Brain involvement in muscular dystrophies with defective dystroglycan glycosylation.
OBJECTIVE
To assess the range and severity of brain involvement, as assessed by magnetic resonance imaging, in 27 patients with mutations in POMT1 (4), POMT2 (9), POMGnT1 (7), Fukutin (4), or LARGE (3), responsible for muscular dystrophies with abnormal glycosylation of dystroglycan (dystroglycanopathies).


METHODS
Blinded review of magnetic resonance imaging brain scans from 27 patients with mutations in 1 of these 5 genes.


RESULTS
Brain magnetic resonance images were normal in 3 of 27 patients; in another 5, only nonspecific abnormalities (ventricular dilatation, periventricular white matter abnormalities, or both) were seen. The remaining 19 patients had a spectrum of structural defects, ranging from complete lissencephaly in patients with Walker-Warburg syndrome to isolated cerebellar involvement. Cerebellar cysts and/or dysplasia and hypoplasia were the predominant features in four patients. Polymicrogyria (11/27) was more severe in the frontoparietal regions in 6, and had an occipitofrontal gradient in 2. Pontine clefts, with an unusual appearance to the corticospinal tracts, were seen in five patients with a muscle-eye-brain-like phenotype, three patients with POMGnT1, one with LARGE, and one with POMT2 mutations. Prominent cerebellar cysts were always seen with POMGnT1 mutations, but rarely seen in POMT1 and POMT2. Brainstem and pontine abnormalities were common in patients with POMT2, POMGnT1, and LARGE mutations.


CONCLUSIONS
Our results expand the spectrum of brain involvement associated with mutations in LARGE, POMGnT1, POMT1, and POMT2. Pontine clefts were visible in some dystroglycanopathy patients. Infratentorial structures were often affected in isolation, highlighting their susceptibility to involvement in these conditions.
Clement
Emma
E
Dubowitz Neuromuscular Unit, Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom.
Mercuri
Eugenio
E
Godfrey
Caroline
C
Smith
Janine
J
Robb
Stephanie
S
Kinali
Maria
M
Straub
Volker
V
Bushby
Kate
K
Manzur
Adnan
A
Talim
Beril
B
Cowan
Frances
F
Quinlivan
Ros
R
Klein
Andrea
A
Longman
Cheryl
C
McWilliam
Robert
R
Topaloglu
Haluk
H
Mein
Rachael
R
Abbs
Stephen
S
North
Kathryn
K
Barkovich
A James
AJ
Rutherford
Mary
M
Muntoni
Francesco
F
D000293:Adolescent; D001921:Brain / Q000002:abnormalities* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D049030:Dystroglycans / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008364:Mannosyltransferases / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009136:Muscular Dystrophies / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D009421:Nervous System Malformations / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype
C113587:FKTN protein, human; D008565:Membrane Proteins; D049030:Dystroglycans; C117674:LARGE1 protein, human; D008364:Mannosyltransferases; D017351:N-Acetylglucosaminyltransferases; C443106:protein O-mannose beta-1,2-N-acetylglucosaminyltransferase; C082696:protein O-mannosyltransferase