARS-related developmental disorders with or without microcephaly.

Die IgA-Vaskulitis (IgAV; ehem. Purpura-Schönlein-Hennoch) ist eine Immunkomplex-vermittelte Vaskulitis der kleinen Gefäße mit einer Inzidenz von etwa 20 pro 100 000 Kindern pro Jahr und damit die häufigste Vaskulitis bei Kindern [1], [2]. Die Hälfte der betroffenen Patienten ist jünger als 6 Jahre und nur 10 % sind älter als 10 Jahre [3]. Die IgAV kann jedoch auch bei Erwachsenen auftreten. Das männliche Geschlecht ist im Vergleich zum weiblichen doppelt so häufig betroffen [2]. Die Entzündung ist durch die Ablagerung von Immunkomplexen in den Gefäßwänden gekennzeichnet. Die genaue Pathogenese der IgAV ist noch nicht geklärt. Klinische und experimentelle Daten deuten jedoch auf einen infektiösen Auslöser und eine genetische Prädisposition hin – beispielsweise Varianten im IgA1-Molekül, die eine gehemmte Proteolyse von Immunkomplexen verursachen. Klinisch weist die überwiegende Mehrheit der betroffenen Kinder eine nicht-thrombozytopenische Purpura, Arthralgie/Arthritis und Bauchschmerzen auf. Darüber hinaus wurden zahlreiche Manifestationen in anderen Organen wie Niere (Glomerulonephritis), Darm (Invagination), Lunge (Alveolarblutung) und Zentralnervensystem (Krampfanfälle, zerebrovaskuläre Thrombosen) berichtet [2], [4], [5]. Weiterhin gibt es einige anekdotische Berichte über das Auftreten eines posterioren reversiblen Enzephalopathie-Syndroms (PRES) bei Patienten mit IgAV [6]–[10].

Heterotopia is a brain malformation caused by a failed migration of cortical neurons during development. Clinical symptoms of heterotopia vary in severity of intellectual disability and may be associated with epileptic disorders. Abnormal neuronal migration is known to be associated with mutations in the doublecortin gene (DCX), the platelet-activating factor acetylhydrolase gene (PAFAH1B1), or tubulin alpha-1A gene (TUBA1A). Recently, a new gene encoding echinoderm microtubule-associated protein-like 1 (EML1) was reported to cause a particular form of subcortical heterotopia, the ribbon-like subcortical heterotopia (RSH). EML1 mutations are inherited in an autosomal recessive manner. Only six unrelated EML1-associated heterotopia-affected families were reported so far. The EML1 protein is a member of the microtubule-associated proteins family, playing an important role in microtubule assembly and stabilization as well as in mitotic spindle formation in interphase. Herein, we present a novel homozygous missense variant in EML1 (NM_004434.2: c.692G>A, NP_004425.2: p.Gly231Asp) identified in a male RSH-affected patient. Our clinical and molecular findings confirm the genotype-phenotype associations of EML1 mutations and RSH. Analyses of patient-derived fibroblasts showed the significantly reduced length of primary cilia. In addition, our results presented, that the mutated EML1 protein did not change binding capacities with tubulin. The data described herein will expand the mutation spectrum of the EML1 gene and provide further insight into molecular and cellular bases of the pathogenic mechanisms underlying RSH.

New genetic testing technologies have revolutionized medicine within the past years. It is foreseeable that the development will continue with the introduction of new techniques. Nevertheless, despite improved technology, an exact clinical description of the phenotype is still necessary and it is important to critically question findings, both before initiating genetic testing and when interpreting the results. We present four brief case vignettes to point out difficulties associated with correctly interpreting genetic findings.

s der 36. Jahrestagung der Gesellschaft für Pädiatrische Gastroenterologie und Ernährung (GPGE) e.V. Basel, 14.–17. April 2021 D ie GPGE-Jahrestagung findet 2021 unter erschwerten Bedingungen in Basel statt: Die COVID-19-Pandemie verlangt uns allen Geduld, eine gute Kondition und viel Kreativität ab. Dennoch haben wir unbeirrt unser Ziel weiterverfolgt, eine qualitativ hochwertige Tagung zu organisieren. Unser Programm sieht viele spannende Themen vor. Die hier publizierten und qualitativ hochstehenden Abstracts über das gesamte Gebiet der pädiatrischen Gastroenterologie, Hepatologie und Ernährung dienen als Basis für rege Diskussionen und den interprofessionellen Austausch während der Tagung. Für angehende Fachärzte und Fachärztinnen sowie Kindergastroenterologen und -gastroenterologinnen gibt es ein umfassendes Vorprogramm, das Grundlagen und praktische Einblicke vermittelt. Wir freuen uns auf den Austausch mit Ihnen und wünschen Ihnen eine interessante Lektüre und spannende Tage live am Bildschirm mit vielen Anregungen und wertvollen virtuellen Begegnungen.

