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Now that targeted therapies for spinal muscular atrophy are available, attempts are being made worldwide to include screening for spinal muscular atrophy in general newborn screening. In Germany, after pilot projects from 2018–2021, it was included in the general newborn screening from October 2021. To ensure a smooth transition, criteria for follow-up were developed together with key stakeholders. At the beginning of the transition to nationwide screening, false positive findings were reported in 3 patients. After optimization of the screening method in the laboratories concerned, all findings have been subsequently confirmed. On average, the first presentation to a neuromuscular center occurred on day 12 of life, and in patients with 2 or 3 SMN2 copies, therapy started on day 26 of life. Compared with the pilot project, there was no significant delay in timing.

Background and objectives: Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients. Here, we report data from the SMArtCARE registry of ambulant patients under nusinersen treatment with a follow-up period of up to 38 months. Methods: SMArtCARE is a disease-specific registry in Germany, Austria and Switzerland. Data are collected as real-world data during routine patient visits. Our analysis included all patients under treatment with nusinersen able to walk independently before start of treatment with focus on changes in motor function. Results: Data from 231 ambulant patients were included in the analysis. During the observation period, 31 pediatric walkers (27.2%) and 31 adult walkers (26.5%) experienced a clinically meaningful improvement of≥30 m in the 6-Minute-Walk-Test. In contrast, only five adult walkers (7.7%) showed a decline in walking distance≥30 m, and two pediatric walkers (1.8%) lost the ability to walk unassisted under treatment with nusinersen. HFMSE and RULM scores improved in pediatric and remained stable in adult patients. Conclusion: Our data demonstrate a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. We not only observed a stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance.

Background The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. Methods SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Results Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Conclusion Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.

The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months.SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM).Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score.Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.

ObjectivesPost-measles increased susceptibility to subsequent infections seems particularly relevant in low-resource settings. We tested the hypothesis that measles causes a specifically increased rate of infections in children, also in a high-resource setting.MethodsWe conducted a retrospective cohort study on a large measles outbreak in Berlin, Germany. All children with measles who presented to hospitals in Berlin were included as cases, children with non-infectious and children with non-measles infectious diseases as controls. Repeat visits within 3 years after the outbreak were recorded.ResultsWe included 250 cases, 502 non-infectious, and 498 infectious disease controls. The relative risk for cases for the diagnosis of an infectious disease upon a repeat visit was 1.6 (95% CI 1.4–2.0, p < 0.001) vs. non-infectious and 1.3 (95% CI 1.1–1.6, p = 0.002) vs. infectious disease controls. 33 cases (27%), 35 non-infectious (12%) and 57 (18%) infectious disease controls presented more than three times due to an infectious disease (p = 0.01, and p = 0.02, respectively). This results in a relative risk of more than three repeat visits due to an infection for measles cases of 1.8 (95% CI 1.3–2.4, p = 0.01), and 1.4 (95% CI 1.0–1.9, p = 0.04), respectively.ConclusionOur study demonstrates for the first time in a high-resource setting, that increased post-measles susceptibility to subsequent infections in children is measles-specific—even compared to controls with previous non-measles infections.

Bachelorarbeit | Angesichts hoher Interventionsraten bei Gebärenden mit niedrigem Ausgangsrisiko ist die Entscheidungsgrundlage für Interventionen neu zu hinterfragen. Die Beurteilung des Geburtsfortschrittes beeinflusst maßgeblich den Einsatz von Medikation und mechanischen Interventionen. Die vaginale Untersuchung als zentraler Parameter für das Voranschreiten der Geburt steht in der Fachwelt auf dem Prüfstand. Die Autorin identifiziert mögliche Alternativen zur Beurteilung des Geburtsfortschrittes und leitet Empfehlungen für die Geburtsbetreuung durch Hebammen ab.

