Migration of post-mitotic neurons from the ventricular zone to the cortical plate during embryogenesiscomprises one of the most critical stages in brain development. Deﬁciency of this process often results inmajor brain malformations, including human lissencephaly (smooth brain). Since discovery of the ﬁrstgenetic cause of lissencephaly, deletions of chromosome 17p13.3 in Miller–Dieker syndrome, rapid progressin our understanding of neuronal migration has been made based on advances in both brain imagingtechnology and molecular genetics. This progress has resulted in a new system of classiﬁcation that beganwith pathological descriptions and has evolved to include patterns on brain imaging, causative genes andmost recently the molecular pathways and proposed modes of migration involved. In this review, wesummarize current knowledge regarding ﬁve genes that cause or contribute to human lissencephaly,including LIS1, 14-3-3e, DCX, RELN and ARX. Each of these is associated with a characteristic pattern ofmalformation that involves the cerebral cortex and sometimes other brain structures. Based on detailedgenotype–phenotype analysis, we can now infer the most likely causative gene based on brain imaging andother clinical ﬁndings, and inversely are becoming able to predict clinical severity based on the speciﬁcmutations detected. We also hypothesize, for the ﬁrst time, a relationship between the speciﬁc type oflissencephaly observed and deﬁciency of speciﬁc modes of neuronal migration.INTRODUCTIONMigration of post-mitotic neurons from the ventricular zone toform the cortical plate comprises one of the most critical stagesin brain development. Our understanding of this complexprocess has progressed based on studies of human malformationsand mouse mutants with deﬁcient neuronal migration, particu-larly the malformation known as lissencephaly (LIS) or ‘smooth-brain’. LIS is characterized by a smooth or nearly smoothcerebral surface. It encompasses a spectrum of gyral malforma-tions from complete agyria (absent gyri) to regional pachygyria(broad gyri), and merges with subcortical band heterotopia(SBH). LIS is always associated with an abnormally thick cortex,reduced or abnormal lamination and diffuse neuronal heterotopia(1,2). SBH or ‘double cortex’ consists of circumferential bandsof heterotopic neurons located just beneath the cortex andseparated from it by a thin band of white matter (3,4).Several different types of LIS have been recognized. Themost common type, known as classical LIS (previously type I),has a very thick 10–20mm cortex and no other major brainmalformations. This is the only type associated with SBH. Lesscommon types are associated with agenesis of the corpuscallosum (ACC) or severe cerebellar hypoplasia (5,6).In this paper, we review recent discoveries regarding themolecular mechanisms that regulate or effect neuronalmigration to the cerebral cortex, emphasizing those derivedfrom studies in humans with LIS. Other genes and proteinsidentiﬁed in humans with periventricular nodular heterotopiaor cobblestone complex malformations (previously typeII LIS), or in mouse mutants have been reviewed elsewhere(7–11).HUMAN LISSENCEPHALY GENESTo date, ﬁve genes have been identiﬁed that cause or contributeto LIS in humans: LIS1, 14-3-3e ,DCX RELN and ARX. Theirrespective subtypes and syndromes are shown in Figures 1and 2, and can usually be distinguished based on detailedanalysis of the phenotype as shown in Figure 3.

/pdf/lissencephaly-and-the-molecular-basis-of-neuronal-migration-46r26yciau.pdf

Lissencephaly and the molecular basis of neuronal migration.

Malformations of cortical development (MCDs) are macroscopic or microscopic abnormalities of the cerebral cortex that arise as a consequence of an interruption to the normal steps of formation of the cortical plate The human cortex develops its basic structure during the first two trimesters of pregnancy as a series of overlapping steps, beginning with proliferation and differentiation of neurons, which then migrate before finally organizing themselves in the developing cortex Abnormalities at any of these stages, be they environmental or genetic in origin, may cause disruption of neuronal circuitry and predispose to a variety of clinical consequences, the most common of which is epileptic seizures, A large number of MCDs have now been described, each with characteristic pathological, clinical, and imaging features The causes of many of these MCDs have been determined through the study of affected individuals, with many MCDs now established as being secondary to mutations in cortical development genes This review will highlight the best-known of the human cortical malformations associated with epilepsy The pathological, clinical, imaging, and etioiogic features of each MCD will be summarized, with representative magnetic resonance imaging (MRI) images shown for each MCD, The malformations tuberous sclerosis, focal cortical dysplasia, hemimegalencephaiy, classical iissencephaly, subcortical band heterotopia, periventricular nodular heterotopia, polymicrogyria, and schizencephaly will be presented

/pdf/malformations-of-cortical-development-and-epilepsy-4umwxio737.pdf

Malformations of cortical development and epilepsy.

