{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T01:17:06Z","timestamp":1789953426674,"version":"4.0.1"},"reference-count":53,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,22]],"date-time":"2018-02-22T00:00:00Z","timestamp":1519257600000},"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>Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients\u2019 group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (\u03b11A and \u03b12\u03b1) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at \u03b11A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the \u03b12\u03b4 subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.<\/jats:p>","DOI":"10.3390\/ijms19020619","type":"journal-article","created":{"date-parts":[[2018,2,22]],"date-time":"2018-02-22T07:05:41Z","timestamp":1519283141000},"page":"619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3524-8052","authenticated-orcid":false,"given":"Merc\u00e8","family":"Izquierdo-Serra","sequence":"first","affiliation":[{"name":"Laboratori de Fisiologia Molecular, Departament de Ci\u00e8ncies Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Mart\u00ednez-Monseny","sequence":"additional","affiliation":[{"name":"Genetic Medicine and Rare Diseases Pediatric Institute, Hospital Sant Joan de D\u00e9u, 08002 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Unit of Child Neurology, Department of Pediatrics, Hospital Infantil Universitario Ni\u00f1o Jes\u00fas de Madrid, 28009 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Carrillo-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Laboratori de Fisiologia Molecular, Departament de Ci\u00e8ncies Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Edo","sequence":"additional","affiliation":[{"name":"Laboratori de Fisiologia Molecular, Departament de Ci\u00e8ncies Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Ortigoza-Escobar","sequence":"additional","affiliation":[{"name":"Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de D\u00e9u, 08002 Barcelona, Spain"},{"name":"U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d3scar","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Pediatric Department, Hospital Virgen de la Salud, 45004 Toledo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6561-2209","authenticated-orcid":false,"given":"Ram\u00f3n","family":"Cancho-Candela","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Pediatrics Department, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Carrasco-Marina","sequence":"additional","affiliation":[{"name":"Neuropediatric Department, Pediatric Service, Hospital Universitario Severo Ochoa, Legan\u00e9s, 28009 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Guti\u00e9rrez-Solana","sequence":"additional","affiliation":[{"name":"Unit of Child Neurology, Department of Pediatrics, Hospital Infantil Universitario Ni\u00f1o Jes\u00fas de Madrid, 28009 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8780-1764","authenticated-orcid":false,"given":"Daniel","family":"Cuadras","sequence":"additional","affiliation":[{"name":"Statistics Department, Fundaci\u00f3 Sant Joan de D\u00e9u, 08002 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Muchart","sequence":"additional","affiliation":[{"name":"Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de D\u00e9u, 08002 Barcelona, Spain"},{"name":"U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Montero","sequence":"additional","affiliation":[{"name":"Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de D\u00e9u, 08002 Barcelona, Spain"},{"name":"U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Artuch","sequence":"additional","affiliation":[{"name":"Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de D\u00e9u, 08002 Barcelona, Spain"},{"name":"U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"P\u00e9rez-Cerd\u00e1","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares (CEDEM), Universidad Aut\u00f3noma de Madrid (UAM), U-746 Centre for Biomedical Research on Rare Diseases (CIBER-ER) Madrid, Instituto de Salud Carlos III, IdiPAZ, 28009 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares (CEDEM), Universidad Aut\u00f3noma de Madrid (UAM), U-746 Centre for Biomedical Research on Rare Diseases (CIBER-ER) Madrid, Instituto de Salud Carlos III, IdiPAZ, 28009 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"P\u00e9rez-Due\u00f1as","sequence":"additional","affiliation":[{"name":"Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de D\u00e9u, 08002 Barcelona, Spain"},{"name":"U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfons","family":"Macaya","sequence":"additional","affiliation":[{"name":"Grup de Recerca en Neurologia Pedi\u00e0trica, Institut de Recerca Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona, Secci\u00f3 de Neurologia Pedi\u00e0trica, Hospital Universitari Vall d\u2019Hebron, 08002 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2330-8449","authenticated-orcid":false,"given":"Jos\u00e9","family":"Fern\u00e1ndez-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Laboratori de Fisiologia Molecular, Departament de Ci\u00e8ncies Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2056-2428","authenticated-orcid":false,"given":"Mercedes","family":"Serrano","sequence":"additional","affiliation":[{"name":"Genetic Medicine and Rare Diseases Pediatric Institute, Hospital Sant Joan de D\u00e9u, 08002 Barcelona, Spain"},{"name":"Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de D\u00e9u, 08002 Barcelona, Spain"},{"name":"U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S1474-4422(12)70040-6","article-title":"Neurology of inherited glycosylation disorders","volume":"11","author":"Freeze","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1203\/00006450-200211000-00003","article-title":"Congenital disorders of glycosylation: A review","volume":"52","author":"Matthijs","year":"2002","journal-title":"Pediatr. 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