Data de publicació electrònica: 23-03-2022 Background and purpose: The therapeutic landscape of spinal muscular atrophy (SMA) has changed dramatically during the past 4 years, but treatment responses differ remarkably between individuals, and therapeutic decision-making remains challenging, underlining the persistent need for validated biomarkers. Methods: We applied untargeted proteomic analyses to determine biomarkers in cerebrospinal fluid (CSF) samples of SMA patients under treatment with nusinersen. Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and enzyme-linked immunosorbent assay. Furthermore, levels of peripheral neurofilament heavy and light chain were determined. Results: Untargeted proteomic analysis of CSF samples of three SMA type 1 patients revealed the lysosomal protease cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1, n = 12; type 2, n = 9; type 3, n = 6; presymptomatically treated, n = 4; age = 0-16 years) revealed a significant decline of cathepsin D levels in SMA patients aged ≥2 months at the start of treatment. Although evident in all older age categories, this decline was only significant in the group of patients who showed a positive motor response. Moreover, downregulation of cathepsin D was evident in muscle biopsies of SMA patients. Conclusions: We identified a decline of cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of "treatment responders" than in "nonresponders." We believe that our results indicate a suitability of cathepsin D levels as a possible biomarker in SMA also in older patients, in combination with analysis of peripheral neurofilament light chain in adolescents or alone in adult patients. Funding: H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). This work was also supported by a grant of the French Muscular Dystrophy Association (AFM-Téléthon;#21466) to A.R. The work of B.W. is supported by the German Research Foundation (Wi945/17-1, SFB 1451 [project-ID 431549029–A01] and GRK1960 [project ID 233886668]), the European Research Council under the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement 956185 (SMABEYOND), and the Center for Molecular Medicine Cologne (project No C18)

Spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) both are rare genetic neuromuscular diseases with progressive loss of motor ability. The neuromotor developmental course of those diseases is well documented. In contrast, there is only little evidence about characteristics of general and specific cognitive development. In both conditions the final motor outcome is characterized by an inability to move autonomously: children with SMA never accomplish independent motoric exploration of their environment, while children with DMD do but later lose this ability again. These profound differences in developmental pathways might affect cognitive development of SMA vs. DMD children, as cognition is shaped by individual motor experiences. DMD patients show impaired executive functions, working memory, and verbal IQ, whereas only motor ability seems to be impaired in SMA. Advanced cognitive capacity in SMA may serve as a compensatory mechanism for achieving in education, career progression, and social satisfaction. This study aimed to relate differences in basic numerical concepts and arithmetic achievement in SMA and DMD patients to differences in their motor development and resulting sensorimotor and environmental experiences. Horizontal and vertical spatial-numerical associations were explored in SMA/DMD children ranging between 6 and 12 years through the random number generation task. Furthermore, arithmetic skills as well as general cognitive ability were assessed. Groups differed in spatial number processing as well as in arithmetic and domain-general cognitive functions. Children with SMA showed no horizontal and even reversed vertical spatial-numerical associations. Children with DMD on the other hand revealed patterns in spatial numerical associations comparable to healthy developing children. From the embodied Cognition perspective, early sensorimotor experience does play a role in development of mental number representations. However, it remains open whether and how this becomes relevant for the acquisition of higher order cognitive and arithmetic skills.

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.

Spinal muscular atrophy (SMA) is a severe, life-limiting neurodegenerative disease. A disease-modifying and approved therapy with nusinersen has been available in Germany since July 2017. Gene therapies offer another promising treatment option through a once in a lifetime administration. In May 2019 a gene replacement therapy for the treatment of SMA was approved for the first time by the U.S. Food and Drug Administration (FDA). An application for approval in Europe has been submitted and is currently pending.This consensus paper was compiled at the invitation of the German Society for Muscular Diseases (DGM) with the participation of all potential German neuromuscular treatment centers, the German section of the Society for Pediatric Neurology (GNP) and with the involvement of the medical scientific advisory board of the DGM. The aim was to define and establish the necessary prerequisites for a safe and successful application of the new gene replacement therapy in clinical practice.Gene replacement therapy with onasemnogene abeparvovec has the potential to significantly influence the course of SMA. Long-term data on sustainability of effects and possible adverse effects of gene replacement therapy are not yet available. The application of this innovative therapy must be carried out in specialized and appropriately qualified treatment centers under strict safety conditions. This article makes suggestions for the necessary framework conditions and gives recommendations for a systematic pretreatment and posttreatment assessment schedule under gene therapy. The effectiveness and safety of the therapy should be systematically documented in an industry-independent and disease-specific register.

