{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:13:04Z","timestamp":1790748784682,"version":"4.1.0"},"reference-count":58,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T00:00:00Z","timestamp":1575244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008977","name":"Universit\u00e4t Ulm","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008977","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":[[2020,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan\u2013McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of <jats:italic>SHANK3<\/jats:italic> models have contributed to the understanding of how the loss of the synaptic protein <jats:italic>SHANK3<\/jats:italic> affects neuronal function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Diffusion tensor imaging\u2010based and automatic volumetric brain mapping were performed in 12 SHANK3\u2010deficient participants (mean age 19\u00a0\u00b1\u00a015\u00a0years) versus 14 age\u2010 and gender\u2010matched controls (mean age 29\u00a0\u00b1\u00a05\u00a0years). Using whole brain\u2013based spatial statistics, we observed a highly significant pattern of white matter alterations in participants with <jats:italic>SHANK3<\/jats:italic> mutations with focus on the long association fiber tracts, particularly the uncinate tract and the inferior fronto\u2010occipital fasciculus. In contrast, only subtle gray matter volumetric abnormalities were detectable. In a back\u2010translational approach, we observed similar white matter alterations in heterozygous isoform\u2013specific Shank3 knockout (KO) mice. Here, in the baseline data sets, the comparison of Shank3 heterozygous KO vs wildtype showed significant fractional anisotropy reduction of the long fiber tract systems in the KO model. The multiparametric Magnetic Resonance Imaging (MRI)\u00a0analysis by DTI and volumetry demonstrated a pathology pattern with severe white matter alterations and only subtle gray matter changes in the animal model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>In summary, these translational data provide strong evidence that the <jats:italic>SHANK3<\/jats:italic>\u2010deficiency\u2013associated pathomechanism presents predominantly with a white matter disease. Further studies should concentrate on the role of <jats:italic>SHANK3<\/jats:italic> during early axonal pathfinding\/wiring and in myelin formation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.50959","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T21:53:57Z","timestamp":1575323637000},"page":"46-58","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Severe white matter damage in <i>SHANK3<\/i> deficiency: a human and translational study"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6235-8145","authenticated-orcid":false,"given":"Sarah","family":"Jesse","sequence":"first","affiliation":[{"name":"Department of Neurology Ulm University Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans\u2010Peter","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Neurology Ulm University Ulm 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