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Journal of Neuropathology & Experimental Neurology:
doi: 10.1097/NEN.0000000000000065
Original Articles

Clinical, Pathologic, and Mutational Spectrum of Dystroglycanopathy Caused by LARGE Mutations

Meilleur, Katherine G. PhD; Zukosky, Kristen MS; Medne, Livija MS; Fequiere, Pierre MD; Powell-Hamilton, Nina MD; Winder, Thomas L. PhD; Alsaman, Abdulaziz MD; El-Hattab, Ayman W. MD; Dastgir, Jahannaz DO; Hu, Ying MS; Donkervoort, Sandra MS; Golden, Jeffrey A. MD; Eagle, Ralph MD; Finkel, Richard MD; Scavina, Mena MD; Hood, Ian C. MB, ChB; Rorke-Adams, Lucy B. MD; Bönnemann, Carsten G. MD

Supplemental Author Material
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Abstract: Dystroglycanopathies are a subtype of congenital muscular dystrophy of varying severity that can affect the brain and eyes, ranging from Walker-Warburg syndrome with severe brain malformation to milder congenital muscular dystrophy presentations with affected or normal cognition and later onset. Mutations in dystroglycanopathy genes affect a specific glycoepitope on α-dystroglycan; of the 14 genes implicated to date, LARGE encodes the glycosyltransferase that adds the final xylose and glucuronic acid, allowing α-dystroglycan to bind ligands, including laminin 211 and neurexin. Only 11 patients with LARGE mutations have been reported. We report the clinical, neuroimaging, and genetic features of 4 additional patients. We confirm that gross deletions and rearrangements are important mutational mechanisms for LARGE. The brain abnormalities overshadowed the initially mild muscle phenotype in all 4 patients. We present the first comprehensive postnatal neuropathology of the brain, spinal cord, and eyes of a patient with a homozygous LARGE mutation at Cys443. In this patient, polymicrogyria was the predominant cortical malformation; densely festooned polymicrogyria were overlaid by a continuous agyric surface. In view of the severity of these abnormalities, Cys443 may be a functionally important residue in the LARGE protein, whereas the mutation p.Glu509Lys of Patient 1 in this study may confer a milder phenotype. Overall, these results expand the clinical and genetic spectrum of dystroglycanopathy.

© 2014 by American Association of Neuropathologists, Inc.


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