Zusammenfassung Hintergrund Die spinale Muskelatrophie (SMA) ist eine schwere, lebenslimitierende neurodegenerative Erkrankung. Seit Juli 2017 steht in Deutschland eine krankheitsmodifizierende und zugelassene Therapie mit Nusinersen zur Verfügung. Eine weitere vielversprechende Behandlungsmöglichkeit durch eine einmalige Applikation bieten konzeptionell Gentherapien. Im Mai 2019 wurde erstmals eine kausale Genersatztherapie zur Behandlung der spinalen Muskelatrophie von der U.S. Food and Drug Administration (FDA) zugelassen, die Zulassung in Europa ist beantragt. Ziele Dieses Konsensuspapier wurde auf Einladung der Deutschen Gesellschaft für Muskelkranke e. V. (DGM) unter Beteiligung der deutschen neuromuskulären Behandlungszentren, der deutschen Sektion der Gesellschaft für Neuropädiatrie (GNP) und unter Mitwirkung des Medizinisch-Wissenschaftlichen Beirates der DGM erarbeitet. Ziel ist es, die notwendigen Voraussetzungen für eine qualitätsgesicherte Anwendung der neuen Gentherapie zu definieren und die Grundlage für die Umsetzung in der klinischen Praxis zu schaffen. Diskussion Die Gentherapie mit Onasemnogene Abeparvovec besitzt das Potenzial, den Krankheitsverlauf der spinalen Muskelatrophie signifikant zu beeinflussen. Langzeitdaten über die Nachhaltigkeit der Wirkung und mögliche unerwünschte Wirkungen liegen derzeit noch nicht vor. Die Anwendung dieser innovativen Therapieform muss in spezialisierten und entsprechend qualifizierten Behandlungszentren unter strengen Sicherheitsauflagen erfolgen. Die vorliegende Arbeit schlägt die hierfür notwendigen Rahmenbedingungen und Empfehlungen für die systematische Vor- und Nachsorge unter Gentherapie vor. Wirksamkeit und Sicherheit der Therapie sollten in einem industrieunabhängigen, krankheitsspezifischen Register systematisch erfasst werden.

Einen speziellen Versorgungsbedarf an medizinischen und sozialen Leistungen haben 14 % aller Kinder und Jugendliche in der Bundesrepublik Deutschland. Nach dem Wechsel in die Erwachsenenmedizin verlieren bis zu 40 % der dann jungen Erwachsenen den Kontakt zum spezialisierten Versorgungssystem. Oftmals finden sie erst den Weg zuruck, wenn sich Komplikationen oder Folgeerscheinungen der chronischen Erkrankung zeigen. Nur wenn Transition als gemeinsame Aufgabe der einzelnen Fachdisziplinen erkannt und auch als strukturelles Instrument in das Versorgungssystem eingefuhrt wird, kann die Situation deutlich verbessert werden. Die betroffenen jungen Menschen konnen dann die ihnen notwendige Unterstutzung auf dem Weg in die erwachsenenmedizinische spezialisierte Betreuung erhalten, und ihre arztliche Betreuung kann sichergestellt werden.

Mit hauslicher Gewalt, korperlicher Misshandlung oder Vernachlassigung von Kindern sind im Rettungsdienst tatige Fachkrafte regelmasig konfrontiert. Dies lost haufig Stress und Handlungsunsicherheit aus. Die Versorgungsforschung zeigt, dass die betroffenen Patienten dringend auf entschiedenes und uberlegtes Handeln aller Akteure im Gesundheitswesen, und damit auch des Rettungswesens, angewiesen sind. Die akuten und chronischen Folgen verpasster Intervention sind verheerend, im Extremfall konnen sie todlich sein. Es soll auf vorhandene Defizite und Schwachstellen in der notfallmedizinischen Versorgung betroffener Kinder hingewiesen werden. Die Leser sollen nach der Lekture in der Lage sein, eine orientierende Gefahrdungsabschatzung von Kindern vornehmen zu konnen, sowie wirksame Interventionen und verfugbare Beratungsangebote kennen. Darstellung relevanter Literatur, eigener Erfahrungen und Vorstellung eines bundesweiten Beratungsprojektes. Frakturen und Hamatome haben altersabhangig eine teils hohe Spezifitat fur Misshandlung. Sie sind, wenn sie ohne plausible Anamnese bei einem Kind auftreten, als sog. gewichtige Anhaltspunkte nach dem Bundeskinderschutzgesetz zu werten und erlauben unter den vorgestellten Bedingungen einen Bruch der Schweigepflicht gegenuber dem Jugendamt. Zusatzlich steht seit dem 01.07.2017 zu jedem der oben genannten Schritte ein telefonisches Beratungsangebot durch Arzte zur Verfugung: die Medizinische Kinderschutz-Hotline, die unter der Nummer 0800 19 210 00 rund um die Uhr kostenlos verfugbar ist. Sie richtet sich an Angehorige der Gesundheitsberufe und somit explizit auch an Fachkrafte im Rettungsdienst und berat zu allen Fragen des Kinderschutzes. Weiterbildung und Beratung aller medizinischen Fachkrafte, die mit Kindern zu tun haben, sind der richtige Weg, um die Behandlung von Misshandlung betroffener Kinder zu verbessern.

