Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG)

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 Ca2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variab...

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Detalles Bibliográficos
Autores: Izquierdo-Serra, Mercè|||0000-0002-3524-8052, Martínez-Monseny, Antonio F., López López, Laura|||0000-0002-8653-6206, Carrillo-García, Julia, Edo Salvador, Ángel, Ortigoza-Escobar, Juan Darío, García Campos, Óscar, Cancho-Candela, Ramón|||0000-0001-6561-2209, Carrasco-Marina, M. Llanos, González Gutiérrez-Solana, Luis|||0000-0003-2890-4565, Cuadras, Daniel|||0000-0001-8780-1764, Muchart, Jordi, Montero, Raquel|||0000-0003-0609-5701, Artuch, R.|||0000-0002-3422-9685, Pérez-Cerdá, Celia, Pérez, Belén|||0000-0001-5801-1704, Pérez-Dueñas, Belén|||0000-0002-4979-2788, Macaya Ruiz, Alfons|||0000-0001-7998-4185, Fernández-Fernández, José Manuel|||0000-0003-2330-8449, Serrano, Mercedes|||0000-0002-2056-2428
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:253453
Acceso en línea:https://ddd.uab.cat/record/253453
https://dx.doi.org/urn:doi:10.3390/ijms19020619
Access Level:acceso abierto
Palabra clave:Ataxia
Cerebellum
Congenital disorders of glycosylation
Magentic resonance Imaging (MRI)
Stroke-like
Ca2.1 voltage-gated calcium channel
Descripción
Sumario: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 Ca2.1 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 Ca2.1 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 Ca2.1 subunits (α 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 contributes to a gain-of-function by lessening Ca2.1 inactivation. Hypoglycosylation of the αδ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the Ca2.1 channel. Ca2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant Ca2.1 N -glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.

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