{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:21:56Z","timestamp":1791231716079,"version":"4.1.0"},"reference-count":98,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T00:00:00Z","timestamp":1693699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Health and Medical Research Council","award":["APP113610"],"award-info":[{"award-number":["APP113610"]}]},{"name":"Australian and New Zealand Association of Neurologists","award":["APP113610"],"award-info":[{"award-number":["APP113610"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb spasticity. There is no disease-modifying treatment currently available. Therefore, standardized, validated outcome measures to facilitate clinical trials are urgently needed. We performed a scoping review of outcome measures and biomarkers for HSP to provide recommendations for future studies and identify areas for further research. We searched Embase, Medline, Scopus, Web of Science, and the Central Cochrane database. Seventy studies met the inclusion criteria, and eighty-three outcome measures were identified. The Spastic Paraplegia Rating Scale (SPRS) was the most widely used (27 studies), followed by the modified Ashworth Scale (18 studies) and magnetic resonance imaging (17 studies). Patient-reported outcome measures (PROMs) were infrequently used to assess treatment outcomes (28% of interventional studies). Diffusion tensor imaging, gait analysis and neurofilament light chain levels were the most promising biomarkers in terms of being able to differentiate patients from controls and correlate with clinical disease severity. Overall, we found variability and inconsistencies in use of outcome measures with a paucity of longitudinal data. We highlight the need for (1) a standardized set of core outcome measures, (2) validation of existing biomarkers, and (3) inclusion of PROMs in HSP clinical trials.<\/jats:p>","DOI":"10.3390\/genes14091756","type":"journal-article","created":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T02:14:50Z","timestamp":1693793690000},"page":"1756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Outcome Measures and Biomarkers for Clinical Trials in Hereditary Spastic Paraplegia: A Scoping Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1485-0228","authenticated-orcid":false,"given":"Sue-Faye","family":"Siow","sequence":"first","affiliation":[{"name":"Sydney Medical School, University of Sydney, Camperdown 2050, Australia"},{"name":"Department of Clinical Genetics, Royal North Shore Hospital, St Leonards 2065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7534-7007","authenticated-orcid":false,"given":"Dennis","family":"Yeow","sequence":"additional","affiliation":[{"name":"Sydney Medical School, University of Sydney, Camperdown 2050, Australia"},{"name":"Neuroscience Research Australia, University of New South Wales, Randwick 2031, Australia"},{"name":"Rare Disease Program, Garvan Institute of Medical Research, Darlinghurst 2010, Australia"},{"name":"Translational Neurogenomics Group, Molecular Medicine Laboratory and Department of Neurology, Concord Hospital, Concord 2139, Australia"},{"name":"Neurodegenerative Service, Prince of Wales Hospital, Randwick 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1100-319X","authenticated-orcid":false,"given":"Laura I.","family":"Rudaks","sequence":"additional","affiliation":[{"name":"Sydney Medical School, University of Sydney, Camperdown 2050, Australia"},{"name":"Department of Clinical Genetics, Royal North Shore Hospital, St Leonards 2065, Australia"},{"name":"Rare Disease Program, Garvan Institute of Medical Research, Darlinghurst 2010, Australia"},{"name":"Translational Neurogenomics Group, Molecular Medicine Laboratory and Department of Neurology, Concord Hospital, Concord 2139, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6421-8074","authenticated-orcid":false,"given":"Fangzhi","family":"Jia","sequence":"additional","affiliation":[{"name":"Sydney Medical School, University of Sydney, Camperdown 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2961-3954","authenticated-orcid":false,"given":"Gautam","family":"Wali","sequence":"additional","affiliation":[{"name":"Sydney Medical School, University of Sydney, Camperdown 2050, Australia"},{"name":"Neuroscience Research Australia, University of New South Wales, Randwick 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn M.","family":"Sue","sequence":"additional","affiliation":[{"name":"Sydney Medical School, University of Sydney, Camperdown 2050, Australia"},{"name":"Neuroscience Research Australia, University of New South Wales, Randwick 2031, Australia"},{"name":"Neurodegenerative