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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.

Additional file 1: Age distribution of patients, volume size, and erythrocyte and leucocyte numbers of CSF and serum samples. Fig. S2 RNA content of 100 KDa column concentrates and filtrates. Fig. S3 Age- and sex-distribution of serum samples. Fig. S4 RNA content of CSF samples in dependence of the storage temperature and RNAse treatment. Fig. S5 RNA content of CSF and serum samples. Fig. S6 Gel analysis of all RNA samples. Fig. S7 Electropherogramms of the RNA samples from serum. Fig. S8 Electropherogramms of the RNA samples from CSF. Fig. S9 Comparison of RNA content and electropherogramms of the RNA samples from CSF and blood-contaminated CSF. Fig. S10 Venn diagrams and UpSet plots form small and long RNA. Fig. S11 Heat maps of small RNA read counts not shown in figure 4. Fig. S12 GO Slim summaries of miR targets from whole CSF, CSF-EV, whole serum, and serum EV. Fig. S13 Heat maps of read counts encompassing all possible comparisons of down- and up-regulated long RNA transcripts. Fig. S14 Venn diagrams of significantly expressed small RNA transcripts, expressed miR, and target transcripts of expressed miR. Fig. S15 Distribution of small RNAs in body fluids and their respective EV.

Additional file 2: Table S2. Correlation between CSF CHIT1 level and age/disease severity scores in nusinersen-naïve patients with SMA. CHIT1 Chitotriosidase 1 concentration, CSF cerebrospinal fluid, HFMSE Hammersmith functional. Motor Scale Expanded; RULM Revised upper limb module, ALSFRS-R revised ALS functional. Rating Scale; n.s. not significant, ρ partial rank correlation coefficient corrected for patients’ height.

Additional file 1: Table S1. Subgroup characteristics. IQR interquartile range.

Background: Modern genetics have in many ways revolutionized clinical routine and have, for instance, shown that formerly distinct disease entities relate to common pathogenic mutations. One such example is the connection between dementia and amyotrophic lateral sclerosis (ALS) in a continuous disease spectrum affirmed by the discovery of shared mutations. Case Report: We describe a new variant in the FIG$_4$ gene in a patient with slowly progressing frontotemporal dementia (FTD) and probable primary lateral sclerosis (PLS). The patient initially showed depressive symptoms and global cognitive deficits. Severe difficulties with language and hallucinations became clearer as the disease progressed. Nuclear medicine imaging and cerebrospinal fluid (CSF) biomarkers were not specific for defined categories of dementia, but neuropsychological testing and clinical features finally led to an allocation of the syndrome to the non-fluent variant of primary progressive aphasia (nfv PPA). Because of increasing limb weakness and bulbar symptoms, motoneuron disease in the form of PLS was diagnosed, strongly supported by elevated CSF neurofilament and electrophysiologic assessments. The detected variant in the FIG$_4$ gene is described as pathogenic or likely pathogenic in common databases and reported once in the literature. While the phenotype of our patient fits the description of FIG$_4$-associated disease in literature, we consider the present variant as VUS in this case. Conclusion: We describe a variant in the FIG$_4$ gene in a patient with slowly progressing FTD and PLS. Mutations in the FIG$_4$ gene have been associated with ALS and PLS; however, this exact mutation was not reported in ALS or PLS patients before. The case illustrates generic diagnostic challenges in patients presenting with genetic variants that offer an explanation for otherwise uncommon symptom combinations but yet are of unknown significance. Open-Access-Publikationsfonds 2020 peerReviewed

ObjectivesRecent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.MethodsHere we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.ConclusionsWe here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.