{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:28:43Z","timestamp":1789907323236,"version":"4.0.1"},"reference-count":24,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013465","name":"French Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["22431"],"award-info":[{"award-number":["22431"]}],"id":[{"id":"10.13039\/100013465","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2022,12]]},"abstract":"Abstract<\/jats:title>\n \n Aims<\/jats:title>\n \n SPTLC1<\/jats:italic>\n \u2010related disorder is a late onset sensory\u2010autonomic neuropathy associated with perturbed sphingolipid homeostasis which can be improved by supplementation with the serine palmitoyl\u2010CoA transferase (SPT) substrate,\n l<\/jats:sc>\n \u2010serine. Recently, a juvenile form of motor neuron disease has been linked to\n SPTLC1<\/jats:italic>\n variants. Variants affecting the p.S331 residue of\n SPTLC1<\/jats:italic>\n cause a distinct phenotype, whose pathogenic basis has not been established. This study aims to define the neuropathological and biochemical consequences of the\n SPTLC1<\/jats:italic>\n p.S331 variant, and test response to\n l<\/jats:sc>\n \u2010serine in this specific genotype.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We report clinical and neurophysiological characterisation of two unrelated children carrying distinct p.S331\n SPTLC1<\/jats:italic>\n variants. The neuropathology was investigated by analysis of sural nerve and skin innervation. To clarify the biochemical consequences of the p.S331 variant, we performed sphingolipidomic profiling of serum and skin fibroblasts. We also tested the effect of\n l<\/jats:sc>\n \u2010serine supplementation in skin fibroblasts of patients with p.S331 mutations.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In both patients, we recognised an early onset phenotype with prevalent progressive motor neuron disease. Neuropathology showed severe damage to the sensory and autonomic systems. Sphingolipidomic analysis showed the coexistence of neurotoxic deoxy\u2010sphingolipids with an excess of canonical products of the SPT enzyme.\n l<\/jats:sc>\n \u2010serine supplementation in patient fibroblasts reduced production of toxic 1\u2010deoxysphingolipids but further increased the overproduction of sphingolipids.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our findings suggest that p.S331\n SPTLC1<\/jats:italic>\n variants lead to an overlap phenotype combining features of sensory and motor neuropathies, thus proposing a continuum in the spectrum of\n SPTLC1<\/jats:italic>\n \u2010related disorders.\n l<\/jats:sc>\n \u2010serine supplementation in these patients may be detrimental.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/nan.12842","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T07:03:33Z","timestamp":1659078213000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The\n SPTLC1<\/i>\n p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment"],"prefix":"10.1111","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9027-343X","authenticated-orcid":false,"given":"Chiara","family":"Fiorillo","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI) University of Genoa Genoa Italy"},{"name":"Unit of Paediatric Neurology and Neuromuscular Disorders IRCCS Institute \u201cG. Gaslini\u201d Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Capodivento","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI) University of Genoa Genoa Italy"},{"name":"UO Clinica Neurologica, IRCCS Ospedale Policlinico San Martino Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Geroldi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI) University of Genoa Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Tozza","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Reproductive and Odontostomatological Science University of Naples \u201cFederico II\u201d Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Moroni","sequence":"additional","affiliation":[{"name":"Child Neurology Unit, Department of Pediatric Neuroscience Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payam","family":"Mohassel","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Cataldi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI) University of Genoa Genoa Italy"},{"name":"Paediatric Neuropsychiatric Unit IRCCS Institute \u201cG. Gaslini\u201d Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Campana","sequence":"additional","affiliation":[{"name":"Paediatric Neuropsychiatric Unit IRCCS Institute \u201cG. Gaslini\u201d Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Morando","sequence":"additional","affiliation":[{"name":"Center of Translational and Experimental Myology IRCCS Institute \u201cG. Gaslini\u201d Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Panicucci","sequence":"additional","affiliation":[{"name":"Center of Translational and Experimental Myology IRCCS Institute \u201cG. Gaslini\u201d Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Pedemonte","sequence":"additional","affiliation":[{"name":"Unit of Paediatric Neurology and Neuromuscular Disorders IRCCS Institute \u201cG. 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Gaslini\u201d Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doriana","family":"Debellis","sequence":"additional","affiliation":[{"name":"Electron Microscopy Facility Istituto Italiano di Tecnologia Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Magri","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Prada","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Iowa Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Bellone","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI) University of Genoa Genoa Italy"},{"name":"Clinical Genetics Unit Ospedale Policlinico IRCCS San Martino Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Salpietro","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI) University of Genoa Genoa Italy"},{"name":"Unit of Paediatric Neurology and Neuromuscular Disorders IRCCS Institute \u201cG. Gaslini\u201d Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Donkervoort","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Gable","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Uniformed Services University of Health Sciences Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sita D.","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Uniformed Services University of Health Sciences Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa M.","family":"Dunn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Uniformed Services University of Health Sciences Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten G.","family":"B\u00f6nnemann","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Taroni","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Bruno","sequence":"additional","affiliation":[{"name":"Center of Translational and Experimental Myology IRCCS Institute \u201cG. 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