{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:43:11Z","timestamp":1792003391468,"version":"4.4.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hereditary spastic paraplegia type 4 (SPG4), caused by variants in SPAST, is the most common form of HSP and exhibits a remarkable phenotypic heterogeneity ranging from late-onset pure presentations to severe, early-onset complex disease. Robust genotype\u2013phenotype correlations and detailed natural history data are lacking, limiting clinical trial readiness.<\/jats:p>\n                  <jats:p>We analyzed 206 patients with genetically confirmed SPG4 enrolled across seven international centers, complemented by high-quality literature-derived cases. Deep phenotyping included standardized motor scales, spasticity ratings, developmental milestones, and patient-reported outcomes. We developed an extended essentiality-mapping framework to classify SPAST missense variants by integrating in silico pathogenicity predictions, evolutionary constraint, physicochemical residue connectivity, and variant enrichment within the human spastin hexamer structure. Plasma neurofilament light chain (pNfL) using was quantified using Simoa in 26 patients and 101 controls.<\/jats:p>\n                  <jats:p>We identified 136 distinct SPAST variants, including 10 novel variants. Variant class segregated strongly by inheritance, with de novo cases enriched for missense variants and inherited cases showing a variety of variant classes with enrichment for truncating variants. Longitudinal analysis revealed two latent trajectories: a rapidly progressive severe subgroup enriched for de novo missense variants, and a biphasic moderate subgroup enriched for inherited truncating variants. Patient stratification integrating spastin essentiality mapping (missense variants affecting essential, neutral, or context-dependent residues) with established genetic modifiers (biallelic pathogenic variants or modifier variants in trans) classified patients into predicted severe and moderate subgroups with divergent age at onset and clinical disease progression. The severe subgroup showed early developmental delays, rapid loss of ambulation, and declining quality of life, while the moderate subgroup displayed delayed but accelerating disease progression. pNfL levels were elevated in both subgroups, most pronounced in severe early disease.<\/jats:p>\n                  <jats:p>This study provides the most detailed natural history of SPG4 to date and introduces a biologically informed stratification framework that links variant class and location to divergent clinical trajectories. These data establish clinically meaningful benchmarks and offer a genotype-based framework to improve anticipatory care and optimize trial design for SPG4.<\/jats:p>","DOI":"10.1093\/brain\/awag150","type":"journal-article","created":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T21:07:13Z","timestamp":1777842433000},"source":"Crossref","is-referenced-by-count":2,"title":["Genotype\u2013structure\u2013phenotype correlations define divergent natural history in early-onset spastic paraplegia type 4"],"prefix":"10.1093","author":[{"given":"Julian E","family":"Alecu","sequence":"first","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]},{"name":"Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, and Center of Neurology, University of T\u00fcbingen , 72076 T\u00fcbingen ,","place":["Germany"]},{"name":"German Center of Neurodegenerative Diseases (DZNE) , 72076 T\u00fcbingen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca M","family":"Schierbaum","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Tam","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Quiroz","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Bernardi","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6892-5189","authenticated-orcid":false,"given":"Kathryn","family":"Yang","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna R","family":"Roller","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, and Center of Neurology, University of T\u00fcbingen , 72076 T\u00fcbingen ,","place":["Germany"]},{"name":"German Center of Neurodegenerative Diseases (DZNE) , 72076 T\u00fcbingen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"D\u00f6bler-Neumann","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, University Children's Hospital , 72076 T\u00fcbingen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim W","family":"Rattay","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, and Center of Neurology, University of T\u00fcbingen , 72076 T\u00fcbingen ,","place":["Germany"]},{"name":"German Center of Neurodegenerative Diseases (DZNE) , 72076 T\u00fcbingen ,","place":["Germany"]},{"name":"Department of Neurology and Center for Rare Neurological Diseases (ZSNE), University Hospital Schleswig-Holstein (UKSH) , Campus Kiel, 24105 Kiel ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carelis","family":"Gonz\u00e1lez-Salazar","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Campinas (UNICAMP) , Campinas, S\u00e3o Paulo, 13083-970 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena A","family":"Zehr","sequence":"additional","affiliation":[{"name":"Cell Biology and Biophysics Unit, National Institute of Neurological Disorders and Stroke , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniils","family":"Skorohodovs","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josh","family":"Rong","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siofra","family":"Carty","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Battaglia","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungbok","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University , Seoul, 03080 ,","place":["South Korea"]},{"name":"Department of Genomic Medicine, Seoul National University , Seoul, 03080 ,","place":["South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jangsup","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University , Seoul, 03080 ,","place":["South Korea"]},{"name":"Department of Genomic Medicine, Seoul National University , Seoul, 03080 ,","place":["South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Christie","sequence":"additional","affiliation":[{"name":"Department of Neurology and Rehabilitation Medicine, Texas Scottish Rite Hospital, University of Texas Southwestern Medical Center , Dallas, TX 75219 ,","place":["USA"]},{"name":"Spastic Paraplegia - Centers of Excellence Research Network (SP-CERN) , Dallas, TX 75219 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonina","family":"Roll-Mecak","sequence":"additional","affiliation":[{"name":"Cell Biology and Biophysics Unit, National Institute of Neurological Disorders and Stroke , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcondes C","family":"Fran\u00e7a Jr","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Campinas (UNICAMP) , Campinas, S\u00e3o Paulo, 13083-970 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Sch\u00fcle","sequence":"additional","affiliation":[{"name":"Division of Neurodegenerative Diseases and Movement Disorders, Department of Neurology, Heidelberg University Hospital and Faculty of Medicine , 69120 Heidelberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7774-5025","authenticated-orcid":false,"given":"Ludger J","family":"Sch\u00f6ls","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, and Center of Neurology, University of T\u00fcbingen , 72076 T\u00fcbingen ,","place":["Germany"]},{"name":"German Center of Neurodegenerative Diseases (DZNE) , 72076 T\u00fcbingen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-4714","authenticated-orcid":false,"given":"Darius","family":"Ebrahimi-Fakhari","sequence":"additional","affiliation":[{"name":"Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School , Boston 02115, MA ,","place":["USA"]},{"name":"Spastic Paraplegia - Centers of Excellence Research Network (SP-CERN) , Boston 02115, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,5]]},"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag150\/68210096\/awag150.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag150\/68210096\/awag150.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T06:52:06Z","timestamp":1777963926000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/advance-article\/doi\/10.1093\/brain\/awag150\/8667235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,5]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/brain\/awag150","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,5]]},"article-number":"awag150"}}