{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:07:00Z","timestamp":1790744820470,"version":"4.1.0"},"reference-count":71,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T00:00:00Z","timestamp":1657497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["RF19.12"],"award-info":[{"award-number":["RF19.12"]}]},{"name":"Italian Ministry of Health","award":["DSCH_BASE19_ORLACCHIO and RICERCABASE_2020_ORLACCHIO"],"award-info":[{"award-number":["DSCH_BASE19_ORLACCHIO and RICERCABASE_2020_ORLACCHIO"]}]},{"name":"Department of Medicine and Surgery of the University of Perugia (Fondo Ricerca di Base)","award":["RF19.12"],"award-info":[{"award-number":["RF19.12"]}]},{"name":"Department of Medicine and Surgery of the University of Perugia (Fondo Ricerca di Base)","award":["DSCH_BASE19_ORLACCHIO and RICERCABASE_2020_ORLACCHIO"],"award-info":[{"award-number":["DSCH_BASE19_ORLACCHIO and RICERCABASE_2020_ORLACCHIO"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inherited neurodegenerative pathology characterized by lower muscle tone and increasing spasticity in the lower limbs is termed hereditary spastic paraplegia (HSP). HSP is associated with changes in about 80 genes and their products involved in various biochemical pathways, such as lipid droplet formation, endoplasmic reticulum shaping, axon transport, endosome trafficking, and mitochondrial function. With the inheritance patterns of autosomal dominant, autosomal recessive, X-linked recessive, and mitochondrial inheritance, HSP is prevalent around the globe at a rate of 1\u20135 cases in every 100,000 individuals. Recent technology and medical interventions somewhat aid in recognizing and managing the malaise. However, HSP still lacks an appropriate and adequate therapeutic approach. Current therapies are based on the clinical manifestations observed in the patients, for example, smoothing the relaxant spastic muscle and physiotherapies. The limited clinical trial studies contribute to the absence of specific pharmaceuticals for HSPs. Our current work briefly explains the causative genes, epidemiology, underlying mechanism, and the management approach undertaken to date. We have also mentioned the latest approved drugs to summarise the available knowledge on therapeutic strategies for HSP.<\/jats:p>","DOI":"10.3390\/ijms23147665","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T21:57:53Z","timestamp":1657576673000},"page":"7665","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment"],"prefix":"10.3390","volume":"23","author":[{"given":"Arun","family":"Meyyazhagan","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haripriya","family":"Kuchi Bhotla","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, CHRIST (Deemed to be University), Bengaluru 560029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6047-3702","authenticated-orcid":false,"given":"Manikantan","family":"Pappuswamy","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, CHRIST (Deemed to be University), Bengaluru 560029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, 06132 Perugia, Italy"},{"name":"Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104430","DOI":"10.1016\/j.ejmg.2022.104430","article-title":"Hereditary spastic paraparesis: The real-world experience from a Neurogenetics outpatient clinic","volume":"65","author":"Cunha","year":"2022","journal-title":"Eur. J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mackay-Sim, A. (2021). Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery. Brain Sci., 11.","DOI":"10.3390\/brainsci11030403"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1159\/000358801","article-title":"The global epidemiology of hereditary ataxia and spastic paraplegia: A systematic review of prevalence studies","volume":"42","author":"Ruano","year":"2014","journal-title":"Neuroepidemiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1007\/s10072-020-04981-7","article-title":"Hereditary spastic paraplegia","volume":"42","author":"Murala","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1007\/s00415-019-09633-1","article-title":"Genotype-phenotype associations in hereditary spastic paraplegia: A systematic review and meta-analysis on 13,570 patients","volume":"268","author":"Torkamandi","year":"2021","journal-title":"J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/S0140-6736(83)92879-9","article-title":"Classification of the hereditary ataxias and paraplegias","volume":"1","author":"Harding","year":"1983","journal-title":"Lancet"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"e122","DOI":"10.1212\/NXG.0000000000000122","article-title":"Clinical and genetic study of hereditary spastic paraplegia in Canada","volume":"3","author":"Chrestian","year":"2016","journal-title":"Neurol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1007\/s00415-014-7598-y","article-title":"Diagnosis, investigation and management of hereditary spastic paraplegias in the era of next-generation sequencing","volume":"262","author":"Hensiek","year":"2015","journal-title":"J. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"660714","DOI":"10.3389\/fnins.2021.660714","article-title":"Hereditary Spastic Paraplegia and Future Therapeutic Directions: Beneficial Effects of Small Compounds Acting on Cellular Stress","volume":"15","author":"Gumeni","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3389\/fneur.2019.00003","article-title":"Management of Hereditary Spastic Paraplegia: A Systematic Review of the Literature","volume":"10","author":"Bellofatto","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1517\/21678707.2016.1153964","article-title":"Hereditary spastic paraplegia: Pathology, genetics and therapeutic prospects","volume":"4","author":"Storti","year":"2016","journal-title":"Expert Opin. Orphan Drugs"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41431-019-0497-z","article-title":"KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia","volume":"28","author":"Pennings","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.mito.2010.07.006","article-title":"Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation","volume":"11","author":"Verny","year":"2011","journal-title":"Mitochondrion"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1001\/archneur.61.6.849","article-title":"Hereditary spastic paraplegia: Clinical genetic study of 15 families","volume":"61","author":"Orlacchio","year":"2004","journal-title":"Arch. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.neulet.2007.04.031","article-title":"Cognitive performance in pure and complicated hereditary spastic paraparesis: A neuropsychological and neuroimaging study","volume":"419","author":"Uttner","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1590\/0004-282X20130248","article-title":"Clinical features and management of hereditary spastic paraplegia","volume":"72","author":"Faber","year":"2014","journal-title":"Arq. Neuropsiquiatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/j.bbamcr.2011.06.011","article-title":"Urban planning of the endoplasmic reticulum (ER): How diverse mechanisms segregate the many functions of the ER","volume":"1813","author":"Lynes","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1146\/annurev-neuro-062111-150400","article-title":"Cellular pathways of hereditary spastic paraplegia","volume":"35","author":"Blackstone","year":"2012","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/embor.2010.92","article-title":"Further assembly required: Construction and dynamics of the endoplasmic reticulum network","volume":"11","author":"Park","year":"2010","journal-title":"EMBO Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1038\/emboj.2008.86","article-title":"FAK-MAPK-dependent adhesion disassembly downstream of L1 contributes to semaphorin3A-induced collapse","volume":"27","author":"Bechara","year":"2008","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1111\/j.1471-4159.2011.07367.x","article-title":"Spartin recruits PKC-\u03b6 via the PKC-\u03b6-interacting proteins ZIP1 and ZIP3 to lipid droplets","volume":"118","author":"Urbanczyk","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1194\/jlr.M002543","article-title":"Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis","volume":"51","author":"Siddique","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3389\/fnins.2020.00074","article-title":"Lipids in the Physiopathology of Hereditary Spastic Paraplegias","volume":"14","author":"Darios","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1469-7580.2011.01363.x","article-title":"Axon-glial interaction in the CNS: What we have learned from mouse models of Pelizaeus-Merzbacher disease","volume":"219","author":"Gruenenfelder","year":"2011","journal-title":"J. Anat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1093\/brain\/awn328","article-title":"Hereditary spastic paraplegia is a novel phenotype for GJA12\/GJC2 mutations","volume":"132","author":"Salsano","year":"2009","journal-title":"Brain"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1002\/glia.21172","article-title":"Central nervous system dysfunction in a mouse model of FA2H deficiency","volume":"59","author":"Potter","year":"2011","journal-title":"Glia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"E376","DOI":"10.1002\/humu.20920","article-title":"Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10","volume":"30","author":"Goizet","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1093\/hmg\/ddn014","article-title":"Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity","volume":"17","author":"Ebbing","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3967","DOI":"10.1038\/onc.2011.109","article-title":"SPG20, a novel biomarker for early detection of colorectal cancer, encodes a regulator of cytokinesis","volume":"30","author":"Lind","year":"2011","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nrm2867","article-title":"A nucleator arms race: Cellular control of actin assembly","volume":"11","author":"Campellone","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1146\/annurev.neuro.30.051606.094302","article-title":"Mitochondrial disorders in the nervous system","volume":"31","author":"DiMauro","year":"2008","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1172\/JCI200420138","article-title":"Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport","volume":"113","author":"Ferreirinha","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15694","DOI":"10.1074\/jbc.M800548200","article-title":"The Hsp60-(p.V98I) mutation associated with hereditary spastic paraplegia SPG13 compromises chaperonin function both in vitro and in vivo","volume":"283","author":"Bross","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12300","DOI":"10.1038\/s41598-019-48762-5","article-title":"MitCHAP-60 and Hereditary Spastic Paraplegia SPG-13 Arise from an Inactive hsp60 Chaperonin that Fails to Fold the ATP Synthase \u03b2-Subunit","volume":"9","author":"Wang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1002\/mds.28885","article-title":"A Novel SPAST Mutation Results in Spastin Accumulation and Defects in Microtubule Dynamics","volume":"37","author":"Chen","year":"2022","journal-title":"Mov. Disord."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1093\/hmg\/ddab367","article-title":"Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice","volume":"31","author":"Piermarini","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/cm.21528","article-title":"New hypothesis for the etiology of SPAST-based hereditary spastic paraplegia","volume":"76","author":"Qiang","year":"2019","journal-title":"Cytoskeleton"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/S1474-4422(19)30235-2","article-title":"Hereditary spastic paraplegia: From diagnosis to emerging therapeutic approaches","volume":"18","author":"Shribman","year":"2019","journal-title":"Lancet. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1089\/neu.2017.5510","article-title":"Impact of Admission Imaging Findings on Neurological Outcomes in Acute Cervical Traumatic Spinal Cord Injury","volume":"35","author":"Farhadi","year":"2018","journal-title":"J. Neurotrauma"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1055\/s-0032-1306388","article-title":"Pelizaeus-Merzbacher disease, Pelizaeus-Merzbacher-like disease 1, and related hypomyelinating disorders","volume":"32","author":"Hobson","year":"2012","journal-title":"Semin. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e279","DOI":"10.1212\/NXG.0000000000000279","article-title":"Novel genotype-phenotype and MRI correlations in a large cohort of patients with SPG7 mutations","volume":"4","author":"Hewamadduma","year":"2018","journal-title":"Neurol. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1038\/ejhg.2015.240","article-title":"SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases","volume":"24","author":"Choquet","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3174\/ajnr.A5935","article-title":"\u201cEars of the Lynx\u201d MRI Sign Is Associated with SPG11 and SPG15 Hereditary Spastic Paraplegia","volume":"40","author":"Pascual","year":"2019","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Martinuzzi, A., Montanaro, D., Vavla, M., Paparella, G., Bonanni, P., Musumeci, O., Brighina, E., Hlavata, H., Rossi, G., and Aghakhanyan, G. (2016). Clinical and Paraclinical Indicators of Motor System Impairment in Hereditary Spastic Paraplegia: A Pilot Study. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153283"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s00415-019-09196-1","article-title":"Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants","volume":"266","author":"Toft","year":"2019","journal-title":"J. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1111\/j.1600-0404.1984.tb07802.x","article-title":"The clinical effect of the GABA-agonist, progabide, on spasticity","volume":"69","author":"Mondrup","year":"1984","journal-title":"Acta Neurol. Scand."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1007\/s00415-015-7707-6","article-title":"Dalfampridine in hereditary spastic paraplegia: A prospective, open study","volume":"262","author":"Anheim","year":"2015","journal-title":"J. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1159\/000449375","article-title":"The Effects of Dalfampridine on Hereditary Spastic Paraparesis","volume":"76","author":"Uygunoglu","year":"2016","journal-title":"Eur. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"758","DOI":"10.2174\/1381612822666151204001830","article-title":"Combined Treatment Fkt-Botulinum Toxin Type A (Btx-A) in Patients with Strumpell-Lorrain Disease","volume":"22","author":"Riccardo","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1007\/s00415-013-7044-6","article-title":"Exome sequencing expands the mutational spectrum of SPG8 in a family with spasticity responsive to l-DOPA treatment","volume":"260","author":"Bettencourt","year":"2013","journal-title":"J. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1111\/ene.13557","article-title":"Severe 5,10-methylenetetrahydrofolate reductase deficiency: A rare, treatable cause of complicated hereditary spastic paraplegia","volume":"25","author":"Perna","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1097\/00002060-199807000-00021","article-title":"Therapeutic electrical stimulation for spasticity: Quantitative gait analysis","volume":"77","author":"Pease","year":"1998","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.pmrj.2014.09.008","article-title":"Robot-assisted gait training in a patient with hereditary spastic paraplegia","volume":"7","author":"Seo","year":"2015","journal-title":"PM R"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1016\/j.apmr.2015.01.012","article-title":"Improved gait performance in a patient with hereditary spastic paraplegia after a continuous intrathecal baclofen test infusion and subsequent pump implantation: A case report","volume":"96","author":"Heetla","year":"2015","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1007\/s00381-016-3122-2","article-title":"Selective dorsal rhizotomy for hereditary spastic paraparesis in children","volume":"32","author":"Sharma","year":"2016","journal-title":"Childs. Nerv. Syst."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3233\/NRE-141196","article-title":"Robotic gait training improves motor skills and quality of life in hereditary spastic paraplegia","volume":"36","author":"Bertolucci","year":"2015","journal-title":"NeuroRehabilitation"},{"key":"ref_59","first-page":"110","article-title":"Access this Article online","volume":"2013","author":"Samuel","year":"2013","journal-title":"Int. J. Physiother. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1016\/j.gaitpost.2014.01.010","article-title":"The effect of hydrotherapy treatment on gait characteristics of hereditary spastic paraparesis patients","volume":"39","author":"Zhang","year":"2014","journal-title":"Gait Posture"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.clineuro.2014.05.024","article-title":"Intrathecal baclofen therapy for the symptomatic treatment of hereditary spastic paraplegia","volume":"123","author":"Margetis","year":"2014","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0987-7053(00)88866-8","article-title":"Intrathecal baclofen normalizes motor strategy for squatting in familial spastic paraplegia: A case study","volume":"30","author":"Dan","year":"2000","journal-title":"Neurophysiol. Clin."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/j.1468-1331.2007.01812.x","article-title":"Double-blind crossover trial of gabapentin in SPG4-linked hereditary spastic paraplegia","volume":"14","author":"Scheuer","year":"2007","journal-title":"Eur. J. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1093\/brain\/awx297","article-title":"Plasma oxysterols: Biomarkers for diagnosis and treatment in spastic paraplegia type 5","volume":"141","author":"Marelli","year":"2018","journal-title":"Brain"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.ajhg.2012.11.021","article-title":"Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia","volume":"92","author":"Martin","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_66","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_67","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.1093\/brain\/awz291","article-title":"Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia","volume":"142","author":"Vaz","year":"2019","journal-title":"Brain"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"116982","DOI":"10.1016\/j.jns.2020.116982","article-title":"Hereditary spastic paraplegia type 11 (SPG11) is associated with obesity and hypothalamic damage","volume":"416","author":"Rezende","year":"2020","journal-title":"J. Neurol. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e20210846","DOI":"10.1084\/jem.20210846","article-title":"Implication of folate deficiency in CYP2U1 loss of function","volume":"218","author":"Pujol","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/s42003-019-0615-z","article-title":"Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis","volume":"2","author":"Boutry","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"690899","DOI":"10.3389\/fmolb.2021.690899","article-title":"Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview","volume":"8","author":"Elsayed","year":"2021","journal-title":"Front. Mol. Biosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7665\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:48:17Z","timestamp":1760140097000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7665"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,11]]},"references-count":71,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23147665"],"URL":"https:\/\/doi.org\/10.3390\/ijms23147665","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,11]]}}}