LIS1-associated classic lissencephaly: A retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs.
BACKGROUND
Patients with LIS1-associated classic lissencephaly typically present with severe psychomotor retardation and drug-resistant epilepsy within the first year.


OBJECTIVE
To analyze the epileptogenic phenotype and response to antiepileptic therapy in LIS1-associated classic lissencephaly.


METHODS
Retrospective evaluation of 22 patients (8 months-24 years) with genetically and radiologically confirmed LIS1-associated classic lissencephaly in 16 study centers.


RESULTS
All patients in our cohort developed drug-resistant epilepsy. In 82% onset of seizures was noted within the first six months of life, most frequently with infantile spasms. Later in infancy the epileptogentic phenotype became more variable and included different forms of focal seizures as well generalized as tonic-clonic seizures, with generalized tonic-clonic seizures being the predominant type. Lamotrigine and valproate were rated most successful with good or partial response rates in 88-100% of the patients. Both were evaluated significantly better than levetiracetam (p<0.05) and sulthiame (p<0.01) in the neuropediatric assessment and better than levetiracetam, sulthiame (p<0.05) and topiramate (p<0.01) in the family survey. Phenobarbital and vigabatrin achieved good or partial response in 62-83% of the patients.


CONCLUSIONS
Our findings suggest that patients with LIS1-associated lissencephaly might benefit most from lamotrigine, valproate, vigabatrin or phenobarbital.
Center for and Institute of Human Genetics, University of Regensburg, Regensburg, Germany. Electronic address: saskia.herbst@ukr.de.
Saskia M
SM
Herbst
Center for and Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
Christiane R
CR
Proepper
Department of Pediatric Neurology, Klinik St. Hedwig, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
Tobias
T
Geis
Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Children's Hospital, University of Munich, Munich, Germany.
Ingo
I
Borggraefe
Department of Child Neurology, Gießen, Germany.
Andreas
A
Hahn
Clemenshospital, Children's Hospital, Münster, Germany.
Otfried
O
Debus
Frühdiagnosezentrum Würzburg, University Children's Hospital, Würzburg, Germany.
Martin
M
Haeussler
University Hospital Cologne, Köln, Germany.
Gero
G
von Gersdorff
University Children's Hospital Muenster, Department of General Pediatrics, Neuropediatrics, Münster, Germany.
Gerhard
G
Kurlemann
Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Children's Hospital, University of Munich, Munich, Germany.
Matthias
M
Ensslen
Department of Neuropediatrics, Westküstenklinikum Heide, Heide, Germany.
Nathalie
N
Beaud
Department of Pediatrics St. Hedwig, St. Josefskrankenhaus Freiburg, Freiburg, Germany.
Joerg
J
Budde
Pediatric Practice, Werne, Germany.
Michael
M
Gilbert
Pediatric Practice, Barsinghausen, Germany.
Ralf
R
Heiming
Pediatric Practice, Kirchberg, Germany.
Rita
R
Morgner
Center of Developmental Neurology Frankfurt, Frankfurt, Germany.
Heike
H
Philippi
Pediatric Neurology, University Children's Hospital Erlangen, Erlangen, Germany.
Sophia
S
Ross
MVZ Human Genetics, Ulm, Germany.
Gertrud
G
Strobl-Wildemann
Landes- Frauen- und Kinderklinik Linz, Linz, Austria.
Kerstin
K
Muelleder
Pediatric Practice, Münster, Germany.
Paul
P
Vosschulte
Genomic Medicine, National Heart and Lung Institute, Imperial College London, Royal Brompton Hospital, London, United Kingdom.
Deborah J
DJ
Morris-Rosendahl
Center for Neuroradiology, Bezirksklinikum Regensburg, University Medical Center, Regensburg, Germany.
Gerhard
G
Schuierer
Center for and Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
Ute
U
Hehr
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000150:complications* / Q000235:genetics*; D000069279:Drug Resistant Epilepsy / Q000150:complications / Q000188:drug therapy*; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007223:Infant; D000077213:Lamotrigine; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010634:Phenobarbital / Q000627:therapeutic use; D010641:Phenotype; D012189:Retrospective Studies; D016896:Treatment Outcome; D014227:Triazines / Q000627:therapeutic use; D014635:Valproic Acid / Q000627:therapeutic use; D020888:Vigabatrin / Q000627:therapeutic use; D055815:Young Adult
D000927:Anticonvulsants; D008869:Microtubule-Associated Proteins; D014227:Triazines; D014635:Valproic Acid; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; D020888:Vigabatrin; D000077213:Lamotrigine; D010634:Phenobarbital
Brain malformation; Epilepsy; Genotype-phenotype relationship; LIS1; Lissencephaly; Treatment