A 6-year-old girl had reduced fetal movements, numerous apneic spells, muscle hypotonia, and developmental motor delay. Her muscle biopsy tissue showed variation in myofiber diameters, small minicores by electron microscopy, and near-uniformity of type I fibers. Although no mutations were detected in RYR1, SEPN1, and DMPK genes, the RAPSN gene revealed one known mutation, p.Asn88Lys, from the mother, and one novel mutation, p.Cys366Gly, from the father. Life-saving pyridostigmine treatment suppressed her apneic spells and improved her motor development.

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

BackgroundMagnetic resonance imaging (MRI) of the brain in children and adolescents is a well-established method in both clinical practice and in neuroscientific research. This practice is sometimes viewed critically, as MRI scans might expose minors (e.g. through scan-associated fears) to more than the legally permissible "minimal burden". While there is evidence that a significant portion of adults undergoing brain MRI scans experience anxiety, data on anxiety in children and adolescents undergoing brain MRI scans is rare. This study therefore aimed to examine the prevalence and level of anxiety in children and adolescents who had MRI scans of the brain, and to compare the results to adults undergoing brain MRI scans, and to children and adolescents undergoing electroencephalography (EEG; which is usually regarded a "minimal burden").MethodParticipants were 57 children and adolescents who had a brain MRI scan (MRI-C; mean age 12.9 years), 28 adults who had a brain MRI scan (MRI-A; mean age 43.7 years), and 66 children and adolescents undergoing EEG (EEG-C; mean age 12.9 years). Anxiety was assessed on the subjective (situational anxiety) and on the physiological level (arousal), before and after the respective examination.ResultsMore than 98% of children and adolescents reported no or only minimal fear during the MRI scan. Both pre- and post-examination, the MRI-C and the MRI-A groups did not differ significantly with respect to situational anxiety (p = 0.262 and p = 0.374, respectively), and to physiological arousal (p = 0.050, p = 0.472). Between the MRI-C and the EEG-C group, there were also no significant differences in terms of situational anxiety (p = 0.525, p = 0.875), or physiological arousal (p = 0.535, p = 0.189). Prior MRI experience did not significantly influence subjective or physiological anxiety parameters.ConclusionsIn this study, children and adolescents undergoing a brain MRI scan did not experience significantly more anxiety than those undergoing an EEG, or adults undergoing MRI scanning. Therefore, a general exclusion of minors from MRI research studies does not appear reasonable.

Female carriers of DMD gene mutations may be symptomatic and show variable skeletal as well as cardiac muscle symptoms. Skeletal muscle can exhibit morphological alterations. However, inflammatory, degenerative and fibrotic changes as seen in Duchenne boys have not been specifically analysed yet, so we addressed the question whether skeletal muscle of female carriers show such alterations. Thirteen carriers with an age range of 3 to 50 years were studied retrospectively. Five out of 13 women had clinically affected relatives. Clinically, most women showed mild muscle weakness, while the CK levels were increased in nine of them. Histomorphological analyses highlighted the typical mosaic pattern of dystrophin-positive and -negative fibres. Regenerating fibres were diffusely scattered and focally pronounced, while endo- and perimysial fibrosis was a variable but constant feature. Infiltration of CD206+TGFs+ macrophages and scattered T cells was noted in the endomysium. TGFb and CCL18, were significantly increased. However, gene expression of markers involved in Th1/Th2 immunity did not reach statistical significance compared to non-diseased controls. In summary, skeletal muscle of clinically manifest female DMD gene mutation carriers shows mild fibrosis and increased regeneration associated with endomysial CD206+TGFβ+ and STAT6+ macrophages, which are most likely involved in fibrotic remodelling.

