{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T03:34:19Z","timestamp":1784691259434,"version":"3.55.0"},"reference-count":23,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"RC 2023 Italian Ministry of Health (RB e SDV)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>NOTCH1-related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in NOTCH1 that neuroradiologically show some overlap with the inflammatory microangiopathy Aicardi-Gouti\u00e8res syndrome (AGS). To report a 16-year-old boy harbouring a novel NOTCH1 mutation who presented neuroradiological features suggestive of enhanced type I interferon signalling. We describe five years of follow-up and review the current literature on NOTCH1-related leukoencephalopathy. Clinical evaluation, standardised scales (SPRS, SARA, CBCL, CDI-2:P, WISCH-IV and VABS-2) and neuroradiological studies were performed, as well as blood DNA analysis. For the literature review, a search was performed on Pubmed, Scopus and Web of Science up to December 2023 using the following text word search strategy: (NOTCH1) AND (leukoencephalopathy). Our patient presents clinical features consistent with other reported cases with NOTCH1 mutations but is among the minority of patients with an onset after infancy. During the five-year follow-up, we observed an increase in the severity of spasticity and ataxia. However, at the age of 16 years, our proband is still ambulatory. As for other reported patients, he manifests psychiatric features ranging from hyperactivity during childhood to anxiety and depression during adolescence. The neuroradiological picture remained essentially stable over five years. In addition to the typical findings of leukoencephalopathy with cysts and calcifications already described, we report the presence of T2-hyperintensity and T1-hypotensity of the transverse pontine fibres, enhancement in the periventricular white matter after gadolinium administration and decreased NAA and Cho peaks in the periventricular white matter on MRS. We identified a novel heterozygous variant in NOTCH1 (c.4788_4799dup), a frame insertion located in extracellular negative regulatory region (NRR)-domain as in previously published cases. Blood interferon signalling was not elevated compared to controls. This case provides further data on a new diagnostic entity, i.e., NOTCH1-related leukoencephalopathy. By describing a standardised five-year follow-up in one case and reviewing the other patients described to date, we outline recommendations relating to monitoring in this illness, emphasising the importance of psychiatric and gastroenterological surveillance alongside neurological and neuropsychological management. Studies are needed to better understand the factors influencing disease onset and severity, which are heterogeneous.<\/jats:p>","DOI":"10.3390\/ijms25052864","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T06:07:53Z","timestamp":1709273273000},"page":"2864","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review"],"prefix":"10.3390","volume":"25","author":[{"given":"Stefania","family":"Della Vecchia","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Neurogenetics, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"},{"name":"Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Tessa","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Neurogenetics, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Pasquariello","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4678-3026","authenticated-orcid":false,"given":"Luis","family":"Seabra","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, University of Paris, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanick J.","family":"Crow","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, University of Paris, 75015 Paris, France"},{"name":"MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Battini","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.ajhg.2014.07.011","article-title":"Mutations in NOTCH1 cause Adams-Oliver syndrome","volume":"95","author":"Stittrich","year":"2014","journal-title":"Am. 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