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Continuous EEG monitoring (cEEG) is frequently used in neurocritical care. The detection of seizures is one of the main objectives. The placement of the EEG electrodes is time consuming, therefore a reduced montage might lead to an increased availability in the ICU setting. It is unknown whether such a reduction of electrodes reduces the number of seizure patterns that are detected. A total of 95 seizure and 95 control EEG sequences from a pediatric epilepsy monitoring unit (EMU) were anonymized and reduced to an eight-lead montage. Two experts evaluated the recordings and the seizure detection rates using the reduced and the full montage were compared. Sensitivity and specificity for the seizure detection were calculated using the original EMU findings as gold standard. The sensitivity to detect seizures was 0.65 for the reduced montage compared to 0.76 for the full montage (p = 0.031). The specificities (0.97 and 0.96) were comparable (p = 1). A total of 4/9 (44%) of the generalized, 12/44 (27%) of the frontal, 6/14 (43%) of the central, 0/1 (0%) of the occipital, 6/20 (30%) of the temporal, and 5/7 (71%) of the parietal seizure patterns were not detected using the reduced montage. The median time difference between the onset of the seizure pattern in the full and reduced montage was 0.026s (IQR 5.651s). In this study the reduction of the EEG montage from 21 to eight electrodes reduced the sensitivity to detect seizure patterns from 0.76 to 0.65. The specificity remained virtually unchanged.

Background Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. Since motor neuron injury is usually not reversible, early diagnosis and treatment are essential to prevent major disability. Our objective was to assess the impact of genetic newborn screening for SMA on outcome. Methods We provided clinical data from 43 SMA patients, identified via polymerase chain reaction of the SMN1 gene from dried blood spots between January 2018 and January 2020 in Germany. Follow-up included neurophysiological examinations and standardized physiotherapeutic testing. Results Detection of SMA with newborn screening was consistent with known incidence in Germany. Birth prevalence was 1:6910; 39.5% had 2 SMN2 copies, 23% had 3 SMN2 copies, 32.5% had 4 copies, and 4.5% had 5 copies of the SMN2 gene. Treatment with SMA-specific medication could be started at the age of 14–39 days in 21 patients. Pre-symptomatically treated patients remained throughout asymptomatic within the observation period. 47% of patients with 2 SMN2 copies showed early, presumably intrauterine onset of disease. These patients reached motor milestones with delay; none of them developed respiratory symptoms. Untreated children with 2 SMN2 copies died. Untreated children with 3 SMN2 copies developed proximal weakness in their first year. In patients with ≥ 4 SMN2 copies, a follow-up strategy of “watchful waiting” was applied despite the fact that one of them was treated from the age of 6 months. Two infant siblings with 4 SMN2 copies were identified with a missed diagnosis of SMA type 3. Conclusion Identification of newborns with infantile SMA and prompt SMA-specific treatment substantially improves neurodevelopmental outcome, and we recommend implementation in the public newborn screening in countries where therapy is available. Electrophysiology is a relevant parameter to support the urgency of therapy. There has to be a short time interval between a positive screening result and referral to a therapy-ready specialized treatment center.

Establishing nucleic acid-based assays for genetic newborn screening (NBS) provides the possibility to screen for genetically encoded diseases like spinal muscular atrophy (SMA), best before the onset of symptoms. Such assays should be easily scalable to 384-well reactions that make the screening of up to 2000 samples per day possible. We developed a test procedure based on a cleanup protocol for dried blood spots and a quantitative (q)PCR to screen for a homozygous deletion of exon 7 of the survival of motor neuron 1 gene (SMN1) that is responsible for >95% of SMA patients. Performance of this setup is evaluated in detail and tested on routine samples. Our cleanup method for nucleic acids from dried blood spots yields enough DNA for diverse subsequent qPCR applications. To date, we have applied this approach to test 213,279 samples within 18 months. Thirty patients were identified and confirmed, implying an incidence of 1:7109 for the homozygous deletion. Using our cleanup method, a rapid workflow could be established to prepare nucleic acids from dried blood spot cards. Targeting the exon 7 deletion, no invalid, false-positive, or false-negative results were reported to date. This allows timely identification of the disease and grants access to the recently introduced treatment options, in most cases before the onset of symptoms. Carriers are not identified, thus, there are no concerns of whether to report them.

