# New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1
## 5 Conclusions  
* First manifestation of proximal muscle weakness should be considered in the clinical diagnosis of SPTLC1-related juvenile ALS
* P.(A20S)-SPTLC1-related ALS leads to muscle denervation accompanied by fiber-type grouping, subsarcolemmal accumulation of mitochondria in type I fibers, and mild inflammation
* Aggregates of proteins or lipids were not identified in patient-derived quadriceps muscle by CARS microscopy
* Proteomic profiling on p.(A20S)-SPTLC1-mutant lymphoblastoid cells unraveled a variety of proteins with potential impact on clinical manifestation of symptoms of SPTLC1-related phenotypical spectrum
* Further functional in vitro studies are needed to systematically address the impact of these proteins in the pathogenesis of increased SPTLC1 function
* The molecular genetic SPTLC1 variant identified in our patient is associated with altered splicing and decrease of protein level
* Increased expression of phosphor-FAK1 in patient-derived quadriceps muscle might contribute to fibrotic degeneration  
**Supplementary Materials:** The following supporting information can be downloaded at: [[https://www.mdpi.com/article/10.3390/genes13050893/s1](https://www.mdpi.com/article/10.3390/genes13050893/s1)]([https://www.mdpi.com/article/10.3390/genes13050893/s1](https://www.mdpi.com/article/10.3390/genes13050893/s1)): Figure S1: GTEx-based in silico analysis of tissue expression of SPTLC1, SPTLC2 and SPTLC3; Figure S2: Staining of juvenile non-disease controls; Figure S3: CARS images of the p.(A20S)-SPTLC1 patient derived quadriceps muscle. Table S1: Proteins significantly dysregulated in immortalized lymphoblastoid cells derived from a juvenile SPTLC1-related ALS patient.  
**Author Contributions:** Conceptualization H.K. and A.R.; clinical investigation and data curation, H.K., F.K., A.G., A.C., P.M., C.N. and A.R.; myopathological investigations, W.S., C.P. and U.S.-S.; C.P., C.N. and A.H. provided the protein clearance data; writing--original draft preparation, H.K. and A.R.; writing--review and editing, H.K., F.K., A.H., A.C., A.G., P.M., C.N., W.S., U.S.-S., C.P. and A.R. All authors have read and agreed to the published version of the manuscript.  
**Funding:** Parts of this study were financed in the framework of the NME-GPS project by the European Regional Development Fund (ERDF). We acknowledge support by the Open Access Publication Fund of the University of Duisburg-Essen. This work was supported by a grant from the French Muscular dystrophy Association (AFM-Telethon; #21644; grant to A.R.).  
**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by local Ethics Committee (19-9011-BO). The approval date was 30 April 2020.  
**Informed Consent Statement:** For all diagnostic steps written informed consent has been obtained from the patient and the parents to publish this paper.  
**Data Availability Statement:** The data that support the findings of this study are available from the corresponding author upon reasonable request.  
**Acknowledgments:** We wish to thank the patient and his family for their willingness to participate in this study. Two authors of this publication are members of European Reference Network for Neuromuscular Diseases.  
**Conflicts of Interest:** The authors declare no conflict of interest.