{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T23:38:30Z","timestamp":1774568310725,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T00:00:00Z","timestamp":1740355200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministero dell\u2019Universit\u00e0 e della Ricerca","award":["CN00000041"],"award-info":[{"award-number":["CN00000041"]}]},{"name":"Italian Ministero dell\u2019Universit\u00e0 e della Ricerca","award":["RF19.12"],"award-info":[{"award-number":["RF19.12"]}]},{"name":"Italian Ministero dell\u2019Universit\u00e0 e della Ricerca","award":["DSCH_BASE19_ORLACCHIO"],"award-info":[{"award-number":["DSCH_BASE19_ORLACCHIO"]}]},{"name":"Italian Ministero dell\u2019Universit\u00e0 e della Ricerca","award":["RICERCABASE_2020_ORLACCHIO"],"award-info":[{"award-number":["RICERCABASE_2020_ORLACCHIO"]}]},{"name":"Italian Ministero dell\u2019Universit\u00e0 e della Ricerca","award":["RICERCA_ATENEO_ALIMENTAZIONE"],"award-info":[{"award-number":["RICERCA_ATENEO_ALIMENTAZIONE"]}]},{"name":"Italian Ministero della Salute","award":["CN00000041"],"award-info":[{"award-number":["CN00000041"]}]},{"name":"Italian Ministero della Salute","award":["RF19.12"],"award-info":[{"award-number":["RF19.12"]}]},{"name":"Italian Ministero della Salute","award":["DSCH_BASE19_ORLACCHIO"],"award-info":[{"award-number":["DSCH_BASE19_ORLACCHIO"]}]},{"name":"Italian Ministero della Salute","award":["RICERCABASE_2020_ORLACCHIO"],"award-info":[{"award-number":["RICERCABASE_2020_ORLACCHIO"]}]},{"name":"Italian Ministero della Salute","award":["RICERCA_ATENEO_ALIMENTAZIONE"],"award-info":[{"award-number":["RICERCA_ATENEO_ALIMENTAZIONE"]}]},{"name":"Dipartimento di Medicina e Chirurgia of the Universit\u00e0 di Perugia","award":["CN00000041"],"award-info":[{"award-number":["CN00000041"]}]},{"name":"Dipartimento di Medicina e Chirurgia of the Universit\u00e0 di Perugia","award":["RF19.12"],"award-info":[{"award-number":["RF19.12"]}]},{"name":"Dipartimento di Medicina e Chirurgia of the Universit\u00e0 di Perugia","award":["DSCH_BASE19_ORLACCHIO"],"award-info":[{"award-number":["DSCH_BASE19_ORLACCHIO"]}]},{"name":"Dipartimento di Medicina e Chirurgia of the Universit\u00e0 di Perugia","award":["RICERCABASE_2020_ORLACCHIO"],"award-info":[{"award-number":["RICERCABASE_2020_ORLACCHIO"]}]},{"name":"Dipartimento di Medicina e Chirurgia of the Universit\u00e0 di Perugia","award":["RICERCA_ATENEO_ALIMENTAZIONE"],"award-info":[{"award-number":["RICERCA_ATENEO_ALIMENTAZIONE"]}]},{"name":"Universit\u00e0 di Perugia","award":["CN00000041"],"award-info":[{"award-number":["CN00000041"]}]},{"name":"Universit\u00e0 di Perugia","award":["RF19.12"],"award-info":[{"award-number":["RF19.12"]}]},{"name":"Universit\u00e0 di Perugia","award":["DSCH_BASE19_ORLACCHIO"],"award-info":[{"award-number":["DSCH_BASE19_ORLACCHIO"]}]},{"name":"Universit\u00e0 di Perugia","award":["RICERCABASE_2020_ORLACCHIO"],"award-info":[{"award-number":["RICERCABASE_2020_ORLACCHIO"]}]},{"name":"Universit\u00e0 di Perugia","award":["RICERCA_ATENEO_ALIMENTAZIONE"],"award-info":[{"award-number":["RICERCA_ATENEO_ALIMENTAZIONE"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hereditary spastic paraplegias (HSPs) represent a group of neurodegenerative disorders characterized by progressive spasticity and weakness in the lower limbs, with no specific treatment available for patients. At the same time, the molecular diagnosis is complicated by the high genetic heterogeneity of this group of diseases, and it can be challenging due to overlapping clinical features with other conditions. Reliable biomarkers could play a fundamental role in diagnosis, prognosis, and therapeutic interventions for HSPs. For this reason, it is necessary to increase the search for biomarkers that can be used to rapidly classify HSPs, follow the natural history of the conditions, and monitor disease correction therapies. This article provides an overview of the current understanding of biomarkers in HSPs, including genetic, biochemical, and clinical biomarkers and new cell imaging-based approaches. In this manuscript, we aim to provide an overview of the current situation in HSP biomarkers, emphasizing the limitations and the necessity of conducting more studies in this field.<\/jats:p>","DOI":"10.3390\/ijms26051950","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T06:47:17Z","timestamp":1740379637000},"page":"1950","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Biomarkers in Hereditary Spastic Paraplegias"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2338-1139","authenticated-orcid":false,"given":"Emanuele","family":"Panza","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Mediche e Chirurgiche, Universit\u00e0 di Bologna, 40138 Bologna, Italy"},{"name":"Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2602-3281","authenticated-orcid":false,"given":"Antonio","family":"Orlacchio","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Perugia, 06123 Perugia, Italy"},{"name":"Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Meyyazhagan, A., and Orlacchio, A. (2022). Hereditary spastic paraplegia: An update. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031697"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Meyyazhagan, A., Kuchi Bhotla, H., Pappuswamy, M., and Orlacchio, A. (2022). The puzzle of hereditary spastic paraplegia: From epide-miology to treatment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147665"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Evangelisti, C., Ramadan, S., Orlacchio, A., and Panza, E. (2024). Experimental cell models for investigating neurodegenerative diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179747"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.expneurol.2014.06.011","article-title":"Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms","volume":"261","author":"Lombardi","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1080\/14789450.2023.2260952","article-title":"Hereditary spastic paraplegias proteome: Common pathways and pathogenetic mechanisms","volume":"20","author":"Martinello","year":"2023","journal-title":"Expert. Rev. Proteom."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4922","DOI":"10.1007\/s00415-023-11811-1","article-title":"Economic evaluation of Motor Neuron Diseases: A nationwide cross-sectional analysis in Germany","volume":"270","author":"Heinrich","year":"2023","journal-title":"J. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1053\/j.sult.2023.03.016","article-title":"Advanced structural Magnetic Resonance Imaging of the spinal cord: Technical aspects and clinical use","volume":"44","author":"Branco","year":"2023","journal-title":"Semin. Ultrasound CT MR"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"114203","DOI":"10.1016\/j.expneurol.2022.114203","article-title":"Hereditary spastic paraplegia: Genetic heterogeneity and common pathways","volume":"357","author":"Panza","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"20503121231221941","DOI":"10.1177\/20503121231221941","article-title":"Hereditary spastic paraplegia: Novel insights into the pathogenesis and management","volume":"12","author":"Awuah","year":"2023","journal-title":"SAGE Open Med."},{"key":"ref_10","first-page":"147","article-title":"Power of NGS-based tests in HSP diagnosis: Analysis of massively parallel sequencing in clinical practice","volume":"24","author":"Galatolo","year":"2023","journal-title":"Neurogenetics"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Rossi, C., Ramadan, S., Evangelisti, C., Ferrari, S., Accadia, M., Toydemir, R.M., and Panza, E. (2023). Case report: Functional characterization of a novel CHD7 intronic variant in patients with CHARGE syndrome. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1082100"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Benvenuto, M., Cesarini, S., Severi, G., Ambrosini, E., Russo, A., Seri, M., Palumbo, P., Palumbo, O., Castori, M., and Panza, E. (2024). Phenotypic description of a patient with ODLURO syndrome and functional characterization of the pathogenetic role of a synonymous variant c.186G>A in KMT2E gene. Genes, 15.","DOI":"10.3390\/genes15040430"},{"key":"ref_13","first-page":"515","article-title":"Practical recommendations for the clinical evaluation of patients with hereditary ataxia and hereditary spastic paraplegia","volume":"39","year":"2024","journal-title":"Neurologia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1111\/ene.15841","article-title":"Peripheral nerve involvement in hereditary spastic paraplegia characterized by quantitative magnetic resonance neurography","volume":"30","author":"Jacobi","year":"2023","journal-title":"Eur. J. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Siow, S.F., Yeow, D., Rudaks, L.I., Jia, F., Wali, G., Sue, C.M., and Kumar, K.R. (2023). Outcome Measures and biomarkers for clinical trials in hereditary spastic paraplegia: A scoping review. Genes, 14.","DOI":"10.3390\/genes14091756"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5784","DOI":"10.1007\/s00415-023-11918-5","article-title":"White matter abnormalities in 15 subjects with SPG76","volume":"270","author":"Alkhalifa","year":"2023","journal-title":"J. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s00401-023-02675-w","article-title":"Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients","volume":"147","author":"Krumm","year":"2024","journal-title":"Acta Neuropathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1093\/brain\/awac391","article-title":"The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15","volume":"146","author":"Saffari","year":"2023","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.pediatrneurol.2024.01.005","article-title":"A Retrospective review of 18 patients with childhood-onset hereditary spastic paraplegia, nine with novel variants","volume":"152","author":"Kilic","year":"2024","journal-title":"Pediatr. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/WNP.0000000000000874","article-title":"A Randomized controlled trial of the effect of repetitive transcranial magnetic stimulation of the motor cortex on lower extremity spasticity in hereditary spastic paraplegia","volume":"40","author":"Bastani","year":"2023","journal-title":"J. Clin. Neurophysiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s10048-022-00695-4","article-title":"Reduced penetrance of an eastern French mutation in ATL1 autosomal-dominant inheritance (SPG3A): Extended phenotypic spectrum coupled with brain 18F-FDG PET","volume":"23","author":"Hocquel","year":"2022","journal-title":"Neurogenetics"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chojdak-\u0141ukasiewicz, J., Sulima, K., Zimny, A., Waliszewska-Pros\u00f3\u0142, M., and Budrewicz, S. (2023). Hereditary spastic paraplegia type 11-clinical, genetic and neuroimaging characteristics. