Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies.
Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria. After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32-50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1, POMT2, POMGNT1, LARGE and FKRP. Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s).
Institut de Pathologie, Centre de Biologie-Pathologie, CHU Lille, 33.3.20446983, France.
Louise
L
Devisme
Céline
C
Bouchet
Marie
M
Gonzalès
Elisabeth
E
Alanio
Anne
A
Bazin
Bettina
B
Bessières
Nicole
N
Bigi
Patricia
P
Blanchet
Dominique
D
Bonneau
Maryse
M
Bonnières
Martine
M
Bucourt
Dominique
D
Carles
Bénedicte
B
Clarisse
Sophie
S
Delahaye
Catherine
C
Fallet-Bianco
Dominique
D
Figarella-Branger
Dominique
D
Gaillard
Bernard
B
Gasser
Anne-Lise
AL
Delezoide
Fabien
F
Guimiot
Madeleine
M
Joubert
Nicole
N
Laurent
Annie
A
Laquerrière
Agnès
A
Liprandi
Philippe
P
Loget
Pascale
P
Marcorelles
Jelena
J
Martinovic
Francoise
F
Menez
Sophie
S
Patrier
Fanny
F
Pelluard
Marie-José
MJ
Perez
Caroline
C
Rouleau
Stéphane
S
Triau
Tania
T
Attié-Bitach
Sandrine
S
Vuillaumier-Barrot
Nathalie
N
Seta
Férechté
F
Encha-Razavi
D001921:Brain / Q000378:metabolism / Q000473:pathology*; D054222:Cobblestone Lissencephaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D049030:Dystroglycans / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005333:Fetus; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D010430:Pentosyltransferases; D011506:Proteins / Q000235:genetics / Q000378:metabolism
C113587:FKTN protein, human; D008565:Membrane Proteins; D011506: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; C443107:FKRP protein, human; D010430:Pentosyltransferases