Lissencephaly in an epilepsy cohort: Molecular, radiological and clinical aspects.

INTRODUCTION: Lissencephaly is a rare malformation of cortical development due to abnormal transmantle migration resulting in absent or reduced gyration. The lissencephaly spectrum consists of agyria, pachygyria and subcortical band heterotopia. In this study we compared genetic aetiology, neuroradiology, clinical phenotype and response to antiepileptic drugs in patients with epilepsy and lissencephaly spectrum malformations. METHODS: The study group consisted of 20 patients - 13 males and 7 females, aged 18 months to 21 years at the time of data collection. Genetic testing was performed by oligonucleotide array comparative genomic hybridization (microarray), multiplex ligation-dependent probe amplification (MLPA), targeted gene panels and whole exome/genome sequencing. All neuroradiological investigations were re-evaluated and the malformations were classified by the same neuroradiologist. Clinical features and response to anti-epileptic drugs (AEDs) were evaluated by retrospective review of medical records. RESULTS: In eleven patients (55%) mutations in PAFAH1B1 (LIS1) or variable microdeletions of 17p13.3 including the PAFAH1B1 gene were detected. Four patients (20%) had tubulin encoding gene mutations (TUBA1A, TUBG1 and TUBGCP6). Mutations in DCX, DYNC1H1, ADGRG1 and WDR62 were identified in single patients. In one patient, a possibly pathogenic intragenic deletion in TRIO was detected. A clear radiologic distinction could be made between tubulinopathies and PAFAH1B1 related lissencephaly. The majority of the patients had therapy resistant epilepsy and epileptic spasms was the most prominent seizure type. The best therapeutic response to seizure control in our cohort was obtained by the ketogenic diet, vigabatrin, clobazam, phenobarbital and valproate. CONCLUSION: The most common genetic aetiologies in our cohort of 20 individuals with epilepsy and lissencephaly spectrum were intragenic deletions or single nucleotide mutations in PAFAH1B1 or larger deletions in 17p13.3, encompassing PAFAH1B1, followed by mutations in tubulin encoding genes. Radiological findings could reliably predict molecular results only in agyria with a posterior to anterior gradient. Radiological and molecular findings did not correlate consistently with severity of clinical outcome or therapeutic response.

Lissencephaly: Expanded imaging and clinical classification.

Lissencephaly ("smooth brain," LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS-LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS-associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS-SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS-SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based- classification).

[Developmental malformations of the cerebral cortex]. / Heterotopie, Polymikrogyrie, Lissenzephalie und Co - Malformationen der kortikalen Hirnentwicklung.

Migration disorders (MD) are increasingly recognized as an important cause of epilepsy and developmental delay. Up to 25 % of children with refractory epilepsy have a cortical malformation. MD encompass a wide spectrum with underlying genetic etiologies and clinical manifestations. Research regarding the delineation of the genetic and molecular basis of these disorders has provided greater insight into the pathogenesis of not only the malformation but also the process involved in normal cortical development. Diagnosis of MD is important since patients who fail three antiepileptic medications are less likely to have their seizures controlled with additional trials of medications and therefore epilepsy surgery should be considered. Recent improvements in neuroimaging have resulted in a significant increase in the recognition of MD. Findings can be subdivided in disorders due to abnormal neurogenesis, neuronal migration, neuronal migration arrest and neuronal organization resulting in different malformations like microcephaly, lissencephaly, schizencephaly and heterotopia. The examination protocol should include T 1-w and T 2-w sequences in adequate slice orientation. T 1-w turbo-inversion recovery sequences (TIR) can be helpful to diagnose heterotopia. Contrast agent is needed only to exclude other differential diagnoses.

Lissencephalic syndromes: brain and beyond.

Lissencephaly has been long maintained a malformation involving only the brain. Classic lissencephaly includes agyria and pachygyria and it is the most severe form of malformations derived from abnormal neuronal migration. It is defined as a smooth or nearly smooth cerebral surface with absence of normal sulci and gyria. It encompasses a group of syndromes which show many different clinical conditions. Four groups are actually distinguished: classic lissencephaly variants, other lissencephalies including forms with unknown pathogenesis, microlissencephaly spectrum and Cobblestone cortical malformations. Several genes and proteins are involved in this syndromic spectrum and each year new molecular data are reported in the literature: classifications in this sense are always in progress. Lissencephaly now is recognised to involve not only the brain but also several other organs and districts including eyes, face, muscles, genital organs, heart and bones. Mental retardation and different form of epilepsies usually drug-resistant are the main clinical signs. The Authors in this topic discuss on this subject, underlying the different forms of lissencephaly their wide heterogeneity and the complex involvement of several organs.

Midbrain-hindbrain involvement in lissencephalies.

OBJECTIVES: To determine the involvement of the midbrain and hindbrain (MHB) in the groups of classic (cLIS), variant (vLIS), and cobblestone complex (CBSC) lissencephalies and to determine whether a correlation exists between the cerebral malformation and the MHB abnormalities. METHODS: MRI scans of 111 patients (aged 1 day to 32 years; mean 5 years 4 months) were retrospectively reviewed. After reviewing the brain involvement on MRI, the cases were reclassified according to known mutation (LIS1, DCX, ARX, VLDLR, RELN, MEB, WWS) or mutation phenotype (LIS1-P, DCX-P, RELN-P, ARX-P, VLDLR-P) determined on the basis of characteristic MRI features. Abnormalities in the MHB were then recorded. For each structure, a score was assigned, ranging from 0 (normal) to 3 (severely abnormal). The differences between defined groups and the correlation between the extent of brain agyria/pachygyria and MHB involvement were assessed using Kruskal-Wallis and chi(2) McNemar tests. RESULTS: There was a significant difference in MHB appearance among the three major groups of cLIS, vLIS, and CBSC. The overall score showed a severity gradient of MHB involvement: cLIS (0 or 1), vLIS (7), and CBSC (11 or 12). The extent of cerebral lissencephaly was significantly correlated with the severity of MHB abnormalities (p = 0.0029). CONCLUSION: Our study focused on posterior fossa anomalies, which are an integral part of cobblestone complex lissencephalies but previously have not been well categorized for other lissencephalies. According to our results and the review of the literature, we propose a new classification of human lissencephalies.