{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T10:04:18Z","timestamp":1784282658092,"version":"3.55.0"},"reference-count":26,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T00:00:00Z","timestamp":1755907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T00:00:00Z","timestamp":1755907200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neuromuscular Diseases"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder that progressively affects motor neurons. Gain-of-function mutations in serine palmitoyltransferase (SPT) genes, notably\n                      <jats:italic toggle=\"yes\">SPTLC1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">SPTLC2<\/jats:italic>\n                      , have been linked to juvenile ALS. Here, we describe two childhood-onset ALS cases with distinct SPTLC2 mutations, providing new insights into sphingolipid dysregulation and its role in ALS pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Material and methods:<\/jats:title>\n                    <jats:p>\n                      Two Chinese patients with early-onset ALS, both carrying\n                      <jats:italic toggle=\"yes\">SPTLC2<\/jats:italic>\n                      mutations, were recruited from Beijing Children's Hospital. We conducted whole-exome sequencing (WES) to identify genetic variants, followed by Sanger sequencing for validation. Sphingolipid profiles were analyzed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS\/MS). Clinical evaluations included neurological assessments, brain MRI and electromyography. Additionally, mutant cell lines were established to assess the functional effects of the specific mutations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Patient 1, a 6-year-old male, exhibited a novel heterozygous de-novo\n                      <jats:italic toggle=\"yes\">SPTLC2<\/jats:italic>\n                      variant (c.197T\u2009&gt;\u2009G, p.T66R). Patient 2, a 7-year-old female, had a recurrent heterozygous de-novo SPTLC2 variant (c.778G\u2009&gt;\u2009A, p.E260K). Both patients showed elevated levels of specific sphingolipids compared to controls, with distinct profiles between the\n                      <jats:italic toggle=\"yes\">SPTLC2<\/jats:italic>\n                      -ALS and\n                      <jats:italic toggle=\"yes\">SPTLC1<\/jats:italic>\n                      -hereditary sensory and autonomic neuropathy type 1 (HSAN1) cases. The novel p.T66R mutation was predicted to alter protein interactions within the SPT complex, potentially impairing sphingolipid homeostasis. Functional studies further revealed that the p.T66R variant reduces the inhibitory regulation of SPT by ORMDL proteins, leading to unrestrained SPT activity and excess sphingolipid production.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Our findings identify a novel\n                      <jats:italic toggle=\"yes\">SPTLC2<\/jats:italic>\n                      variant linked to childhood-onset ALS and reveal altered sphingolipid profiles associated with different genetic mutations. These results underscore the importance of sphingolipid metabolism in ALS and suggest potential avenues for targeted therapeutic interventions. Further research is needed to explore treatment options aimed at modulating sphingolipid levels and correcting genetic defects, as well as investigating potential biomarkers for early diagnosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/22143602251370586","type":"journal-article","created":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T01:47:15Z","timestamp":1756000035000},"page":"655-664","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Characterization of novel and recurrent\n                    <i>SPTLC2<\/i>\n                    variants in childhood-onset amyotrophic lateral sclerosis: Insights into sphingolipid dysregulation"],"prefix":"10.1177","volume":"13","author":[{"given":"Xiaona","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China"},{"name":"Laboratory for Clinical Medicine, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9122-1006","authenticated-orcid":false,"given":"Kenneth","family":"Gable","sequence":"additional","affiliation":[{"name":"Uniformed Services University of the Health Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sita D.","family":"Gupta","sequence":"additional","affiliation":[{"name":"Uniformed Services University of the Health Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"KaiLi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Anhui Provincial Children's Hospital, Hefei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingbing","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Junfeix Technology Co., Ltd., Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten G","family":"B\u00f6nnemann","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9187-8705","authenticated-orcid":false,"given":"Teresa M","family":"Dunn","sequence":"additional","affiliation":[{"name":"Uniformed Services University of the Health Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4138-2992","authenticated-orcid":false,"given":"Hui","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China"},{"name":"Laboratory for Clinical Medicine, Capital Medical University, 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