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Int. J. Mol. Sci. 2018, 19(2), 619; doi:10.3390/ijms19020619

Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy

Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain
Genetic Medicine and Rare Diseases Pediatric Institute, Hospital Sant Joan de Déu, 08002 Barcelona, Spain
Unit of Child Neurology, Department of Pediatrics, Hospital Infantil Universitario Niño Jesús de Madrid, 28009 Madrid, Spain
Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de Déu, 08002 Barcelona, Spain
U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain
Pediatric Department, Hospital Virgen de la Salud, 45004 Toledo, Spain
Pediatric Neurology Unit, Pediatrics Department, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain
Neuropediatric Department, Pediatric Service, Hospital Universitario Severo Ochoa, Leganés, 28009 Madrid, Spain
Statistics Department, Fundació Sant Joan de Déu, 08002 Barcelona, Spain
Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Universidad Autónoma de Madrid (UAM), U-746 Centre for Biomedical Research on Rare Diseases (CIBER-ER) Madrid, Instituto de Salud Carlos III, IdiPAZ, 28009 Madrid, Spain
Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona, Secció de Neurologia Pediàtrica, Hospital Universitari Vall d’Hebron, 08002 Barcelona, Spain
Both authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Received: 10 January 2018 / Revised: 15 February 2018 / Accepted: 18 February 2018 / Published: 22 February 2018
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases)
View Full-Text   |   Download PDF [2561 KB, uploaded 23 February 2018]   |  


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’ group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α) 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 α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α2δ 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. View Full-Text
Keywords: ataxia; cerebellum; congenital disorders of glycosylation; magentic resonance Imaging (MRI); stroke-like; CaV2.1 voltage-gated calcium channel ataxia; cerebellum; congenital disorders of glycosylation; magentic resonance Imaging (MRI); stroke-like; CaV2.1 voltage-gated calcium channel

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Izquierdo-Serra, M.; Martínez-Monseny, A.F.; López, L.; Carrillo-García, J.; Edo, A.; Ortigoza-Escobar, J.D.; García, Ó.; Cancho-Candela, R.; Carrasco-Marina, M.L.; Gutiérrez-Solana, L.G.; Cuadras, D.; Muchart, J.; Montero, R.; Artuch, R.; Pérez-Cerdá, C.; Pérez, B.; Pérez-Dueñas, B.; Macaya, A.; Fernández-Fernández, J.M.; Serrano, M. Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy. Int. J. Mol. Sci. 2018, 19, 619.

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