Clinical, pathologic, and mutational spectrum of dystroglycanopathy caused by LARGE mutations
| Autor: | Livija Medne, Carsten G. Bönnemann, Sandra Donkervoort, Pierre R. Fequiere, Lucy B. Rorke-Adams, Katherine G. Meilleur, Ayman W. El-Hattab, Ian C. Hood, Abdulaziz Al-Saman, Jeffrey A. Golden, Richard S. Finkel, Jahannaz Dastgir, Ying Hu, Nina Powell-Hamilton, Ralph C. Eagle, Thomas L. Winder, Mena Scavina, Kristen Zukosky |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Pathology medicine.medical_specialty Neurexin Neuropathology Biology medicine.disease_cause N-Acetylglucosaminyltransferases Polymorphism Single Nucleotide Muscular Dystrophies Article Pathology and Forensic Medicine Cellular and Molecular Neuroscience Fatal Outcome Laminin medicine Polymicrogyria Humans Child Dystroglycans Gene Mutation Homozygote Infant General Medicine medicine.disease Phenotype Pedigree Neurology Child Preschool biology.protein Congenital muscular dystrophy Female Neurology (clinical) |
| Zdroj: | Journal of neuropathology and experimental neurology. 73(5) |
| ISSN: | 1554-6578 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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