Background It is well known that physical abuse of children all too often escapes detection. Fractures are among the potential consequences of physical abuse but are also com- mon in childhood because of accidents. A question frequently addressed to the Medical Child Protection Hotline (Medizini- sche Kinderschutzhotline) is how fractures due to abuse can be distinguished from accidental fractures. Methods This review is based on pertinent publications retrieved by a search in PubMed and in the Cochrane Data- base, as well as on the authors' experience in a pediatric emergency department with ca. 29 000 consultations per year and in a child protection outpatient clinic with ca. 100 consultations per year. Results Fractures due to abuse are especially common among infants; their incidence is estimated at 56.8/100 000 among infants less than six months old and 39.8/100 000 among infants aged 6 to 11 months. In consideration of the age of the child, the type of fracture, the history, and other factors, a high probability of abuse can be suspected in many cases, so that further measures can be initiated. Conclusion All physicians involved in the care of children (even if only occasionally) should be aware of the major indicators of likely physical abuse and of the available oppor- tunities for counseling and intervention. Failures to diagnose child abuse are associated with high rates of recurrence and mortality.

Neuromuscular diseases in childhood, adolescence and adulthood are rare or very rare diseases and for many of them the prevalence and incidence are unknown. Causal therapies are currently used for individual disease entities only. Nevertheless, new genetic methods, a better understanding of the pathophysiology and multidisciplinary treatment concepts help to improve patient life expectancy and quality of life. As a result, more and more patients with an early disease onset reach adulthood and further care in adult medicine is necessary. This imposes new challenges particularly on neurology and the requirements for interdisciplinary cooperation in adult medicine are increased.How can transition be made meaningful? Where do structural and content problems stand out?Using the example of Duchenne muscular dystrophy, the content and structural requirements for transition are presented and important aspects and possible problems are pointed out.The transition process is complex and requires time and personnel resources. If carried out sensibly, it can lead to a better and more efficient care of patients in the long term and thus can also become economically more effective.

Kinderschutz betrifft alle Ärzt*innen und stellt meist einen Stressfaktor sowie eine multidisziplinäre Herausforderung dar. Trotz des durch das Bundeskinderschutzgesetz geschaffenen rechtlichen Rahmens schätzen viele Ärzt*innen ihr Wissen diesbezüglich als unzureichend[zum vollständigen Text gelangen Sie über die oben angegebene URL], 67. Jahrestagung der Norddeutschen Gesellschaft für Kinder- und Jugendmedizin (NDGKJ)

Neuromuskulare Erkrankungen im Kindes‑, Jugend- und Erwachsenenalter sind seltene und sehr seltene Erkrankungen; bei vielen sind Pravalenz und Inzidenz nicht bekannt. Kausale Therapien kommen derzeit nur bei einzelnen Krankheitsentitaten zum Einsatz. Dennoch fuhren neue genetische Methoden, ein besseres Verstandnis der Pathophysiologie und multidisziplinare Behandlungskonzepte zu einer Verbesserung von Diagnostik und Therapie mit einer Steigerung von Lebenserwartung und Lebensqualitat. Das fuhrt dazu, dass Patienten mit fruhem Erkrankungsbeginn haufiger als fruher das Erwachsenenalter erreichen und eine Weiterversorgung in der Erwachsenenmedizin erforderlich ist. Dabei kommen insbesondere auf die Neurologie zunehmende Herausforderungen zu, es wachsen die Anforderungen an eine interdisziplinare Zusammenarbeit in der Erwachsenenmedizin. Wie kann die Transition sinnvoll gestaltet werden, wo zeichnen sich strukturelle und inhaltliche Probleme ab? Anhand der Duchenne-Muskeldystrophie sollen die inhaltlichen und strukturellen Anforderungen an den Transitionsprozess dargestellt und auf Schwierigkeiten bei der Umsetzung hingewiesen werden. Der Transitionsprozess ist komplex und erfordert zeitliche wie personelle Ressourcen. Das Ziel ist eine kontinuierliche spezialisierte medizinische Versorgung und eine Ubernahme der Gesundheitsfursorge durch den Patienten.

