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The\n                    <jats:italic>ARSA<\/jats:italic>\n                    variants c.256C&gt;T, p.(Arg86Trp), c.257G&gt;A, p.(Arg86Gln) and c.542T&gt;G, p.(Ile181Ser) are associated with predominantly cognitive decline. This multinational study analyzed MLD onset type, presenting signs\/symptoms, cognitive function, gross motor function, central motor tract involvement, MRI severity score, peripheral neuropathy, and survival of 47 patients (three homozygous for c.256C&gt;T and five, twelve and 27 compound heterozygous for c.256C&gt;T, c.257G&gt;A, or c.542T&gt;G and another\n                    <jats:italic>ARSA<\/jats:italic>\n                    variant, respectively). Eleven underwent hematopoietic stem cell transplantation (HSCT). Onset was late\u2010juvenile (46.8%) or adult (44.7%) with predominantly cognitive decline (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200940\/41 symptomatic patients). At diagnosis, untreated patients typically retained independent walking (100%), sparing of central motor tracts (87.5%), and absence of demyelinating neuropathy (95.5%), which persisted in follow\u2010up for most (76.5%, 71.4%, and 64.7%, respectively). Early\u2010juvenile onset and rapid motor decline occurred only in patients compound heterozygous for c.256C&gt;T and a severe second variant (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20094), showing central motor tract involvement at diagnosis. One untreated and one treated patient died of disease progression, and another from HSCT complications. All other treated patients retained independent walking, and four of five tested normal cognitive function. Median MRI severity score remained lower in treated (13) than untreated patients (25). The phenotype of c.256C&gt;T carriers depends on the severity of the second\n                    <jats:italic>ARSA<\/jats:italic>\n                    variant. Patients harboring c.257G&gt;A or c.542T&gt;G show late\u2010juvenile or adult onset with cognitive decline and preserved motor function, usually associated with sparing of central motor tracts. In these patients, cognitive function and MRI severity score should be preferred treatment outcomes.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70072","type":"journal-article","created":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T12:03:42Z","timestamp":1754136222000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<i>ARSA<\/i>\n                    Variants Associated With Cognitive Decline and Long\u2010Term Preservation of Motor Function in Metachromatic Leukodystrophy"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2945-6784","authenticated-orcid":false,"given":"Shanice","family":"Beerepoot","sequence":"first","affiliation":[{"name":"Amsterdam Leukodystrophy Center, Department of Child Neurology Emma Children's Hospital, Amsterdam UMC, Location Vrije Universiteit  Amsterdam the Netherlands"},{"name":"Amsterdam Neuroscience Cellular &amp; Molecular Mechanisms, Vrije Universiteit  Amsterdam the Netherlands"},{"name":"Nierkens and Lindemans Group, Princess M\u00e1xima Center for Pediatric Oncology  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1601-7379","authenticated-orcid":false,"given":"Daphne H.","family":"Schoenmakers","sequence":"additional","affiliation":[{"name":"Amsterdam Leukodystrophy Center, Department of Child Neurology Emma Children's Hospital, Amsterdam UMC, Location Vrije Universiteit  Amsterdam the Netherlands"},{"name":"Amsterdam Neuroscience Cellular &amp; Molecular Mechanisms, Vrije Universiteit  Amsterdam the Netherlands"},{"name":"Platform \u201cMedicine for Society\u201d, Department of Endocrinology and Metabolism Amsterdam UMC, Location University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7476-4087","authenticated-orcid":false,"given":"Francesca","family":"Fumagalli","sequence":"additional","affiliation":[{"name":"San Raffaele Telethon Institute for Gene Therapy (SR\u2010TIGET), IRCCS San Raffaele Scientific Institute  Milan Italy"},{"name":"Pediatric Immunohematology Unit and BMT Program IRCCS San Raffaele Scientific Institute  Milan Italy"},{"name":"Neurology and Neurophysiology Unit IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2706-7163","authenticated-orcid":false,"given":"Samuel","family":"Groeschel","sequence":"additional","affiliation":[{"name":"Neuropaediatrics, General Paediatrics, Diabetology, Endocrinology and Social Paediatrics University of T\u00fcbingen, University Hospital T\u00fcbingen  T\u00fcbingen 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