{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:03:44Z","timestamp":1787580224216,"version":"build-2736575974"},"reference-count":47,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>GLUT1 deficiency syndrome (GLUT1DS1; OMIM #606777) is a rare genetic metabolic disease, characterized by infantile-onset epileptic encephalopathy, global developmental delay, progressive microcephaly, and movement disorders (e.g., spasticity and dystonia). It is caused by heterozygous mutations in the SLC2A1 gene, which encodes the GLUT1 protein, a glucose transporter across the blood-brain barrier (BBB). Most commonly, these variants arise de novo resulting in sporadic cases, although several familial cases with AD inheritance pattern have been described. Twenty-seven Italian pediatric patients, clinically suspect of GLUT1DS from both sporadic and familial cases, have been enrolled. We detected by trios sequencing analysis 25 different variants causing GLUT1DS. Of these, 40% of the identified variants (10 out of 25) had never been reported before, including missense, frameshift, and splice site variants. Their structural mapping on the X-ray structure of GLUT1 strongly suggested the potential pathogenic effects of these novel disease-related mutations, broadening the genotypic spectrum heterogeneity found in the SLC2A1 gene. Moreover, 24% is located in a vulnerable region of the GLUT1 protein that involves transmembrane 4 and 5 helices encoded by exon 4, confirming a mutational hotspot in the SLC2A1 gene. Lastly, we investigated possible correlations between mutation type and clinical and biochemical data observed in our GLUT1DS cohort, revealing that splice site and frameshift variants are related to a more severe phenotype and low CSF parameters.<\/jats:p>","DOI":"10.3390\/ijms232113560","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T08:40:16Z","timestamp":1667896816000},"page":"13560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Molecular Genetics of GLUT1DS Italian Pediatric Cohort: 10 Novel Disease-Related Variants and Structural Analysis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5675-5347","authenticated-orcid":false,"given":"Alessia","family":"Mauri","sequence":"first","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy"},{"name":"Newborn Screening and Genetic Metabolic Diseases Unit, V. Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Duse","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, V. Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1142-6392","authenticated-orcid":false,"given":"Giacomo","family":"Palm","sequence":"additional","affiliation":[{"name":"Structural Biology Center, Human Technopole, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3295-0655","authenticated-orcid":false,"given":"Roberto","family":"Previtali","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, V. Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4092-7412","authenticated-orcid":false,"given":"Stefania Maria","family":"Bova","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, V. Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Olivotto","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, V. Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Newborn Screening and Genetic Metabolic Diseases Unit, V. Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Coscia","sequence":"additional","affiliation":[{"name":"Structural Biology Center, Human Technopole, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2851-3441","authenticated-orcid":false,"given":"Pierangelo","family":"Veggiotti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy"},{"name":"Pediatric Neurology Unit, V. Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9571-0862","authenticated-orcid":false,"given":"Cristina","family":"Cereda","sequence":"additional","affiliation":[{"name":"Newborn Screening and Genetic Metabolic Diseases Unit, V. Buzzi Children\u2019s Hospital, 20154 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1056\/NEJM199109053251006","article-title":"Defective Glucose Transport across the Blood-Brain Barrier as a Cause of Persistent Hypoglycorrhachia, Seizures, and Developmental Delay","volume":"325","author":"Trifiletti","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_2","unstructured":"De Vivo, D.C., Leary, L., and Wang, D. (2002). Glucose transporter 1 deficiency syndrome and other glycolytic defects. J. Child Neurol., 17, discussion 3S24-5."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S0074-7742(02)51008-4","article-title":"Glucose transporter protein syndromes","volume":"51","author":"Wang","year":"2002","journal-title":"Int. Rev. 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