Background The introduction of newborn screening (NBS) for spinal muscular atrophy (SMA) has increased the early diagnosis of 5q-associated SMA in presymptomatic and symptomatic preterm infants. National and international recommendations for treating preterms and newborns < 38 weeks of gestational age are unavailable. Our retrospective multicentre study aimed to evaluate the postnatal clinical course of preterm infants with 5q-associated SMA diagnosed since the implementation of NBS in Germany in 2021 and to summarize the German experience regarding the decision-making process for available treatment regimens for preterm infants with ≤ 3 survival of motor neuron 2 ( SMN2 ) copies. Results Twelve preterm infants with 5q-associated SMA and a mean gestational age of 34.0 weeks (range: 26.1–36.8) and birth weight of 2022 g (range: 645–3370) were reported from 8/20 German SMA NBS follow-up centers using a pseudonymized questionnaire. Confirmatory diagnosis, including SMN2 copy number, was completed on average on postnatal day 13. All patients had a biallelic deletion of exon 7 or exons 7 and 8 of the survival of motor neuron 1 ( SMN1 ) gene, with SMN2 copy numbers of two in 10 patients and three in two patients. The neonatal course was complicated by respiratory distress due to prematurity ( n  = 2), sepsis ( n  = 2), and jaundice ( n  = 2). At birth, 11 preterm infants (91.6%) were presymptomatic. However, the neurological status of one patient deteriorated at five weeks of age (postconceptional age of 41.8 weeks) prior to the start of treatment. Disease-modifying treatments were initiated in all patients at a mean postconceptional age of 38.8 weeks, with the majority receiving onasemnogene abeparvovec (83.3%, including 2 patients with prior risdiplam bridge therapy). Notably, consensus among participating experts from German neuromuscular centers resulted in 83.3% of patients receiving disease-modifying treatment at term. Conclusions Premature infants with SMA require interdisciplinary care in close collaboration with the neuromuscular center. SMA NBS facilitates early initiation of disease-modifying therapy, ideally during the presymptomatic phase, which significantly influences the prognosis of the newborn.

PurposeARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder.MethodsWe collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated.ResultsDe novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder.ConclusionWe confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

The aim of this study was to assess the psychosocial burden in parents of children with spinal muscular atrophy (SMA), detected by newborn screening (NBS), for which first pilot projects started in January 2018 in Germany. The survey, performed 1–2 years after children’s diagnosis of SMA via NBS, included 3 parent-related questionnaires to evaluate the psychosocial burden, quality of life (QoL)/satisfaction and work productivity and activity impairment in the families. 42/44 families, detected between January 2018 and February 2020, could be investigated. Interestingly, statistical analysis revealed a significant difference between families with children that received SMN-targeted therapy vs. children with a wait-and-see strategy as to social burden (p = 0.016) and personal strain/worries about the future (p = 0.02). However, the evaluation of QoL showed no significant differences between treated vs. untreated children. Fathers of treated children felt more negative impact regarding their productivities at work (p = 0.005) and more negative effects on daily activities (p = 0.022) than fathers of untreated children. Thus, NBS in SMA has a psychosocial impact on families, not only in terms of diagnosis but especially in terms of treatment, and triggers concerns about the future, emphasizing the need for comprehensive multidisciplinary care. Understanding the parents’ perspective allows genetic counselors and NBS programs to proactively develop a care plan for parents during the challenging time of uncertainty, anxiety, frustration, and fear of the unknown.

Intorduction: Most studies on the progression of childhood-onset multiple sclerosis (MS) involve relatively short follow-up periods, focusing primarily on neurological outcomes and disability progression. The influence of these and other factors on the health-related quality of life is not known. To gain a comprehensive understanding of early-onset MS, it is crucial to evaluate the effects of treatment and the disease on quality of life. Method: This pilot project aimed to evaluate the feasibility of using an online survey tool for long-term follow-up data collection from patients with childhood-onset MS. An anonymized, monocentric, prospective survey was conducted on a convenience cohort of patients treated at a certified centre for neuromuscular diseases in childhood between 2007 and 2019. Results: A total of 27 patients completed the survey. There were no mandatory items, therefore some patients chose not to answer all the questions in the questionnaire. Patients exhibited promising educational achievements, low neurological disease burden, and high resilience. However, anxiety, depression, and pain significantly impacted their perceived health status. Conclusion:This single-centre study has yielded new insights into childhood-onset MS. To enable more accurate comparisons across different centres and countries, it is essential to establish a minimum data set and questionnaire subset for patients with paediatric-onset MS transitioning into adulthood.

