The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment
| العنوان: | The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment |
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| المؤلفون: | Chiara Fiorillo, Giovanna Capodivento, Alessandro Geroldi, Stefano Tozza, Isabella Moroni, Payam Mohassel, Matteo Cataldi, Chiara Campana, Simone Morando, Chiara Panicucci, Marina Pedemonte, Noemi Brolatti, Sabrina Siliquini, Monica Traverso, Serena Baratto, Doriana Debellis, Stefania Magri, Valeria Prada, Emilia Bellone, Vincenzo Salpietro, Sandra Donkervoort, Kenneth Gable, Sita D. Gupta, Teresa M. Dunn, Carsten G. Bönnemann, Franco Taroni, Claudio Bruno, Angelo Schenone, Paola Mandich, Lucilla Nobbio, Maria Nolano |
| المصدر: | Neuropathology and Applied Neurobiology. 48 |
| بيانات النشر: | Wiley, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | l-serine, Sphingolipids, Histology, SPTLC1, Serine C-Palmitoyltransferase, Peripheral Nervous System Diseases, Pathology and Forensic Medicine, HSAN, Neurology, Physiology (medical), Mutation, Serine, Humans, S331, motor neuron, sphingolipids, Neurology (clinical), Hereditary Sensory and Autonomic Neuropathies, Motor Neuron Disease |
| الوصف: | SPTLC1-related disorder is a late onset sensory-autonomic neuropathy associated with perturbed sphingolipid homeostasis which can be improved by supplementation with the serine palmitoyl-CoA transferase (SPT) substrate, l-serine. Recently, a juvenile form of motor neuron disease has been linked to SPTLC1 variants. Variants affecting the p.S331 residue of SPTLC1 cause a distinct phenotype, whose pathogenic basis has not been established. This study aims to define the neuropathological and biochemical consequences of the SPTLC1 p.S331 variant, and test response to l-serine in this specific genotype.We report clinical and neurophysiological characterisation of two unrelated children carrying distinct p.S331 SPTLC1 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 l-serine supplementation in skin fibroblasts of patients with p.S331 mutations.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-sphingolipids with an excess of canonical products of the SPT enzyme. l-serine supplementation in patient fibroblasts reduced production of toxic 1-deoxysphingolipids but further increased the overproduction of sphingolipids.Our findings suggest that p.S331 SPTLC1 variants lead to an overlap phenotype combining features of sensory and motor neuropathies, thus proposing a continuum in the spectrum of SPTLC1-related disorders. l-serine supplementation in these patients may be detrimental. |
| تدمد: | 1365-2990 0305-1846 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0c0adef0de11c681ceab6cde003990b7Test https://doi.org/10.1111/nan.12842Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0c0adef0de11c681ceab6cde003990b7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13652990 03051846 |
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