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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: Prompt treatment after genetic NBS for SMA substantially improves outcome in infantile SMA. However, deficiency of SMN-protein can cause damage of motor neurons even prior to birth., Objective: To describe the neurological status at the time of NBS and the reversibility of neurological deficits in a cohort of patients with only two copies of the SMN2 gene., Methods: We present motor, respiratory, and bulbar outcomes of 21 SMA patients identified in newborn screening projects in Germany. Inclusion criteria was initiation of SMN targeted medication at less than 6 weeks of age and a minimum age of 9 months at last examination., Results: Twelve patients (57%) developed completely normally, reaching motor milestones in time and having no bulbar or respiratory problems. Three children (14.5%) caught up after initial delay in motor development. Six patients (29%) developed proximal weakness despite early treatment: Three of them (14.5%) achieved the ability to walk with assistance and the other three (14.5%) showed an SMA type 2 phenotype at the age of 16-30 months. One patient (4.8%) had respiratory problems. Three children (14.5%) had mild chewing problems and two individuals (9.5%) needed feeding via gastrotube. Initial CHOP-INTEND values below 30 could be indicative of a less favourable outcome, whereas values above 50 could indicate a good outcome, however in-depth statistic due to the small case number is not predictive., Conclusion: More than 70% of SMA patients with two SMN2 copies can achieve independent ambulation with immediate initiation of therapy. However, caregivers and paediatricians must be informed about the possibility of less favourable outcomes when discussing therapeutic strategies.

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.

In spite of the improvements in care and the emergence of disease-modifying treatments, Duchenne muscular dystrophy (DMD) remains a life-limiting disease of adolescence and (young) adulthood. Palliative care approaches and principles should be integrated from the point of diagnosis and implemented throughout the lifespan. A nationwide cross-sectional survey based on a mixed-method-design of qualitative and quantitative research approaches evaluated the structural implementation and perception of palliative care for DMD in Germany. Data analyses revealed that palliative care was predominantly provided at the primary care level by pediatricians, general practitioners and specialized multi-professional outpatient structures. The majority of patients did not utilize the scopes of specialized palliative structures. Simultaneously, insufficiently treated complex symptoms, emergent and elective hospitalizations and barriers in transitioning into adult care presented a considerable burden. A collaborative integrated model with a close cooperation of patients, families and care providers is proposed involving task areas and interfaces complementing primary and specialized palliative care (1) management of complex symptoms, (2) crisis support, (3) intermittent relief of the strain for caregivers, (4) coordination of care, (5) advance care planning and (6) end-of-life care. Specialized palliative care should be used as an "add-on" approach in time of need rather than as a prognosis or disease stage., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to research, authorship, and/or publication of this article and received no financial support for the research, authorship, and/or publication of this article. This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit-sectors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Spinal muscular atrophy and muscular dystrophy Duchenne belong to the group of rare neuromuscular diseases manifesting in early childhood. Therapeutic options for some of these rare monogenic diseases have changed significantly in recent years. Molecular therapies such as direct gene transfer or alternative processing of the disease-specific gene play an important role in this transformation.In particular, the course of 5q-associated spinal muscle atrophy has changed significantly due to the availability of such causal therapies, while the results of ongoing studies are still pending for most muscle diseases. In the area of neuromuscular diseases, an achievable therapeutic goal is to slow the progression, but not complete healing. Currently, only limited data are available. In particular, the long-term effectiveness and the possible risks are still unknown. Therefore, these therapies should be used under strictly monitored conditions.

Background: 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., Objective: 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., Conclusion: 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.

Although the value of newborn screening (NBS) for early detection and treatment opportunity in SMA patients is generally accepted, there is still an ongoing discussion about the best strategy in children with 4 and more copies of the SMN2 gene. This gene is known to be the most important but not the only disease modifier.In our SMA-NBS pilot project in Germany comprising 278,970 infants screened between January 2018 and November 2019 were 38 positive cases with a homozygous SMN1 deletion. 40% of them had 4 or more SMN2 copies. The incidence for homozygous SMN1 deletion was 1 : 7350, which is within the known range of SMA incidence in Germany.Of the 15 SMA children with 4 SMN2 copies, one child developed physical signs of SMA by the age of 8 months. Reanalysis of the SMN2 copy number by a different test method revealed 3 copies. Two children had affected siblings with SMA Type III, who were diagnosed only after detection of the index patient in the NBS. One had a positive family history with an affected aunt (onset of disease at the age of 3 years). Three families were lost to medical follow up; two because of socioeconomic reasons and one to avoid the psychological stress associated with the appointments.Decisions on how to handle patients with 4 SMN2 copies are discussed in the light of the experience gathered from our NBS pilot SMA program.

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.

Background: Survival and quality of life for patients affected by spinal muscular atrophy (SMA) are thought to have improved over the last decade due to changes in care. In addition, targeted treatments for SMA have been developed based on a better understanding of the molecular pathology. In 2016 and 2017, nusinersen was the first drug to be approved for treatment of all types of SMA in the United States and in Europe based on well-controlled clinical trials in a small subgroup of pediatric SMA patients. Systems are required to monitor treated and untreated SMA patients in a real-life environment to optimize treatment and care, and to provide outcome data to regulators, payers, and the SMA community., Methods: Within SMArtCARE, we conduct a prospective, multicenter non-randomized registration and outcome study. SMArtCARE collects longitudinal data on all available SMA patients independent of their actual treatment regime as disease-specific SMA registry. For this purpose, we provide an online platform for SMA patients seen by health-care providers in Germany, Austria and Switzerland. All data are collected during routine patient visits. Items for data collection are aligned with the international consensus for SMA registries. Data analysis is carried out independent of commercial partners., Conclusion: A prospective monitoring of all SMA patients will lead to a better understanding of the natural history of SMA and the influence of drug treatment. This is crucial to improve the care of SMA patients. Further, we will establish a network for neuromuscular centers to share experience with SMA patients and to promote research projects on SMA., Trial Registration: German Clinical Trials Register ("Deutsches Register klinischer Studien") DRKS00012699. Registered 09 August 2018. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00012699 .