Clinical, pathologic, and mutational spectrum of dystroglycanopathy caused by LARGE mutations.
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.
From the National Institute of Nursing Research, Bethesda, Maryland (KGM); National Institute of Neurological Disorders and Stroke, Bethesda, Maryland (KZ, JD, YH, SD, CGB); Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (LM, LBR-A); Division of Pediatric Neurology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama (PF); Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware (NP-H, MS); Prevention Genetics, Marshfield, Wisconsin (TLW); Pediatric Neurology Department, National Neuroscience Institute (AA), and Division of Medical Genetics, Department of Pediatrics, The Children's Hospital (AWE), King Fahad Medical City; and College of Medicine, King Saud bin Abdulaziz University for Health Sciences (AA,AWE), Riyadh, Kingdom of Saudi Arabia; Department of Pathology, Brigham and Women's Hospital (JAG); and Harvard Medical School (JAG), Boston, Massachusetts; Department of Pathology, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania (RE); Nemours Children's Hospital, Orlando, Florida (RF); and Medical Examiner's Office, Mount Holly, New Jersey (ICH).
Katherine G
KG
Meilleur
Kristen
K
Zukosky
Livija
L
Medne
Pierre
P
Fequiere
Nina
N
Powell-Hamilton
Thomas L
TL
Winder
Abdulaziz
A
Alsaman
Ayman W
AW
El-Hattab
Jahannaz
J
Dastgir
Ying
Y
Hu
Sandra
S
Donkervoort
Jeffrey A
JA
Golden
Ralph
R
Eagle
Richard
R
Finkel
Mena
M
Scavina
Ian C
IC
Hood
Lucy B
LB
Rorke-Adams
Carsten G
CG
Bönnemann
D002648:Child; D002675:Child, Preschool; D049030:Dystroglycans / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
C483081:DAG1 protein, human; D049030:Dystroglycans; C117674:LARGE1 protein, human; D017351:N-Acetylglucosaminyltransferases