Electrographic pattern recognition: A simple tool to predict clinical outcome in children with lissencephaly.

PURPOSE: To describe and correlate the clinical, radiological and EEG findings in children with lissencephaly. METHOD: Retrospective record analysis of children with lissencephaly presenting to tertiary health centre in Northern India was performed. Radiological classification and severity scoring were done. EEG findings were categorized into three patterns and its association with clinical severity was studied. RESULTS: Twenty-eight children (males = 17) with lissencephaly were enrolled. Median age at diagnosis was 6.5months (range 3days-3years). Global developmental delay (median social quotient (SQ) = 25 (range15-68) was seen in all; motor deficits in 23 (82 %); epilepsy in 21 (75 %); behavioural problems in 18 (64 %); ophthalmic problems in 17 (61 %); microcephaly in 13 (46 %); feeding difficulty in 12 (43 %). Radiologically, classical Type I lissencephaly was seen in 18(64 %), cobblestone variant (Type II) in 5 (18 %) and microlissencephaly in 5 (18 %). Grade 4 (diffuse pachygyria) radiologic severity was most common (severity grade 1-6); no cases with severity score 5 or 6 were seen. The clinical profile did not correspond with radiological severity grading. EEG pattern recognition revealed pattern I in 14 (50 %); pattern II in 6 (21 %); pattern III in 8 (29 %). Children with pattern III EEG had drug resistant epilepsy and severe developmental delay. No relationship between EEG patterns and radiological severity grading was evident. CONCLUSION: EEG is better predictor of clinical status and outcome rather than radiological severity grading. EEG pattern III is associated with severe developmental delay and drug resistant epilepsy.

Lissencephaly: mechanistic insights from animal models and potential therapeutic strategies.

Lissencephaly is a severe human neuronal migration defect characterized by a smooth cerebral surface, mental retardation and seizures. The two most common genes mutated in patients with lissencephaly are LIS1 and DCX. LIS1 was the first gene cloned that was important for neuronal migration in any organism, and heterozygous mutations or deletions of LIS1 are found in the majority of patients with lissencephaly, while DCX mutations were found in males with X-linked lissencephaly. In this review, we will discuss how an understanding of the molecular and cellular pathways disrupted in model organisms with Lis1 and Dcx mutations or knock-down not only provide insights into the normal processes of neuronal migration, including neurogenesis, but they also may lead to potential novel therapeutic strategies for these severe cortical malformations.

A novel strategy for therapeutic intervention for the genetic disease: preventing proteolytic cleavage using small chemical compound.

Haploinsufficiency is a state of genetic disease, which is caused by hemizygous mutations of functional alleles. Lissencephaly is a typical example of haploinsufficiency disorders characterized by a smooth cerebral surface, thick cortex and dilated lateral ventricules associated with mental retardation and seizures due to defective neuronal migration. LIS1 was the first gene cloned in an organism, which was deleted or mutated in patients with lissencephaly in a heterozygous fashion. Series of studies uncovered that LIS1 is an essential regulator of cytoplasmic dynein. In particular, we reported that LIS1 is essential for dynein transport to the plus-end of microtubules by kinesin, which is essential for maintaining proper distribution of cytoplasmic dynein within the cell. Fortuitously, we found that a substantial fraction of LIS1 is degraded by the cystein protease, calpain after reaching the plus-end of microtubules. We further demonstrated that inhibition of calpain-mediated LIS1 degradation increased LIS1 level at the cortex of the cell, resulting in therapeutic benefit using genetic mouse models with reduced levels of LIS1. Our work might provide a potential therapeutic approach for the treatment of a fraction of haploinsufficiency disorders through augmenting reduced proteins by the targeting inhibition of degradation machinery.