Background: IgA vasculitis/Henoch-Schoenlein purpura (IgAV/HSP) is a systemic small vessel vasculitis of unknown pathogenesis predominantly affecting children. While skin, GI tract, joints, and kidneys are frequently affected and considered, central nervous system (CNS) involvement of this disease is underestimated. Methods: We provide a case report and systematically review the literature on IgAV, collecting data on the spectrum of neurological manifestations. Results: We report on a 7-year-old girl with IgAV who presented with diplopia and afebrile focal seizures, which preceded the onset of purpura. Cranial magnetic resonance imaging was consistent with posterior reversible encephalopathy syndrome (PRES), showing typical focal bilateral parietal swelling and cortical and subcortical high signal intensities on T2-fluid attenuated inversion recovery (FLAIR) images predominantly without diffusion restriction. Cerebrospinal fluid analysis and blood tests excluded systemic inflammation or vasculitis. Interestingly, hypertension was not a hallmark of the developing disease in the initial phase of PRES manifestation. Renal disease and other secondary causes for PRES were also excluded. Supportive- and steroid treatment resulted in restitution ad integrum. Reviewing the literature, we identified 28 other cases of IgAV with CNS involvement. Severe CNS involvement includes seizures, cerebral edema, or hemorrhage, as well as PRES. Thirteen patients fulfilled all diagnostic criteria of PRES. The mean age was 11.2 years (median 8.0, range 5-42 years), with no reported bias toward gender or ethnic background. Treatment regimens varied from watchful waiting to oral and intravenously steroids up to plasmapheresis. Three cases showed permanent CNS impairment. Conclusion: Collectively, our data demonstrate that (I) severe CNS involvement such as PRES is an underappreciated feature of IgAV, (II) CNS symptoms may precede other features of IgAV, (III) PRES can occur in IgAV, and differentiation from CNS vasculitis is challenging, (IV) pathogenesis of PRES in the context of IgAV remains elusive, which hampers treatment decisions. We, therefore, conclude that clinical awareness and the collection of structured data are necessary to elucidate the pathophysiological connection of IgAV and PRES.

Aging is the most significant determinant for brain iron accumulation in the deep grey matter. Data on brain iron evolution during brain maturation in early childhood are limited. The purpose of this study was to investigate age-related iron deposition in the deep grey matter in children using quantitative susceptibility (QSM) and R2* mapping. We evaluated brain MRI scans of 74 children (age 6–154 months, mean 40 months). A multi-echo gradient-echo sequence obtained at 3 Tesla was used for the QSM and R2* calculation. Susceptibility of the pallidum, head of caudate nucleus, and putamen was correlated with age and compared between sexes. Susceptibility changes in all three nuclei correlated with age (correlation coefficients for QSM/R2*: globus pallidus 0.955/0.882, caudate nucleus 0.76/0.65, and putamen 0.643/0.611). During the first 2 years, the R2* values increased more rapidly than the QSM values, indicating a combined effect of iron deposition and myelination, followed by a likely dominating effect of iron deposition. There was no significant gender difference. QSM and R2* can monitor myelin maturation processes and iron accumulation in the deep grey nuclei of the brain in early life and may be a promising tool for the detection of deviations of this normal process. Susceptibility in the deep nuclei is almost similar early after birth and increases more quickly in the pallidum. The combined use of QSM and R2* analysis is beneficial.

Background After introducing the first Cochlear Implants also in children theses are grown with electrical intracochlear stimulation and subsequent auditory cortical development. Over the meantime the positioning of the electrode was changed orientated on the development of electrode design, ability to insert atraumatic and on the widening of the indications towards highfrequency deafness. Methods In this pilot study we analysed five prelingually deafened patients implanted as child in the late 90’s and had a reimplantation 2016 or later. We compared CT and DVT (cone beam CT) scans of the temporal bone and measured the insertion angle, the cochlear coverage, the total length of the electrode in the cochlea and the distance of the first active electrode to the round window. Moreover, we compared their speech understanding before and after reimplantation. Results The results show a lowering in the insertion angle, the cochlear coverage, the total length of the electrode in the cochlea, in the distance of the first active electrode to the round window and in the speech understanding after reimplantation. Conclusion These results show a difference in the depth of insertion while the speech understanding is not significantly improving in this group—although the technology is advanced. The influence of auditory maturation with CI in these patients will be discussed.