LIS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity.
OBJECTIVE
With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype.


METHODS
Retrospective study. Subjects A total of 63 patients with posteriorly predominant lissencephaly.


METHODS
Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined.


RESULTS
Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly.


CONCLUSIONS
Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations.
Saillour
Yoann
Y
Conseil National de la Recherche Scientifique, Université Paris Descartes (Unités Mixtes de Recherche 8104) and Institut National de la Santé et de la Recherche Médicale (INSERM) U567, Paris, France.
Carion
Nathalie
N
Quelin
Chloé
C
Leger
Pierre-Louis
PL
Boddaert
Nathalie
N
Elie
Caroline
C
Toutain
Annick
A
Mercier
Sandra
S
Barthez
Marie Anne
MA
Milh
Mathieu
M
Joriot
Sylvie
S
des Portes
Vincent
V
Philip
Nicole
N
Broglin
Dominique
D
Roubertie
Agathe
A
Pitelet
Gaelle
G
Moutard
Marie Laure
ML
Pinard
Jean Marc
JM
Cances
Claude
C
Kaminska
Anna
A
Chelly
Jamel
J
Beldjord
Chérif
C
Bahi-Buisson
Nadia
N
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009460:Neurologic Examination; D010641:Phenotype; D055815:Young Adult
D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human