Service, Prince of Wales Hospital, Randwick 2031, Australia"},{"name":"School of Clinical Medicine, UNSW Medicine & Health, University of New South Wales, Kensington 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3482-6962","authenticated-orcid":false,"given":"Kishore R.","family":"Kumar","sequence":"additional","affiliation":[{"name":"Sydney Medical School, University of Sydney, Camperdown 2050, Australia"},{"name":"Rare Disease Program, Garvan Institute of Medical Research, Darlinghurst 2010, Australia"},{"name":"Translational Neurogenomics Group, Molecular Medicine Laboratory and Department of Neurology, Concord Hospital, Concord 2139, Australia"},{"name":"School of Clinical Medicine, UNSW Medicine & Health, University of New South Wales, Kensington 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,3]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1093\/brain\/awp056","article-title":"Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: A population-based study","volume":"132","author":"Erichsen","year":"2009","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1001\/jamaneurol.2013.1707","article-title":"Hereditary ataxia and spastic paraplegia in Portugal: A population-based prevalence study","volume":"70","author":"Coutinho","year":"2013","journal-title":"JAMA Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Vander Stichele, G., Durr, A., Yoon, G., Sch\u00fcle, R., Blackstone, C., Esposito, G., Buffel, C., Oliveira, I., Freitag, C., and van Rooijen, S. (2022). An integrated modelling methodology for estimating global incidence and prevalence of hereditary spastic paraplegia subtypes SPG4, SPG7, SPG11, and SPG15. BMC Neurol., 22.","DOI":"10.1186\/s12883-022-02595-4"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13023-021-01915-0","article-title":"Healthcare needs, expectations, utilization, and experienced treatment effects in patients with hereditary spastic paraplegia: A web-based survey in the Netherlands","volume":"16","author":"Kerstens","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_6","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_7","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_8","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s11910-021-01099-x","article-title":"Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia","volume":"21","author":"Saputra","year":"2021","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1093\/brain\/awab386","article-title":"Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia","volume":"145","author":"Banneau","year":"2022","journal-title":"Brain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"27004","DOI":"10.1038\/srep27004","article-title":"Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia","volume":"6","author":"Wali","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/stem.1569","article-title":"Loss of Spastin Function Results in Disease-Specific Axonal Defects in Human Pluripotent Stem Cell-Based Models of Hereditary Spastic Paraplegia","volume":"32","author":"Denton","year":"2014","journal-title":"Stem Cells"},{"key":"ref_13","first-page":"72","article-title":"Microtubule-targeting drugs rescue axonal swellings in cortical neurons from spastin knockout mice","volume":"6","author":"Fassier","year":"2013","journal-title":"Dis. Model. Mech."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"401","DOI":"10.3389\/fnins.2020.00401","article-title":"Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons","volume":"14","author":"Wali","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1242\/bio.20147641","article-title":"Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia","volume":"3","author":"Fan","year":"2014","journal-title":"Biol. Open"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/s41588-022-01027-w","article-title":"A call for an integrated approach to improve efficiency, equity and sustainability in rare disease research in the United States","volume":"54","author":"Halley","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"e7586","DOI":"10.1136\/bmj.e7586","article-title":"SPIRIT 2013 explanation and elaboration: Guidance for protocols of clinical trials","volume":"346","author":"Chan","year":"2013","journal-title":"BMJ"},{"key":"ref_19","first-page":"449","article-title":"How to select outcome measurement instruments for outcomes included in a \"Core Outcome Set\"\u2014A practical guideline","volume":"17","author":"Prinsen","year":"2016","journal-title":"Curr. Control. Trials Cardiovasc. