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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.

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 a pilot project 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 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.

Background: Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. Since motor neuron injury is mostly not reversible, early diagnosis and treatment are essential to prevent major disability. The aim of this study was to assess the impact of newborn screening (NBS) for SMA on clinical outcome. Methods: The pilot project started in January 2018 in Germany and is still ongoing. Genetic screening via PCR of the SMN1 gene from dried blood spots was implemented in the routine NBS structure. Follow-up included neurophysiological examinations, CHOP INTEND and HINE-2.Results: Among 297,163 screened children, 43 cases of SMA were identified, resulting in an incidence of 1:6910. In 21 patients with ≤3 SMN2 copies, treatment with nusinersen according to the FDA/EMA guidelines was started age 14-39 days. Median follow-up period, regarding motor milestones was 12.3 months (range 1.5-26 months). All pre-symptomatically treated patients remained asymptomatic as far as age at last examination already allows this statement. 41% of patients with 2 SMN2 copies had already early, mostly subtle signs of disease. These patients reached motor milestones, however with a certain delay. None developed respiratory symptoms. Two untreated patients with 2 SMN2 copies died. Four untreated patients with 3 SMN2 copies, one of whom was initially diagnosed with 4 SMN2 copies by a different method, developed proximal weakness at ages 6-11 months. Two siblings of babies with 4 SMN2 copies were identified with a missed diagnosis of SMA 3. Conclusion: Identification of newborns with infantile SMA improves neurodevelopmental outcome enormously. It should be introduced in all countries where therapy is available. Detection of SMA via NBS did not increase the incidence compared to the known incidence rate. Early treatment of patients with 4 SMN2 copies should be considered.