{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:29:55Z","timestamp":1789583395644,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>MEDNIK syndrome (Mental Retardation, Enteropathy, Deafness, Neuropathy, Ichthyosis and Keratodermia) is a severe hyper-rare condition resulting from the biallelic variants in the AP1S1 gene, implicated in intracellular trafficking and copper homeostasis. Only 18 affected individuals (seven AP1S1 pathogenic variants overall) have been reported to date, with a high early lethality due to life-threatening congenital enteropathy. Seven patients have been empirically treated with zinc. Due to the paucity of literature data, little is known about the clinical course of individuals affected by MEDNIK syndrome, and the possible early association with epilepsy needs to be investigated. We present the first case of Italian origin affected by MEDNIK syndrome carrying a new homozygous AP1S1 stop variant, presenting with congenital severe enteropathy and feeding-related seizures, thus representing an early, singular manifestation of the disease. We describe her clinical course and the zinc acetate therapeutic experience. We also reviewed the literature focusing on clinical manifestations (especially neurological), brain neuroimaging and the symptom evolution of patients with AP1S1-related MEDNIK syndrome and discuss possible future therapeutic attempts.<\/jats:p>","DOI":"10.3390\/jcm15010106","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:27:47Z","timestamp":1766500067000},"page":"106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Feeding-Triggered Seizures in a Newborn with AP1S1-Related MEDNIK Syndrome: Expanding the Phenotype of a Hyper-Rare Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5976-1873","authenticated-orcid":false,"given":"Anna","family":"Cavalli","sequence":"first","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Arcispedale Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0976-1258","authenticated-orcid":false,"given":"Francesca","family":"Peluso","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Santa Maria Nuova Hospital, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Frattini","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Arcispedale Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0092-5604","authenticated-orcid":false,"given":"Carlo Alberto","family":"Cesaroni","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Arcispedale Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9594-6442","authenticated-orcid":false,"given":"Carolina","family":"Bondi","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Arcispedale Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Malmusi","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Arcispedale Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelaide","family":"Peruzzi","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Santa Maria Nuova Hospital, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8856-9722","authenticated-orcid":false,"given":"Susanna","family":"Rizzi","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Arcispedale Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1501-0146","authenticated-orcid":false,"given":"Agnese","family":"Pantani","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Arcispedale Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8236-8316","authenticated-orcid":false,"given":"Gabriele","family":"Trimarchi","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Santa Maria Nuova Hospital, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nives","family":"Melli","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Arcispedale Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9037-4297","authenticated-orcid":false,"given":"Antonio","family":"Novelli","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Zuntini","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Santa Maria Nuova Hospital, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104698","DOI":"10.1016\/j.isci.2022.104698","article-title":"Estimating the Number of Diseases\u2014The Concept of Rare, Ultra-Rare, and Hyper-Rare","volume":"25","author":"Smith","year":"2022","journal-title":"iScience"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00439-004-1193-8","article-title":"An Atypical Form of Erythrokeratodermia Variabilis Maps to Chromosome 7q22","volume":"116","author":"Saba","year":"2005","journal-title":"Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Montpetit, A., C\u00f4t\u00e9, S., Brustein, E., Drouin, C.A., Lapointe, L., Boudreau, M., Meloche, C., Drouin, R., Hudson, T.J., and Drapeau, P. (2008). Disruption of AP1S1, Causing a Novel Neurocutaneous Syndrome, Perturbs Development of the Skin and Spinal Cord. PLoS Genet., 4.","DOI":"10.1371\/journal.pgen.1000296"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1093\/brain\/awt012","article-title":"MEDNIK Syndrome: A Novel Defect of Copper Metabolism Treatable by Zinc Acetate Therapy","volume":"136","author":"Martinelli","year":"2013","journal-title":"Brain"},{"key":"ref_5","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (2024). IDEDNIK Syndrome. GeneReviews\u00ae [Internet], University of Washington."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/nyas.12426","article-title":"AP1S1 Defect Causing MEDNIK Syndrome: A New Adaptinopathy Associated with Defective Copper Metabolism","volume":"1314","author":"Martinelli","year":"2014","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/s41392-022-01229-y","article-title":"Copper Homeostasis and Cuproptosis in Health and Disease","volume":"7","author":"Chen","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wi\u0119cek, S., and Paprocka, J. (2024). Disorders of Copper Metabolism in Children\u2014A Problem Too Rarely Recognized. Metabolites, 14.","DOI":"10.3390\/metabo14010038"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1007\/s11011-018-0313-4","article-title":"MEDNIK Syndrome with a Frame Shift Causing Mutation in AP1S1 Gene and Literature Review of the Clinical Features","volume":"33","author":"Incecik","year":"2018","journal-title":"Metab. Brain Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1177\/10935266231177402","article-title":"Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant","volume":"26","author":"Lu","year":"2023","journal-title":"Pediatr. Dev. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1007\/s00109-024-02482-0","article-title":"Revising Pathogenesis of AP1S1-Related MEDNIK Syndrome: A Missense Variant in the AP1S1 Gene as a Causal Genetic Lesion","volume":"102","author":"Rackova","year":"2024","journal-title":"J. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4385128","DOI":"10.1155\/ijog\/4385128","article-title":"Clinical and Genetic Functional Validation of a Novel AP1S1 Mutation Causing MEDNIK Syndrome","volume":"2025","author":"Duan","year":"2025","journal-title":"Int. J. Genomics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s00439-020-02168-w","article-title":"AP1S1 Missense Mutations Cause a Congenital Enteropathy via an Epithelial Barrier Defect","volume":"139","author":"Klee","year":"2020","journal-title":"Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1002\/humu.9442","article-title":"Frequency and Localization of Mutations in the 106 Exons of theRYR1 Gene in 50 Individuals with Malignant Hyperthermia","volume":"27","author":"Galli","year":"2006","journal-title":"Hum. Mutat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"E575","DOI":"10.1002\/humu.20991","article-title":"Functional Characterization of Ryanodine Receptor (RYR1) Sequence Variants Using a Metabolic Assay in Immortalized B-Lymphocytes","volume":"30","author":"Zullo","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1111\/j.1399-0004.2010.01493.x","article-title":"Novel Missense Mutations and Unexpected Multiple Changes of RYR1 Gene in 75 Malignant Hyperthermia Families","volume":"79","author":"Tammaro","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1016\/j.bja.2018.06.028","article-title":"Genetic Epidemiology of Malignant Hyperthermia in the UK","volume":"121","author":"Miller","year":"2018","journal-title":"Br. J. Anaesth."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: Public Archive of Relationships among Sequence Variation and Human Phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cai, S., Gong, J.-Y., Yang, J., and Wang, J.-S. (2019). Anemia Following Zinc Treatment for Wilson\u2019s Disease: A Case Report and Literature Review. BMC Gastroenterol., 19.","DOI":"10.1186\/s12876-019-1038-5"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Litwin, T., Antos, A., Bembenek, J., Przyby\u0142kowski, A., Kurkowska-Jastrz\u0119bska, I., Skowro\u0144ska, M., and Cz\u0142onkowska, A. (2023). Copper Deficiency as Wilson\u2019s Disease Overtreatment: A Systematic Review. Diagnostics, 13.","DOI":"10.3390\/diagnostics13142424"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1097\/MPG.0000000000001787","article-title":"Wilson\u2019s Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition","volume":"66","author":"Socha","year":"2018","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s10238-024-01302-6","article-title":"Role of Zinc in Health and Disease","volume":"24","author":"Stiles","year":"2024","journal-title":"Clin. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"An, Y., Li, S., Huang, X., Chen, X., Shan, H., and Zhang, M. (2022). The Role of Copper Homeostasis in Brain Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232213850"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1523\/JNEUROSCI.3699-04.2005","article-title":"NMDA Receptor Activation Mediates Copper Homeostasis in Hippocampal Neurons","volume":"25","author":"Schlief","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1111\/ejn.16370","article-title":"The Physiological and Pathophysiological Roles of Copper in the Nervous System","volume":"60","author":"Gale","year":"2024","journal-title":"Eur. J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/j.braindev.2011.08.002","article-title":"Menkes Disease and Infantile Epilepsy","volume":"33","author":"Prasad","year":"2011","journal-title":"Brain Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1111\/cns.13373","article-title":"Clinical Features and Outcome of Wilson\u2019s Disease with Generalized Epilepsy in Chinese Patients","volume":"26","author":"Wang","year":"2020","journal-title":"CNS Neurosci. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.seizure.2010.07.018","article-title":"Partial Status Epilepticus Induced by Hypocupremia in a Patient with Wilson\u2019s Disease","volume":"19","author":"Benbir","year":"2010","journal-title":"Seizure"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1136\/pn-2025-004598","article-title":"Hypocupraemia-Related Drug-Refractory Seizures in Wilson Disease","volume":"25","author":"Mahajan","year":"2025","journal-title":"Pract. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e59","DOI":"10.1016\/j.jns.2013.07.209","article-title":"Increased Seizure Frequency Due to the Copper Deficiency in Wilson\u2019s Disease","volume":"333","author":"Kaleagasi","year":"2013","journal-title":"J. Neurol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/13543784.2021.1840550","article-title":"Repurposing Elesclomol, an Investigational Drug for the Treatment of Copper Metabolism Disorders","volume":"30","author":"Gohil","year":"2021","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1186\/s12967-023-04533-5","article-title":"Elesclomol, a Copper-Transporting Therapeutic Agent Targeting Mitochondria: From Discovery to Its Novel Applications","volume":"21","author":"Tarin","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e193107","DOI":"10.1172\/JCI193107","article-title":"Elesclomol-Copper Therapy Improves Neurodevelopment in Two Children with Menkes Disease","volume":"135","author":"Serrano","year":"2025","journal-title":"J. Clin. Investig."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/106\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T05:27:21Z","timestamp":1766813241000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["jcm15010106"],"URL":"https:\/\/doi.org\/10.3390\/jcm15010106","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]}}}