Zahlreiche Forschungszentren setzen die Magnetresonanztomographie (MRT) zu Studienzwecken an Minderjährigen ein. Angesichts dieser Forschungspraxis werden jedoch ethische Bedenken bezüglich der Belastung, der die Studienteilnehmer während der MRT-Untersuchung ausgesetzt sind, diskutiert. Ziel der Studie ist daher zu evaluieren, ob eine MRT-Untersuchung negative Emotionen bei Kindern und Jugendlichen induziert, die stärker sind als die gegenwärtig als «minimale Belastung» eingestufte Untersuchungsmethode der Elektroenzephalographie (EEG). Weiterhin wird die durch eine MRT-Untersuchung von Kindern und Jugendlichen induzierte emotionale Belastung mit der einer MRT-Untersuchung von Erwachsenen verglichen. Untersuchungsmethodenbezogene Emotionen werden in der vorliegenden Studie bei Kindern und Jugendlichen beiderlei Geschlechts im Alter von 8 bis 17;11 Jahren, bei denen ein MRT des Cerebrums mit medizinischer Indikation durchgeführt wird, erhoben. Eine Stichprobe von Kindern und Jugendlichen, die mittels EEG mit medizinischer Indikation untersucht wird, dient als Vergleichsgruppe sowie eine Stichprobe von erwachsenen Patienten im Alter von 18 bis 65 Jahren, bei denen eine medizinisch indizierte MRT-Untersuchung durchgeführt wird. Die Studie befindet sich zurzeit in der Phase der Datenerhebung. Die Intention des folgenden Beitrags besteht darin, das Studiendesign des MRT-Forschungsprojekts vorzustellen.

Cerebellar cysts are rare findings in pediatric neuroimaging and rather characteristic for dystroglycanopathies and GPR56-related encephalopathy. We aim to report on seven children with cerebellar cysts showing absence of weakness and ruling out mutations within eight dystroglycanopathy genes and GPR56. Data about neurological and ophthalmological features, outcome, and creatine kinase values were collected from clinical histories and follow-up examinations. All MR images were qualitatively evaluated for infra- and supratentorial abnormalities. A SNP 6.0-Array was performed in three children. The POMT1, POMT2, POMGnT1, FKRP, FKTN, LARGE, ISPD, B3GALNT2, and GPR56 genes were screened in all patients by Sanger sequencing. Seven children from five families were studied. Ataxia, intellectual disability, and language impairment were found in all patients, ocular motor apraxia in five, and severe myopia in three. None of the patients had weakness, only three a minimally increased creatine kinase value. Qualitative neuroimaging evaluation showed cerebellar cysts and dysplasia in the cerebellar hemispheres and vermis in all children. Additional findings were an enlarged fourth ventricle in all children, vermian hypoplasia and brain stem morphological abnormalities in five. The SNP array showed no pathogenetic imbalances in all children evaluated. In all patients, no mutations were found in POMT1, POMT2, POMGnT1, FKRP, FKTN, LARGE, ISPD, B3GALNT2, and GPR56. The peculiar combination of the same clinical and neuroimaging findings in our patients highly suggests that this phenotype may represent a novel entity, possibly falling within the spectrum of dystroglycanopathies.

Background/Purpose: Neuronal migration disorders may cause severe pharmacoresistant epilepsy in early infancy. Molecular genetic changes such as microdeletions are possible etiologies. Neurosurgery has to be considered early especially in isolated unilateral involvement. Case Report: We report a case of a female newborn presenting high-frequent tonic seizures. Malformation of cortical development could be seen in the MRI concerning the left frontal lobe, partly as polymicrogyria extending up to the parietal region. EEG showed an isolated left localized burst suppression pattern as a sign of severe malfunction of the left hemisphere. B6, PB, PHT, LEV, STM, TPM, OXC, VGB, and steroids had no effect in controlling seizures; VGB and TPM showed at least a reduction of seizure frequency. The mother of the patient is suffering from frontal lobe epilepsy since the age of 18. Genetics of patient and her mother showed a micro-duplication 17q12 in both. An association with developmental delay and epileptic seizures is described in the literature. Furthermore change in DEPDC5-gene (c.1474C > T;p.R492X) was detected in both. Those mutations are found in patients with familial focal epilepsy with variable foci. In some of these patients focal cortical dysplasia type IIa was detected. Results: Left hemispherectomy at the age of 5 months was performed. Histological analysis showed a focal cortical dysplasia type IIa. Single tonic seizures and infantile spasm have been registered during the postoperative process. During the follow up developmental progress has been observed and one year after surgery even with reduction of AED the child is seizure free. Conclusion: A genetic analysis indicating familial epilepsy is no contraindication for neurosurgical treatment in case of distinct MRI and congruent clinical and EEG findings.

Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype.

Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS.