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242417530"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2343410","DOI":"10.1001\/jamanetworkopen.2023.43410","article-title":"Multimodal analysis of secondary cerebellar alterations after pediatric traumatic brain injury","volume":"6","author":"Keleher","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ehnert, S., Hauser, S., Hengel, H., H\u00f6flinger, P., Sch\u00fcle, R., Lindig, T., Baets, J., Deconinck, T., de Jonghe, P., and Histing, T. (2024). Vitamin D3 deficiency and osteopenia in spastic paraplegia type 5 indicate impaired bone homeostasis. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-53057-5"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1002\/mds.29755","article-title":"Plasma neurofilaments: Potential biomarkers of SPG11-related hereditary spastic paraplegia","volume":"39","author":"Krumm","year":"2024","journal-title":"Mov. Disord."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1002\/mds.29524","article-title":"Plasma neurofilament light chain is elevated in adaptor protein complex 4-related hereditary spastic paraplegia","volume":"38","author":"Alecu","year":"2023","journal-title":"Mov. Disord."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"fcae132","DOI":"10.1093\/braincomms\/fcae132","article-title":"CSF neurofilament light chain profiling and quantitation in neurological diseases","volume":"6","author":"Leckey","year":"2024","journal-title":"Brain Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41582-024-00955-x","article-title":"Neurofilaments as biomarkers in neurological disorders\u2014Towards clinical application","volume":"20","author":"Khalil","year":"2024","journal-title":"Nat. Rev. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Morikawa, T., Takahashi, M., Izumi, Y., Bamba, T., Moriyama, K., Hattori, G., Fujioka, R., Miura, S., and Shibata, H. (2023). Oleic acid-containing phosphatidylinositol is a blood biomarker candidate for SPG28. Biomedicines, 11.","DOI":"10.3390\/biomedicines11041092"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Panza, E., Martinelli, D., Magini, P., Dionisi Vici, C., and Seri, M. (2019). Hereditary spastic paraplegia is a common phenotypic finding in ARG1 deficiency, P5CS deficiency and HHH Syndrome: Three inborn errors of metabolism caused by alteration of an interconnected pathway of glutamate and urea cycle metabolism. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00131"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1093\/brain\/awv143","article-title":"Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia","volume":"138","author":"Coutelier","year":"2015","journal-title":"Brain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1093\/brain\/awv247","article-title":"ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: Loss of function effect and plausibility of a dominant negative mechanism","volume":"139","author":"Panza","year":"2016","journal-title":"Brain"},{"key":"ref_33","first-page":"1873","article-title":"Clinical, biochemical, and genotypical characteristics in urea cycle mitochondrial transporter disorders","volume":"28","author":"Bilgin","year":"2024","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s40981-024-00726-z","article-title":"Postoperative hyperammonemic encephalopathy due to unexpected constipation in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: A case report","volume":"10","author":"Tachibana","year":"2024","journal-title":"JA Clin. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/jimd.12564","article-title":"The role and control of arginine levels in arginase 1 deficiency","volume":"46","author":"Diaz","year":"2023","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1080\/15548627.2023.2170962","article-title":"Blockage of autophagosome-lysosome fusion through SNAP29 O-GlcNAcylation promotes apoptosis via ROS production","volume":"19","author":"Pellegrini","year":"2023","journal-title":"Autophagy"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/jmi.13223","article-title":"CellProfiler plugins\u2014An easy image analysis platform integration for containers and python tools","volume":"296","author":"Weisbart","year":"2024","journal-title":"J. Microsc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1111\/ene.15756","article-title":"New cellular imaging-based method to distinguish the SPG4 subtype of hereditary spastic paraplegia","volume":"30","author":"Sardina","year":"2023","journal-title":"Eur. J. Neurol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/1950\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:41:26Z","timestamp":1760028086000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/1950"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,24]]},"references-count":38,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26051950"],"URL":"https:\/\/doi.org\/10.3390\/ijms26051950","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,24]]}}}