Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.

Background Nusinersen is an intrathecally administered antisense oligonucleotide (ASO) that improves motor function in patients with spinal muscular atrophy (SMA). In addition to efficacy, the safety of a therapy is the decisive factor for the success of the treatment. For some ASOs, various organ toxicities have been described, such as thrombocytopenia, renal and liver impairment, or coagulation abnormalities. However, systematic data on laboratory parameters under treatment with nusinersen are mainly available from studies in infants and children. Therefore, our aim was to assess the safety of nusinersen therapy in adult SMA patients. Methods Laboratory data from 404 nusinersen injections performed in 50 adult patients with SMA type 2 and type 3 were retrospectively analyzed. Results The total observation period was 76.9 patient-years, and patients received up to 12 injections. Our data provides no new safety concerns. In cerebrospinal fluid (CSF), the mean white blood cell count and lactate remained stable over time. Total CSF protein increased by 2.9 mg/dL. No change in mean platelet count was observed under therapy. Only one patient showed sporadic mild thrombocytopenia. Coagulation parameters and inflammatory markers were stable. The mean creatinine level decreased by 0.09 mg/dL. Analysis of mean liver enzyme levels revealed no relevant changes during treatment. Conclusion Our data demonstrate a favorable safety profile of nusinersen therapy in adult SMA patients under longer-term “real-world” conditions. In particular, we found no evidence of clinically relevant platelet declines, coagulopathies, or renal or hepatic organ toxicities, which are common concerns with the use of ASOs.

Background: Myasthenia gravis (MG) is an autoimmune neuromuscular disease, with gut microbiota considered to be a pathogenetic factor. Previous pilot studies have found differences in the gut microbiota of patients with MG and healthy individuals. To determine whether gut microbiota has a pathogenetic role in MG, we compared the gut microbiota of patients with MG with that of patients with non-inflammatory and inflammatory neurological disorders of the peripheral nervous system (primary endpoint) and healthy volunteers (secondary endpoint). Methods: Faecal samples were collected from patients with MG ( n = 41), non-inflammatory neurological disorder (NIND, n = 18), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 6) and healthy volunteers ( n = 12). DNA was isolated from these samples, and the variable regions of the 16S rRNA gene were sequenced and statistically analysed. Results: No differences were found in alpha- and beta-diversity indices computed between the MG, NIND and CIDP groups, indicating an unaltered bacterial diversity and structure of the microbial community. However, the alpha-diversity indices, namely Shannon, Chao 1 and abundance-based coverage estimators, were significantly reduced between the MG group and healthy volunteers. Deltaproteobacteria and Faecalibacterium were abundant within the faecal microbiota of patients with MG compared with controls with non-inflammatory diseases. Conclusion: Although the overall diversity and structure of the gut microbiota did not differ between the MG, NIND and CIDP groups, the significant difference in the abundance of Deltaproteobacteria and Faecalibacterium supports the possible role of gut microbiota as a contributor to pathogenesis of MG. Further studies are needed to confirm these findings and to develop possible treatment strategies.

Objective To study the impact of time to diagnosis on cardiac Mayo stages, treatment outcome, and overall survival. Methods We retrospectively analyzed 77 consecutive patients diagnosed between 2015 and 2020 with AL amyloidosis and cardiac involvement. Medical history was recorded in standardized form with the help of a questionnaire. Results Time from onset of symptoms of cardiac failure to diagnosis was correlated with the severity of cardiac involvement in modified Mayo 2004 and revised Mayo 2012 staging systems (rs = 0.30, 95% CI: 0.07‐0.50, P = .007 and rs = 0.25, 95% CI: 0.01‐0.45, P = .03). Patients with advanced Mayo 2004 stages received reduced‐intensity regimens and had a lower probability to achieve adequate hematologic‐ and cardiac response after first‐line treatment than patients with early stages (rs = 0.28, 95% CI: 0.04‐0.48, P = .01 and rs = 0.72, 95% CI: 0.55‐0.82, P < .0001) and poorer overall survival (P = .0004). Compared with patients diagnosed within the first year, patients diagnosed after 13‐18 or ≥19 months from first symptoms had a 3‐ to 5 times higher risk of dying. Our data indicate that there is a 12‐month window within which the diagnosis of AL amyloidosis needs to be established to avoid early deterioration and death. Conclusions Sensitizing physicians and raising awareness for the disease are crucial for timely diagnosis and may improve the outcome of the disease.

The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.