{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T10:12:58Z","timestamp":1791886378087,"version":"4.3.4"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T00:00:00Z","timestamp":1710460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"State Ministry for Education and Research in Saxony"},{"name":"Germany Ministry","award":["100601615"],"award-info":[{"award-number":["100601615"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. This perception has been altered in recent years, as a growing number of leukodystrophies have been described as having an onset in adulthood. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis.<\/jats:p>\n               <jats:p>We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later displayed severe degeneration and loss. In addition, despite the loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed.<\/jats:p>\n               <jats:p>A structural comparison of the variants in CST3 suggests that specific truncations of cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level.<\/jats:p>","DOI":"10.1093\/brain\/awae085","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T23:13:41Z","timestamp":1710371621000},"page":"3562-3572","source":"Crossref","is-referenced-by-count":11,"title":["Dominant <i>CST3<\/i> variants cause adult onset leukodystrophy without amyloid angiopathy"],"prefix":"10.1093","volume":"147","author":[{"given":"Caroline G","family":"Bergner","sequence":"first","affiliation":[{"name":"Department of Neurology, University Hospital Leipzig , Leipzig 04103 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjolein","family":"Breur","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Emma Children\u2019s Hospital, Amsterdam University Medical Centers, and Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, Cellular & Molecular Mechanisms, VU University Amsterdam , Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Clara","family":"Soto-Bernardini","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Leipzig , Leipzig 04103 ,","place":["Germany"]},{"name":"Center for Research in Biotechnology (CIB), Costa Rica Institute of Technology (TEC) , Cartago 159-7050 ,","place":["Costa Rica"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9714-9682","authenticated-orcid":false,"given":"Lisa","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Leipzig , Leipzig 04103 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Lier","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Leipzig , Leipzig 04103 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7289-2552","authenticated-orcid":false,"given":"Diana","family":"Le Duc","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center , Leipzig 04103 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linnaeus","family":"Bundalian","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center , Leipzig 04103 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Schubert","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center , Leipzig 04103 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1535-3146","authenticated-orcid":false,"given":"David","family":"Brenner","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hosptital Ulm , Ulm 89070 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedmar R","family":"Kreuz","sequence":"additional","affiliation":[{"name":"Center of Human Genetics Tuebingen , Tuebingen 72076 ,","place":["Germany"]},{"name":"CeGaT GmbH Tuebingen , Tuebingen 72076 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Schulte","sequence":"additional","affiliation":[{"name":"Center of Human Genetics Tuebingen , Tuebingen 72076 ,","place":["Germany"]},{"name":"CeGaT GmbH Tuebingen , Tuebingen 72076 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quinten","family":"Waisfisz","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam University Medical Centers location Vrije Universiteit Amsterdam , 1081 HV Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Bugiani","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Emma Children\u2019s Hospital, Amsterdam University Medical Centers, and Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, Cellular & Molecular Mechanisms, VU University Amsterdam , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Department of Pathology, Amsterdam University Medical Centers , Amsterdam, 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6058-9545","authenticated-orcid":false,"given":"Wolfgang","family":"K\u00f6hler","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Leipzig , Leipzig 04103 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinrich","family":"Sticht","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg , Erlangen 91054 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rami","family":"Abou Jamra","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center , Leipzig 04103 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8912-0954","authenticated-orcid":false,"given":"Marjo 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