Dermatomyositis (DM) can occur in both adults and juveniles with considerable clinical differences. The links between immune-mediated mechanisms and vasculopathy with respect to development of perifascicular pathology are incompletely understood. We investigated skeletal muscle from newly diagnosed, treatment-naïve juvenile (jDM) and adult dermatomyositis (aDM) patients focusing on hypoxia-related pathomechanisms, vessel pathology, and immune mechanisms especially in the perifascicular region. Therefore, we assessed the skeletal muscle biopsies from 21 aDM, and 15 jDM patients by immunohistochemistry and electron microscopy. Transcriptional analyses of genes involved in hypoxia, as well as in innate and adaptive immunity were performed by quantitative Polymerase chain reaction (qPCR) of whole tissue cross sections including perifascicular muscle fibers. Through these analysis, we found that basic features of DM, like perifascicular atrophy and inflammatory infiltrates, were present at similar levels in jDM and aDM patients. However, jDM was characterized by predominantly hypoxia-driven pathology in perifascicular small fibers and by macrophages expressing markers of hypoxia. A more pronounced regional loss of capillaries, but no relevant activation of type-1 Interferon (IFN)-associated pathways was noted. Conversely, in aDM, IFN-related genes were expressed at significantly elevated levels, and Interferon-stimulated gene (ISG)15 was strongly positive in small perifascicular fibers whereas hypoxia-related mechanisms did not play a significant role. In our study we could provide new molecular data suggesting a conspicuous pathophysiological ‘dichotomy’ between jDM and aDM: In jDM, perifascicular atrophy is tightly linked to hypoxia-related pathology, and poorly to innate immunity. In aDM, perifascicular atrophy is prominently associated with molecules driving innate immunity, while hypoxia-related mechanisms seem to be less relevant. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0308-5) contains supplementary material, which is available to authorized users.

Summary Background Dopamine transporter deficiency syndrome is the first identified parkinsonian disorder caused by genetic alterations of the dopamine transporter. We describe a cohort of children with mutations in the gene encoding the dopamine transporter ( SLC6A3 ) with the aim to improve clinical and molecular characterisation, reduce diagnostic delay and misdiagnosis, and provide insights into the pathophysiological mechanisms. Methods 11 children with a biochemical profile suggestive of dopamine transporter deficiency syndrome were enrolled from seven paediatric neurology centres in the UK, Germany, and the USA from February, 2009, and studied until June, 2010. The syndrome was characterised by detailed clinical phenotyping, biochemical and neuroradiological studies, and SLC6A3 mutation analysis. Mutant constructs of human dopamine transporter were used for in-vitro functional analysis of dopamine uptake and cocaine-analogue binding. Findings Children presented in infancy (median age 2·5 months, range 0·5–7) with either hyperkinesia (n=5), parkinsonism (n=4), or a mixed hyperkinetic and hypokinetic movement disorder (n=2). Seven children had been initially misdiagnosed with cerebral palsy. During childhood, patients developed severe parkinsonism-dystonia associated with an eye movement disorder and pyramidal tract features. All children had raised ratios of homovanillic acid to 5-hydroxyindoleacetic acid in cerebrospinal fluid, of range 5·0–13·2 (normal range 1·3–4·0). Homozygous or compound heterozygous SLC6A3 mutations were detected in all cases. Loss of function in all missense variants was recorded from in-vitro functional studies, and was supported by the findings of single photon emission CT DaTSCAN imaging in one patient, which showed complete loss of dopamine transporter activity in the basal nuclei. Interpretation Dopamine transporter deficiency syndrome is a newly recognised, autosomal recessive disorder related to impaired dopamine transporter function. Careful characterisation of patients with this disorder should provide novel insights into the complex role of dopamine homoeostasis in human disease, and understanding of the pathophysiology could help to drive drug development. Funding Birmingham Children's Hospital Research Foundation, Birth Defects Foundation Newlife, Action Medical Research, US National Institutes of Health, Wellchild, and the Wellcome Trust.

Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P

ZusammenfassungDie Muskeldystrophie Duchenne ist eine X-gebundene rezessive Erkrankung, die bei 1:3 500 Knaben auftritt. Sie wird durch Mutationen im DMD-Gen verursacht. Die Mutationen resultieren in einem Verlust von Dystrophin, dies führt zur progredienten Muskeldegeneration. Der Krankheitsverlauf ist durch eine progrediente, proximal betonte Muskelschwäche gekennzeichnet, die ohne Behandlung zu einem Gehverlust um das 10. Lebensjahr und zum frühzeitigen Tod um das 20. Lebensjahr durch Ateminsuffizienz oder Herzversagen führt. Durch symptomatische Therapien kann der Krankheitsverlauf positiv beeinflusst werden, besonders durch die Etablierung der nicht invasiven Beatmung konnte die Lebenserwartung erheblich verlängert werden. In den letzten Jahren wurden verschiedene Ansätze einer kausalen Therapie untersucht. Am weitesten gediehen ist das “exon skipping”, dessen Wirksamkeit in internationalen, multizentrischen Phase-III Studien untersucht wird.

