{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:52:05Z","timestamp":1790833925916,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018696","name":"HORIZON EUROPE Health","doi-asserted-by":"publisher","award":["101119924\u2014BE\u2010LIGHT"],"award-info":[{"award-number":["101119924\u2014BE\u2010LIGHT"]}],"id":[{"id":"10.13039\/100018696","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CP22\/00141"],"award-info":[{"award-number":["CP22\/00141"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI18\/00101"],"award-info":[{"award-number":["PI18\/00101"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Hereditary spastic paraplegias (HSP) are rare neurodegenerative disorders marked by spasticity and lower limb weakness. The most common type, SPG4, is usually autosomal dominant and caused by\n                      <jats:italic>SPAST<\/jats:italic>\n                      gene variants, typically presenting as pure HSP. We describe five individuals from three unrelated families who meet the clinical criteria for cerebral palsy and carry biallelic\n                      <jats:italic>SPAST<\/jats:italic>\n                      variants. We aim to increase the clinical and genetic understanding of\n                      <jats:italic>SPAST<\/jats:italic>\n                      \u2010related disorders and explore the underlying abnormal cellular mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed comprehensive phenotyping and genetic analysis.\n                      <jats:italic>In silico<\/jats:italic>\n                      and functional studies were conducted using confocal microscopy on fibroblast cultures derived from carriers of the biallelic\n                      <jats:italic>SPAST<\/jats:italic>\n                      variants, a monoallelic\n                      <jats:italic>SPAST<\/jats:italic>\n                      variant, and a healthy control.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Individuals exhibited early\u2010onset complex HSP with a diverse range of encephalopathy severity, spasticity, and neuronoaxonal involvement, occasionally leading to the diagnosis of cerebral palsy. Whole\u2010exome sequencing identified homozygous and compound heterozygous\n                      <jats:italic>SPAST<\/jats:italic>\n                      variants. Functional studies demonstrated reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient\u2010derived fibroblasts, supporting the pathogenicity of the variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      We provide the first evidence of biallelic inheritance in\n                      <jats:italic>SPAST<\/jats:italic>\n                      \u2010related disorders, supported by functional analysis, expanding the clinical spectrum to include moderate\u2010to\u2010severe early\u2010onset encephalopathy. Our findings emphasize the importance of genetic diagnosis in cerebral palsy for prognosis, counseling, and personalized therapy. The identified variants reveal the genetic complexity of\n                      <jats:italic>SPAST<\/jats:italic>\n                      \u2010related disease and suggest a threshold effect of spastin levels in phenotypic variation. Cellular mechanisms such as mitochondrial dynamics and membrane morphology may contribute to pathogenesis and warrant further investigation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70206","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T09:00:33Z","timestamp":1758877233000},"page":"108-121","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Expanding Hereditary Spastic Paraplegias Limits: Biallelic\n                    <i>SPAST<\/i>\n                    Variants in Cerebral Palsy Mimics"],"prefix":"10.1002","volume":"13","author":[{"given":"Gregorio A.","family":"Nolasco","sequence":"first","affiliation":[{"name":"Pediatric Neurology Department Hospital Sant Joan de D\u00e9u  Barcelona Spain"},{"name":"Institut de Recerca Sant Joan de D\u00e9u  Esplugues de Llobregat Barcelona 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