Dystroglycanopathies are a subtype of congenital muscular dystrophy (CMD) of varying severity that can affect the brain and eyes, ranging from Walker-Warburg syndrome with severe brain malformation to milder CMD presentations with affected or normal cognition and later onset. Mutations in dystroglycanopathy genes affect a specific glycoepitope on α-dystroglycan (αDG); of the 14 genes implicated to date, LARGE is the glycosyltransferase that adds the final xylose and glucuronic acid, allowing αDG 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 1 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.

No abstract

No abstract

No abstract