One thousand five hundred sixty-eight RSV infections were documented prospectively in 1,541 pediatric patients. Of these, 20 (1.3%) had acquired the RSV infection while treated by mechanical ventilation for reasons other than the actual RSV infection (group ventilated mechanically). The clinical characteristics of children who were infected with respiratory syncytial virus (RSV) infection while ventilated mechanically for other reasons are described and compared with a matched control group. Sixty percent of the group ventilated mechanically had at least one additional risk factor for a severe course of infection (prematurity 50%, chronic lung disease 20%, congenital heart disease 35%, immunodeficiency 20%). The median age at diagnosis in the group ventilated mechanically was 4.2 months. The matched pairs analysis (group ventilated mechanically vs. control group) revealed a higher proportion of patients with hypoxemia and apnoea in the group ventilated mechanically; more patients in the control group showed symptoms of airway obstruction (wheezing). At least one chest radiography was performed in 95% of the patients (n = 19) in the group ventilated mechanically versus 45% (n = 9) in the control group (P = 0.001). The frequency of pneumonia was 40% in the group ventilated mechanically and 20% in the control group. Despite existing consensus recommendations, only two patients (10%) of the group ventilated mechanically had received palivizumab previously. Significantly more patients in the group ventilated mechanically received antibiotic treatment (85% vs. 45%, P = 0.008), and attributable mortality was higher in the group ventilated mechanically (15% [n = 3] vs. 0% in the control group, P = 0.231). Children treated by long term mechanical ventilation may acquire RSV infection by transmission by droplets or caregivers and face an increased risk of a severe course of RSV infection. The low rate of immunoprophylaxis in this particular risk group should be improved. J. Med. Virol. 81:160–166, 2009. © 2008 Wiley-Liss, Inc.

Objectives: Dermatomyositis (DM) can occur in both adults and children with considerable clinical differences. The links between immune-mediated mechanisms and vasculopathy with respect to development of perifascicular atrophy are incompletely understood. We investigated skeletal muscle from newly diagnosed[for full text, please go to the a.m. URL], 60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN)

The identification of an ever increasing number of gene defects in patients with neuromuscular disorders has disclosed both marked phenotype and genotype variability and considerable disease overlap. In order to offer an economic strategy to characterise the molecular defect in patients with unclassified neuromuscular disorders, we designed DNA marker sets for linkage analysis of 62 distinct neuromuscular disorders gene loci, including all known muscular dystrophies, congenital myopathies, congenital myasthenic syndromes and myotonias. Genotyping of marker loci of 140 clinically well-characterised families with unclassified neuromuscular disorders reduced the number of candidates to one or two genes in 49 % of the families. Subsequent mutation analysis and genome-wide scans enabled the determination of the genetic defect in 31 % of the families including the identification of a new gene and a new mutation in an unexpected candidate gene. This highlights the effective application of this approach both for diagnostic strategies as well as for the identification of new loci and genes.

Objective: Thyroid hormones, besides having other functions, are known to be essential for the development of the human brain. Recently the monocarboxylate transporter 8 (MCT8) was identified as a thyroid hormone transporter which is expressed in different regions of the human brain. Here we describe in detail the clinical and biochemical features in response to thyroid hormone administration of a boy carrying an MCT8 mutation (A150V) in the second transmembrane domain. Methods: To study the functional impact of the mutation we performed triiodothyronine (T3) uptake, immunofluorescence and dimerization studies. Results: Thyroid hormone (l-thyroxine (LT4) and LT3) administration did not result in any significant clinical changes; however, with high doses of LT4, alone or in combination with T3, TSH suppression was achieved. We could show a robust uptake of 125I-T3 for wild type (WT) MCT8, whereas no specific uptake could be detected for the mutant A150V. Subcellular localization of WT and mutant MCT8 revealed a strong cell surface expression for the WT MCT8, in contrast to A150V, which is mostly retained intracellularly with only weak cell surface expression. We could also demonstrate for the first time that WT MCT8 as well as the mutant are able to form multimers. Conclusion: Our findings open a wide field of possible interaction within the central nervous system and will help to understand the crucial role of MCT8 in early fetal brain development.