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Disease onset ranges from infancy to adulthood, with earlier onset associated with more rapid progression. Neurofilament light chain (NfL), a sensitive marker of axonal injury, has been extensively investigated as a biomarker for neurodegenerative disorders, including GM2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To evaluate its clinical utility as a biomarker for GM2, NfL was measured in patients with GM2 enrolled in a Phase 2b, multinational, rater-blinded study of levacetylleucine [NCT03759665], and in its open-label Extension Phase (EP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nineteen participants had viable samples for NfL analysis at baseline, after six weeks of treatment, and after a six-week washout; 10 had samples in the long-term EP. After the initial 6-week treatment phase, NfL concentration declined a mean\u2009\u2212\u20098.9% (SD 13%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.008), followed by a rebound of\u2009+\u20099.2% (SD 16.1%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.022) during the post-treatment 6-week washout. Changes in NfL correlated with the statistically significant and clinically meaningful changes captured on the primary Clinical Impression of Change in Severity (CI-CS), and secondary Scale for the Assessment and Rating of Ataxia (SARA) and Modified Disability Rating Scale (mDRS). In the EP, patients showed a mean NfL reduction of\u2009\u2212\u200916.9% after 1\u00a0year (SD 15.0;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.010) and\u2009\u2212\u200933.5% after 2\u00a0years (SD 12.8;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) of levacetylleucine treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings support NfL as a promising surrogate outcome candidate for GM2 and link biochemical improvement with functional benefit, which is reasonably likely to predict both disease activity and treatment response\/clinical benefit.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-13984-x","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:11:50Z","timestamp":1784279510000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurofilament light chain (NfL) as a surrogate outcome measure for GM2 gangliosidoses"],"prefix":"10.1007","volume":"273","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3982-0914","authenticated-orcid":false,"given":"Kyriakos","family":"Martakis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas J.","family":"Abreu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua J.","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter R.","family":"Baker II","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Billington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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He has received research funding support from Amicus Therapeutics, BioMarin Pharmaceutical, Sangamo Therapeutics, Sanofi, Takeda Pharmaceuticals. JJB has received consulting fees and\/or honoraria from Acer, Amgen (Horizon), BioMarin, CVS Caremark, Denali, Eton Pharmaceuticals, Intrabio, Orchard Therapeutics, Otsuka, RegenxBio, Sanofi Genzyme, Takeda, Ultragenyx, and Zevra as a medical expert. He has participated in clinical trials funded by Aeglea, Denali, Homology, iEcure, PassageBio, Recordati, Sangamo, Sanofi Genzyme, Takeda, and Ultragenyx. IB, CF, MG, and JK are employees and shareholders of IntraBio Inc; TF and MF are employees and shareholders of IntraBio Inc and hold patents related to the use of acetylleucine. TAB has received advisory board honorarium from IntraBio Inc. MCP is an employee and shareholder of IntraBio Inc. He has received scientific advisory board honorarium from Zevra, served as journal editor for SSIEM; Journal of Inherited Metabolic Disease and JIMD Reports and Sage; Journal of Child Neurology, received publishing royalties from Wolters Kluwer, Up-To-Date, Pediatric Neurology and served as a consultant for IntraBio. He received research support from Orphazyme\/Zevra, Glycomine, Azafaros, National Institute of Diabetes and Digestive and Kidney Diseases, and Idorsia Pharmaceuticals Ltd. MS is Joint Chief Editor of the Journal of Neurology, Editor in Chief of Frontiers of Neuro-otology and Section Editor of F1000. He has received speaker\u2019s honoraria from Abbott, Auris Medical, Biogen, Eisai, Gr\u00fcnenthal, GSK, Henning Pharma, Interacoustics, J&J, MSD, NeuroUpdate, Otometrics, Pierre-Fabre, TEVA, UCB, and Viatris. He received support for clinical studies from Decibel, U.S.A., Cure within Reach, U.S.A. and Heel, Germany. He distributes \u201cM-glasses\u201d and \u201cPositional vertigo App\u201d. He acts as a consultant for Abbott, AurisMedical, Bulbitec, Heel, Sensorion, Vifor and Vertify. He is a scientific founder, investor and shareholder of IntraBio. LS is a consultant and shareholder in IntraBio Inc. TBE received honoraria for lecturing from Actelion and Sanofi Genzyme and fees for the blinded rater services from IntraBio.Other authors have no relevant disclosures to report.","order":1,"name":"Ethics","label":"Conflicts of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted in accordance with the International Conference for Harmonization (of Technical Requirements for Pharmaceuticals for Human Use), Good Clinical Practice Guideline, the General Data Protection Regulator, and the Declaration of Helsinki. Approval for the study (clinicaltrials.gov\u00a0identifier\u00a0NCT03759665, EudraCT number\u00a02018\u2013004406-25, and DR KS-ID:\u00a0DRKS00017539) was obtained by National Regulatory Authorities in each country (German Federal Institute for Drugs and Medical Devices, Spain Agency of Medicines and Medical Devices, UK Medicines and Healthcare products Regulatory Agency, and US Food and Drug Administration) and the applicable responsible central research ethics committees\/institutional review boards for each center (Ethics Committee of Ludwig Maximilian University of Munich (19\u2013119), Bellvitge Hospital University Clinical Research Ethics Committee (AC004\/19), North West\u2013Greater Manchester South (260774), Mayo Clinic Institutional Review Board (19\u2013000373), Office of Science and Research Institutional Review Board, New York University School of Medicine (i17-01666), and University of California Los Angeles Institutional Review Board (19\u2013000348)). Written informed consent was obtained for all study participants by the patient or, if applicable, their parent or legal representative.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Informed consent was obtained from all individual participants included in the study and\/or their legal guardian(s).","order":3,"name":"Ethics","label":"Informed consent","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"467"}}