Background 5q spinal muscular atrophy (SMA) is a disabling and life-limiting neuromuscular disease. In recent years, novel therapies have shown to improve clinical outcomes. Yet, the absence of reliable biomarkers renders clinical assessment and prognosis of possibly already affected newborns with a positive newborn screening result for SMA imprecise and difficult. Therapeutic decisions and stratification of individualized therapies remain challenging, especially in symptomatic children. The aim of this proof-of-concept and feasibility study was to explore the value of 1 H-nuclear magnetic resonance (NMR)-based metabolic profiling in identifying non-invasive diagnostic and prognostic urinary fingerprints in children and adolescents with SMA. Results Urine samples were collected from 29 treatment-naïve SMA patients (5 pre-symptomatic, 9 SMA 1, 8 SMA 2, 7 SMA 3), 18 patients with Duchenne muscular dystrophy (DMD) and 444 healthy controls. Using machine-learning algorithms, we propose a set of prediction models built on urinary fingerprints that showed potential diagnostic value in discriminating SMA patients from controls and DMD, as well as predictive properties in separating between SMA types, allowing predictions about phenotypic severity. Interestingly, preliminary results of the prediction models suggest additional value in determining biochemical onset of disease in pre-symptomatic infants with SMA identified by genetic newborn screening and furthermore as potential therapeutic monitoring tool. Conclusions This study provides preliminary evidence for the use of 1 H-NMR-based urinary metabolic profiling as diagnostic and prognostic biomarker in spinal muscular atrophy.

Background: The Balance Error Scoring System (BESS) is a commonly used method for clinically evaluating balance after traumatic brain injury. The utilization of force plates, characterized by their cost-effectiveness and portability, facilitates the integration of instrumentation into the BESS protocol. Despite the enhanced precision associated with instrumented measures, there remains a need to determine the clinical significance and feasibility of such measures within pediatric cohorts. Objective: To report a comprehensive set of posturographic measures obtained during instrumented BESS and to examine the concurrent validity, reliability, and feasibility of instrumented BESS in the pediatric point of care setting. Methods: Thirty-seven participants (18 female; aged 13.32 ± 3.31 years) performed BESS while standing on a force plate to simultaneously compute stabilometric measures (instrumented BESS). Ellipse area (EA), path length (PL), and sway velocity (VM) were obtained for each of the six BESS positions and compared with the respective BESS scores. Additionally, the effects of sex and age were explored. A second BESS repetition was performed to evaluate the test–retest reliability. Feedback questionnaires were handed out after testing to evaluate the feasibility of the proposed protocol. Results: The BESS total score was 20.81 ± 6.28. While there was no statistically significant age or sex dependency in the BESS results, instrumented posturography demonstrated an age dependency in EA, VM, and PL. The one-leg stance on a soft surface resulted in the highest BESS score (8.38 ± 1.76), EA (218.78 cm2 ± 168.65), PL (4386.91 mm ± 1859.00), and VM (21.93 mm/s ± 9.29). The Spearman’s coefficient displayed moderate to high correlations between the EA (rs = 0.429–0.770, p = 0.001–0.009), PL (rs = 0.451–0.809, p = 0.001–0.006), and VM (rs = 0.451–0.809, p = 0.001–0.006) when compared with the BESS scores for all testing positions, except for the one-leg stance on a soft surface. The BESS total score significantly correlated during the first and second repetition (rs = 0.734, p ≤ 0.001), as did errors during the different testing positions (rs = 0.489–0.799, p ≤ 0.001–0.002), except during the two-legged stance on a soft surface. VM and PL correlated significantly in all testing positions (rs = 0.465–0.675, p ≤ 0.001–0.004; (rs = 0.465–0.675, p ≤ 0.001–0.004), as did EA for all positions except for the two-legged stance on a soft surface (rs = 0.392–0.581, p ≤ 0.001–0.016). A total of 92% of participants stated that the instructions for the testing procedure were very well-explained, while 78% of participants enjoyed the balance testing, and 61% of participants could not decide whether the testing was easy or hard to perform. Conclusions: Instrumented posturography may complement clinical assessment in investigating postural control in children and adolescents. While the BESS score only allows for the consideration of a total score approximating postural control, instrumented posturography offers several parameters representing the responsiveness and magnitude of body sway as well as a more differentiated analysis of movement trajectory. Concise instrumented posturography protocols should be developed to augment neuropediatric assessments in cases where a deficiency in postural control is suspected, potentially stemming from disruptions in the processing of visual, proprioceptive, and/or vestibular information.

Purpose Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Methods Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. Results We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3 , DYSF , ANO5 , DMD , RYR1 , TTN , COL6A2 , and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1 , were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Conclusion Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.