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

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          Abstract

          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 Ca V2.1 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 Ca V2.1 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 Ca V2.1 subunits (α 1A 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 α 1A contributes to a gain-of-function by lessening Ca V2.1 inactivation. Hypoglycosylation of the α 2δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the Ca V2.1 channel. Ca V2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant Ca V2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.

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          Voltage-gated calcium channels.

          Voltage-gated calcium (Ca(2+)) channels are key transducers of membrane potential changes into intracellular Ca(2+) transients that initiate many physiological events. There are ten members of the voltage-gated Ca(2+) channel family in mammals, and they serve distinct roles in cellular signal transduction. The Ca(V)1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells. The Ca(V)2 subfamily is primarily responsible for initiation of synaptic transmission at fast synapses. The Ca(V)3 subfamily is important for repetitive firing of action potentials in rhythmically firing cells such as cardiac myocytes and thalamic neurons. This article presents the molecular relationships and physiological functions of these Ca(2+) channel proteins and provides information on their molecular, genetic, physiological, and pharmacological properties.
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            Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model.

            Although the trigeminal nerve innervates the meninges and participates in the genesis of migraine headaches, triggering mechanisms remain controversial and poorly understood. Here we establish a link between migraine aura and headache by demonstrating that cortical spreading depression, implicated in migraine visual aura, activates trigeminovascular afferents and evokes a series of cortical meningeal and brainstem events consistent with the development of headache. Cortical spreading depression caused long-lasting blood-flow enhancement selectively within the middle meningeal artery dependent upon trigeminal and parasympathetic activation, and plasma protein leakage within the dura mater in part by a neurokinin-1-receptor mechanism. Our findings provide a neural mechanism by which extracerebral cephalic blood flow couples to brain events; this mechanism explains vasodilation during headache and links intense neurometabolic brain activity with the transmission of headache pain by the trigeminal nerve.
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              Pathophysiology of migraine.

              Migraine is a collection of perplexing neurological conditions in which the brain and its associated tissues have been implicated as major players during an attack. Once considered exclusively a disorder of blood vessels, compelling evidence has led to the realization that migraine represents a highly choreographed interaction between major inputs from both the peripheral and central nervous systems, with the trigeminovascular system and the cerebral cortex among the main players. Advances in in vivo and in vitro technologies have informed us about the significance to migraine of events such as cortical spreading depression and activation of the trigeminovascular system and its constituent neuropeptides, as well as about the importance of neuronal and glial ion channels and transporters that contribute to the putative cortical excitatory/inhibitory imbalance that renders migraineurs susceptible to an attack. This review focuses on emerging concepts that drive the science of migraine in both a mechanistic direction and a therapeutic direction.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                22 February 2018
                February 2018
                : 19
                : 2
                : 619
                Affiliations
                [1 ]Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain; merce.izquierdo@ 123456upf.edu (M.I.-S.); julia.carrillo@ 123456upf.edu (J.C.-G.); albert.edo01@ 123456estudiant.upf.edu (A.E.)
                [2 ]Genetic Medicine and Rare Diseases Pediatric Institute, Hospital Sant Joan de Déu, 08002 Barcelona, Spain; afmartinez@ 123456hsjdbcn.org
                [3 ]Unit of Child Neurology, Department of Pediatrics, Hospital Infantil Universitario Niño Jesús de Madrid, 28009 Madrid, Spain; laural.marin@ 123456hotmail.com (L.L.); lgutierrez.hnjs@ 123456salud.madrid.org (L.G.G.-S.)
                [4 ]Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de Déu, 08002 Barcelona, Spain; jortigoza@ 123456sjdhospitalbarcelona.org (J.D.O.-E.); jmuchart@ 123456hsjdbcn.org (J.M.); rmontero@ 123456hsjdbcn.org (R.M.); rartuch@ 123456hsjdbcn.org (R.A.); bperez@ 123456hsjdbcn.org (B.P.-D.)
                [5 ]U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain
                [6 ]Pediatric Department, Hospital Virgen de la Salud, 45004 Toledo, Spain; oscargarcam@ 123456hotmail.com
                [7 ]Pediatric Neurology Unit, Pediatrics Department, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain; rcanchoc@ 123456saludcastillayleon.es
                [8 ]Neuropediatric Department, Pediatric Service, Hospital Universitario Severo Ochoa, Leganés, 28009 Madrid, Spain; maria.llanos@ 123456salud.madrid.org
                [9 ]Statistics Department, Fundació Sant Joan de Déu, 08002 Barcelona, Spain; dcuadras@ 123456fsjd.org
                [10 ]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; cpcerda@ 123456cbm.csic.es (C.P.-C.); bperez@ 123456cbm.csic.es (B.P.)
                [11 ]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; amacaya@ 123456vhebron.net
                Author notes
                [* ]Correspondence: jmanuel.fernandez@ 123456upf.edu (J.M.F.-F.); mserrano@ 123456hsjdbcn.org (M.S.); Tel.: +34-93-316-0854 (J.M.F.-F.); +34-93-253-2100 (M.S.); Fax: +34-93-316-0901 (J.M.F.-F.); +34-93-280-3626 (M.S.)
                [†]

                Both authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-6561-2209
                https://orcid.org/0000-0001-8780-1764
                https://orcid.org/0000-0003-2330-8449
                https://orcid.org/0000-0002-2056-2428
                Article
                ijms-19-00619
                10.3390/ijms19020619
                5855841
                29470411
                7c1e98eb-6ac3-4a22-8af8-39ddaf5945ac
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 January 2018
                : 18 February 2018
                Categories
                Article

                Molecular biology
                ataxia,cerebellum,congenital disorders of glycosylation,magentic resonance imaging (mri),stroke-like,cav2.1 voltage-gated calcium channel

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