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.3389\/fneur.2018.01017","article-title":"Clinical Trial Designs and Measures in Hereditary Spastic Paraplegias","volume":"9","author":"Trummer","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_21","first-page":"132","article-title":"Developing core outcome sets for clinical trials: Issues to consider","volume":"13","author":"Williamson","year":"2012","journal-title":"Curr. Control. Trials Cardiovasc. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1097\/XEB.0000000000000050","article-title":"Guidance for conducting systematic scoping reviews","volume":"13","author":"Peters","year":"2015","journal-title":"Int. J. Evid. Based Healthc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.11124\/JBIES-20-00167","article-title":"Updated methodological guidance for the conduct of scoping reviews","volume":"18","author":"Peters","year":"2020","journal-title":"JBI Evid. Synth."},{"key":"ref_24","unstructured":"Veritas Health Innovation, Melbourne Australia (2023, July 12). Covidence Systematic Review Software. Available online: www.covidence.org."},{"key":"ref_25","unstructured":"U.S. Food and Drug Administration (2023, June 02). Clinical Outcome Assessment (COA): Frequently Asked Questions, Available online: https:\/\/www.fda.gov\/about-fda\/clinical-outcome-assessment-coa-frequently-asked-questions#COADefinition."},{"key":"ref_26","unstructured":"Group OCfE-BMLoEW (2023, July 12). The Oxford 2011 Levels of Evidence. Available online: http:\/\/www.cebm.net\/index.aspx?o=56532011."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lassmann, C., Ilg, W., Schneider, M., Volker, M., Haeufle, D.F.B., Schule, R., Giese, M., Schols, L., and Rattay, T.W. (2022). Specific gait changes in prodromal hereditary spastic paraplegia type 4\u2014preSPG4 study. Medrxiv, 21.","DOI":"10.1101\/2022.04.20.22274071"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1093\/brain\/awac155","article-title":"The prodromal phase of hereditary spastic paraplegia type 4: The preSPG4 cohort study","volume":"146","author":"Rattay","year":"2023","journal-title":"Brain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1007\/s12311-021-01302-2","article-title":"Progression of Functional Gait in Hereditary Spastic Paraplegias","volume":"21","author":"Machado","year":"2022","journal-title":"Cerebellum"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.nicl.2018.05.031","article-title":"SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage","volume":"19","author":"Faber","year":"2018","journal-title":"NeuroImage Clin."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/acn3.51518","article-title":"Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4","volume":"9","author":"Kessler","year":"2022","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_33","first-page":"S225","article-title":"Biological course and natural history of hereditary spastic paraplegia type 11 (SPG11)","volume":"33","author":"Musacchio","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1079","DOI":"10.1212\/WNL.0000000000200819","article-title":"Inertial Gait Sensors to Measure Mobility and Functioning in Hereditary Spastic Paraplegia: A Cross-Sectional Multicenter Clinical Study","volume":"99","author":"Regensburger","year":"2022","journal-title":"Neurology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1093\/brain\/awx273","article-title":"Hereditary spastic paraplegia type 5: Natural history, biomarkers and a randomized controlled trial","volume":"140","author":"Schols","year":"2017","journal-title":"Brain"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3389\/fnins.2020.00111","article-title":"Efficacy of a Combined Treatment of Botulinum Toxin and Intensive Physiotherapy in Hereditary Spastic Paraplegia","volume":"14","author":"Paparella","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_37","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_38","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1093\/brain\/awn059","article-title":"Composite cerebellar functional severity score: Validation of a quantitative score of cerebellar impairment","volume":"131","author":"Charles","year":"2008","journal-title":"Brain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1001\/archneurol.2011.2713","article-title":"Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia","volume":"69","author":"Charles","year":"2012","journal-title":"Arch. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Simonini, C., Zucchi, E., Bedin, R., Martinelli, I., Gianferrari, G., Fini, N., Sorau, G., Liguori, R., Vacchiano, V., and Mandrioli, J. (2021). CSF Heavy Neurofilament May Discriminate and Predict Motor Neuron Diseases with Upper Motor Neuron Involvement. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111623"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1159\/000493986","article-title":"Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study","volume":"18","author":"Zucchi","year":"2018","journal-title":"Neurodegener. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1002\/acn3.583","article-title":"Serum neurofilament light chain is increased in hereditary spastic paraplegias","volume":"5","author":"Wilke","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_43","first-page":"1","article-title":"Potential markers for sample size estimations in hereditary spastic paraplegia type 5","volume":"16","author":"Lin","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_44","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_45","doi-asserted-by":"crossref","first-page":"117211","DOI":"10.1016\/j.jns.2020.117211","article-title":"Elevated hydroxycholesterols in Norwegian patients with hereditary spastic paraplegia SPG5","volume":"419","author":"Prestsaeter","year":"2020","journal-title":"J. Neurol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1111\/dmcn.13025","article-title":"Time-course of myelination and atrophy on cerebral imaging in 35 patients with PLP1-related disorders","volume":"58","author":"Sarret","year":"2016","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.ridd.2012.09.005","article-title":"Full body gait analysis may improve diagnostic discrimination between hereditary spastic paraplegia and spastic diplegia: A preliminary study","volume":"34","author":"Turcot","year":"2013","journal-title":"Res. Dev. Disabil."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1111\/dmcn.13082","article-title":"Kinematic gait deficits at the trunk and pelvis: Characteristic features in children with hereditary spastic paraplegia","volume":"58","author":"Adair","year":"2016","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_49","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_50","first-page":"434","article-title":"Functional effects of botulinum toxin type a in the hip adductors and subsequent stretching in patients with hereditary spastic paraplegia","volume":"51","author":"Lith","year":"2019","journal-title":"J. Rehabil. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ejpn.2021.11.003","article-title":"The use of intrathecal baclofen for management of spasticity in hereditary spastic paraparesis: A case series","volume":"36","author":"Pointon","year":"2022","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.gaitpost.2019.07.144","article-title":"A service evaluation of gait correction surgery for patients with hereditary spastic paraplegia","volume":"73","author":"Henderson","year":"2019","journal-title":"Gait Posture"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1002\/acn3.50907","article-title":"Slowed vertical saccades as a hallmark of hereditary spastic paraplegia type 7","volume":"6","author":"Milenkovic","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_54","first-page":"S490","article-title":"Speech biomarkers in hereditary spastic paraplegia","volume":"36","author":"Olchik","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1007\/s10072-020-04341-5","article-title":"Autosomal dominant SPG9: Intrafamilial variability and onset during pregnancy","volume":"41","author":"Marelli","year":"2020","journal-title":"Neurol. Sci."},{"key":"ref_56","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_57","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_58","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ejmg.2020.103992","article-title":"Dystonia as initial presentation of compound heterozygous GBA2 mutations: Expanding the phenotypic spectrum of SPG46","volume":"63","author":"Kloth","year":"2020","journal-title":"Eur. J. Med. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"fcab221","DOI":"10.1093\/braincomms\/fcab221","article-title":"High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegia","volume":"3","author":"Alecu","year":"2021","journal-title":"Brain Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1002\/mds.27812","article-title":"Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism","volume":"34","author":"Gamez","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1093\/brain\/awz102","article-title":"FAHN\/SPG35: A narrow phenotypic spectrum across disease classifications","volume":"142","author":"Rattay","year":"2019","journal-title":"Brain"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1080\/10790268.2018.1543926","article-title":"Spinal direct current stimulation (tsDCS) in hereditary spastic paraplegias (HSP): A sham-controlled crossover study","volume":"44","author":"Ardolino","year":"2021","journal-title":"J. Spinal Cord. Med."