Malformations of cortical development (MCD) are important causes of chronic epilepsy in human beings. A blanket term, MCD encompasses many varied developmental disorders with diverse clinical manifestations in patients that neurologists, paediatricians, and learning disability psychiatrists will encounter. Advances in imaging and genetics have led to a significant increase in our understanding of MCD, which has in turn enriched our knowledge of human epileptogenesis and normal brain development and function. In this review, I discuss some of the most common or enlightening MCD: focal cortical dysplasia, periventricular heterotopia, polymicrogyria, band heterotopia and lissencephaly, dysembryoplastic neuroepithelial tumours, and microdysgenesis. Clinical and imaging features, genetic aetiologies, treatments, and the insights that have resulted from MCD study are covered. The burden of epilepsy due to MCD is significant and there is still much to learn about MCD.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474442203006203.pdf

Malformations of cortical development: burdens and insights from important causes of human epilepsy

Lissencephalies are congenital malformations responsible for epilepsy and mental retardation in children. A number of distinct lissencephaly syndromes have been characterized, according to the aspect and the topography of the cortical malformation, the involvement of other cerebral structures and the identified genetic defect. A mutation in TUBA1A, coding for alpha 1 tubulin, was recently identified in a mutant mouse associated with a behavioural disorder and a disturbance of the laminar cytoarchitectony of the isocortex and the hippocampus. Mutations of TUBA1A were subsequently found in children with mental retardation and brain malformations showing a wide spectrum of severities. Here we describe four fetuses with TUBA1A mutations and a prenatal diagnosis of major cerebral dysgeneses leading to a termination of pregnancy due to the severity of the prognosis. The study of these fetuses at 23, 25, 26 and 35 gestational weeks shows that mutations of TUBA1A are associated with a neuropathological phenotypic spectrum which consistently encompasses five brain structures, including the neocortex, hippocampus, corpus callosum, cerebellum and brainstem. Less constantly, abnormalities were also identified in basal ganglia, olfactory bulbs and germinal zones. At the microscopical level, migration abnormalities are suggested by abnormal cortical and hippocampal lamination, and heterotopic neurons in the cortex, cerebellum and brainstem. There are also numerous neuronal differentiation defects, such as the presence of immature, randomly oriented neurons and abnormal axon tracts and fascicles. Thus, the TUBA1A phenotype is distinct from LIS1, DCX, RELN and ARX lissencephalies. Compared with the phenotypes of children mutated for TUBA1A, these prenatally diagnosed fetal cases occur at the severe end of the TUBA1A lissencephaly spectrum. This study emphasizes the importance of neuropathological examinations in cases of lissencephaly for improving our knowledge of the distinct pathogenetic and pathophysiological mechanisms.

Neuropathological phenotype of a distinct form of lissencephaly associated with mutations in TUBA1A

Introduction: Posterior quadrantic dysplasia (PQD), a developmental malformation involving the temporal, parietal, and occipital lobes of one cerebral hemisphere, leads to intractable epilepsy. Objective: To characterize the clinical features of 19 patients with PQD and analyze the postsurgical outcome of those who underwent resection of dysplastic tissue. Methods: The extent and nature of the malformation were primarily assessed with high-resolution brain imaging. Fourteen patients underwent complete or partial temporoparieto-occipital resection or temporal resection associated with parieto-occipital disconnection. Postoperative follow-up period ranged from 8 months to 7 years. The authors used the Engel classification for postoperative outcome. Results: All patients were sporadic. Clinical features included infantile spasms, partial seizures, mental retardation, mild hemiparesis, and visual field defects. Neuroimaging localized the malformation within the posterior cerebral quadrant contralateral to the neurologic deficit and demonstrated hemihemimegalencephaly in 14 of 19 patients and multilobar cortical dysplasia in 5 of 19 patients. The authors observed class I outcome in six patients. Two patients had class II and four patients had class III outcome. Class IV outcome was seen in two patients. After surgery, two patients developed mild hemiparesis, and two developed a visual field defect. Conclusions: Widespread cortical dysplasia is more frequent in the posterior quadrant. In our series, posterior quadrantic dysplasia represents either hemi-hemimegalencephaly or multilobar cortical dysplasia. Individuals with posterior quadrantic dysplasia share a spectrum of clinical features. The intractable epilepsy in these patients may be alleviated by a large quadrantic temporoparieto-occipital resection.

Posterior quadrantic dysplasia or hemi-hemimegalencephaly: a characteristic brain malformation.

Subcortical band heterotopia (SBH) is seen predominantly in females, resulting from mutations in the X-linked doublecortin (DCX) gene, and can present with mild mental retardation and epilepsy. Males carrying DCX mutations usually demonstrate lissencephaly and are clinically much more severely affected. This article reports two cases of males with SBH indistinguishable from the female phenotype, both resulting from somatic mosaicism for DCX mutation.

Males with epilepsy, complete subcortical band heterotopia, and somatic mosaicism for DCX

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Males with epilepsy, complete subcortical band heterotopia, and somatic mosaicism for DCX