Clinical, Pathologic, and Mutational Spectrum of Dystroglycanopathy Caused byLARGEMutations

Abstract

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.

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“…LARGE1 is a member of the N ‐acetylglucosaminyltransferase gene family and encodes a glycosyltransferase which participates in glycosylation of alpha‐dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. Mutation and deletion of this gene have been reported in congenital muscular dystrophy with severe mental retardation (Clarke et al, ; Meilleur et al, ).…”

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“…Each patient harbored predicted pathogenic mutations in a different gene required for the glycosylation of αDG: LARGE , FKRP , or POMT2 (Table 1). The LARGE patient has been reported in a previous publication [33].…”

“…Overall, the FKRP patient had the mildest clinical and muscle biopsy findings, while the patient with the POMT2 mutations had the most severe findings. Brain magnetic resonance imaging showed minor white matter and structural abnormalities in the LARGE patient [33] and POMT2 patient (data not shown). Hypoglycosylation of αDG is the primary causative factor in the pathogenesis of dystroglycanopathy [34].…”

“…The human brain specifically undergoes greatest expansion in the occipital, temporal, and lateral parietal cortices [12]. Such regional growth dynamics suggest one possible basis for the spatial arrangement of the typical cortical malformation in the dystroglycanopathies, which are fundamentally due to breaches in basement membrane integrity, resulting in cellular over-migration beyond the confines of the [1, 7, 33, 50]. These particular growth dynamics may also underlie some of the differences between human patients and mouse models [3].…”

Dystroglycanopathies: About Numerous Genes Involved in Glycosylation of One Single Glycoprotein

“…Mutations in LARGE (so called because of its size), first reported in 2003 [48], have been found in foetal cases [49] as well as in individuals, 15 patients with different clinical presentations from 12 families [50,51], contrary to LARGE2 which has never been described as mutated.…”