},{"key":"ref_63","first-page":"173","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":"2021","journal-title":"J. Clin. Neurophysiol. Off. Publ. Am. Electroencephalogr. Soc."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1002\/mds.28523","article-title":"Randomized Trial of Botulinum Toxin Type A in Hereditary Spastic Paraplegia\u2014The SPASTOX Trial","volume":"36","author":"Faber","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1186\/s13063-022-06729-4","article-title":"Protocol for the development of an international Core Outcome Set for treatment trials in adults with epilepsy: The EPilepsy outcome Set for Effectiveness Trials Project (EPSET)","volume":"23","author":"Mitchell","year":"2022","journal-title":"Trials"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1007\/s11136-017-1765-4","article-title":"COSMIN Risk of Bias checklist for systematic reviews of Patient-Reported Outcome Measures","volume":"27","author":"Mokkink","year":"2018","journal-title":"Qual. Life Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1212\/01.wnl.0000228242.53336.90","article-title":"The Spastic Paraplegia Rating Scale (SPRS): A reliable and valid measure of disease severity","volume":"67","author":"Klimpe","year":"2006","journal-title":"Neurology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1590\/0004-282x20160047","article-title":"Translation and validation into Brazilian Portuguese of the Spastic Paraplegia Rating Scale (SPRS)","volume":"74","author":"Servelhere","year":"2016","journal-title":"Arq. De Neuro-Psiquiatr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"325","DOI":"10.3389\/fnins.2020.00325","article-title":"Multimodal MRI Longitudinal Assessment of White and Gray Matter in Different SPG Types of Hereditary Spastic Paraparesis","volume":"14","author":"Montanaro","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_70","first-page":"576","article-title":"Inter- and intra-rater reliability of the Modified Ashworth Scale: A systematic review and meta-analysis","volume":"54","year":"2018","journal-title":"Eur. J. Phys. Rehabil. Med."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"(2002). ATS statement: Guidelines for the six-minute walk test. Am. J. Respir. Crit. Care Med., 166, 111\u2013117.","DOI":"10.1164\/ajrccm.166.1.at1102"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Stewart, A., Sherbourne, C.D., Ware, J.E., Hays, R.D., Wells, K.B., Berry, S.H., Kamberg, C., Nelson, E.C., Davies, A.R., and Rogers, W.H. (1992). Measuring Functioning and Well Being: The Medical Outcomes Study Approach, Duke University Press.","DOI":"10.7249\/CB361"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2050312116671725","DOI":"10.1177\/2050312116671725","article-title":"SF-36 total score as a single measure of health-related quality of life: Scoping review","volume":"4","author":"Lins","year":"2016","journal-title":"SAGE Open Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/sc.2010.61","article-title":"Health-related quality of life in patients with hereditary spastic paraplegia in Estonia","volume":"49","author":"Braschinsky","year":"2011","journal-title":"Spinal Cord."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"106888","DOI":"10.1016\/j.clineuro.2021.106888","article-title":"Functional gait measures correlate to fear of falling, and quality of life in patients with Hereditary Spastic Paraplegia: A cross-sectional study","volume":"209","author":"Gassner","year":"2021","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3109\/07853890109002087","article-title":"EQ-5D: A measure of health status from the EuroQol Group","volume":"33","author":"Rabin","year":"2001","journal-title":"Ann. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1002\/acn3.51358","article-title":"Neurofilament light chain is a cerebrospinal fluid biomarker in hereditary spastic paraplegia","volume":"8","author":"Kessler","year":"2021","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Alecu, J.E., Saffari, A., Ziegler, M., Jordan, C., Tam, A., Kim, S., Leung, E., Szczaluba, K., Mierzewska, H., and King, S.D. (2023). Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4-Related Hereditary Spastic Paraplegia. Mov. Disord., online ahead of print.","DOI":"10.1002\/mds.29524"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Gaiottino, J., Norgren, N., Dobson, R., Topping, J., Nissim, A., Malaspina, A., Bestwick, J.P., Monsch, A.U., Regeniter, A., and Lindberg, R.L. (2013). Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075091"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1007\/s00415-020-10387-4","article-title":"Thalamic atrophy in patients with pure hereditary spastic paraplegia type 4","volume":"268","author":"Romero","year":"2021","journal-title":"J. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1002\/mrm.25548","article-title":"Toward tract-specific fractional anisotropy (TSFA) at crossing-fiber regions with clinical diffusion MRI","volume":"74","author":"Mishra","year":"2015","journal-title":"Magn. Reson. Med."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Rezende, T.J.R., de Albuquerque, M., Lamas, G.M., Martinez, A.R.M., Campos, B.M., Casseb, R.F., Silva, C.B., Branco, L.M.T., D\u2019Abreu, A., and Lopes-Cendes, I. (2015). Multimodal MRI-based study in patients with SPG4 mutations. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117666"},{"key":"ref_83","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_84","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.clinph.2012.01.010","article-title":"A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee","volume":"123","author":"Groppa","year":"2012","journal-title":"Clin. Neurophysiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"967","DOI":"10.3389\/fneur.2019.00967","article-title":"Motor Evoked Potentials in Hereditary Spastic Paraplegia\u2014A Systematic Review","volume":"10","author":"Siow","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1002\/acn3.51725","article-title":"Mobile digital gait analysis objectively measures progression in hereditary spastic paraplegia","volume":"10","author":"Loris","year":"2023","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.3389\/fneur.2019.01193","article-title":"Optical Coherence Tomography in a Cohort of Genetically Defined Hereditary Spastic Paraplegia: A Brief Research Report","volume":"10","author":"Vavla","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e200052","DOI":"10.1212\/NXG.0000000000200052","article-title":"Toward the Definition of Patient-Reported Outcome Measurements in Hereditary Spastic Paraplegia","volume":"9","author":"Amprosi","year":"2023","journal-title":"Neurol. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/j.1468-1331.2011.03443.x","article-title":"Disease severity affects quality of life of hereditary spastic paraplegia patients","volume":"19","author":"Klimpe","year":"2012","journal-title":"Eur. J. Neurol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.clineuro.2014.02.002","article-title":"Hereditary spastic paraparesis in adults. A clinical and genetic perspective from Tuscany","volume":"120","author":"Orsucci","year":"2014","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"S217","DOI":"10.1097\/00005650-198903001-00018","article-title":"Generic and Disease-Specific Measures in Assessing Health Status and Quality of Life","volume":"27","author":"Patrick","year":"1989","journal-title":"Med. Care"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1073516","DOI":"10.3389\/fnins.2023.1073516","article-title":"Reduced acetylated \u03b1-tubulin in SPAST hereditary spastic paraplegia patient PBMCs","volume":"17","author":"Wali","year":"2023","journal-title":"Front Neurosci."},{"key":"ref_93","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."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Kirkham, J.J., Davis, K., Altman, D.G., Blazeby, J.M., Clarke, M., Tunis, S., and Williamson, P.R. (2017). Core Outcome Set-STAndards for Development: The COS-STAD recommendations. PLoS Med., 14.","DOI":"10.1371\/journal.pmed.1002447"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.3389\/fneur.2018.01117","article-title":"Neuroimaging in Hereditary Spastic Paraplegias: Current Use and Future Perspectives","volume":"9","author":"Vasconcellos","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"515","DOI":"10.3389\/fneur.2020.00515","article-title":"Brain Magnetic Spectroscopy Imaging and Hereditary Spastic Paraplegia: A Focused Systematic Review on Current Landmarks and Future Perspectives","volume":"11","author":"Vavla","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"116620","DOI":"10.1016\/j.jns.2019.116620","article-title":"Ophthalmological changes in hereditary spastic paraplegia and other genetic diseases with spastic paraplegia","volume":"409","author":"Sallum","year":"2020","journal-title":"J. Neurol. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"16635","DOI":"10.1038\/s41598-021-95995-4","article-title":"Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia","volume":"11","author":"Wali","year":"2021","journal-title":"Sci. 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