Causes and Consequences of Gray Matter Heterotopia

Abstract

The objective of this article is to review the pathophysiological bases of gray matter heterotopia and to appreciate their involvement in brain cortical development and functional consequences, namely epilepsy. The development of the cerebral cortex results from complex sequential processes including cell proliferation, cell migration, cortical organization, and formation of neuronal networks. Disruption of these steps yields different types of cortical malformations including gray matter heterotopia, characterized by the ectopic position of neurons along the ventricular walls or in the deep white matter. Cortical malformations are major causes of epilepsy, being responsible for up to 40% of drug-resistant epilepsy, and the cognitive level of affected patients varies from normal to severely impaired. This review reports data from human patients and animal models highlighting the genetic causes for these disorders affecting not only neuronal migration but also the proliferation of cortical progenitors. Therefore, gray matter heterotopias should not be considered as solely due to an abnormal neuronal migration and classifying them as such may be too restrictive. The review will also summarize literature data indicating that besides ectopic neurons, neighbor cortical areas also play a consistent role in epileptogenesis, supporting the notion that plastic changes secondary to the initial malformation are instrumental in the pathophysiology of epilepsy in affected patients.

Therapeutic effect of perinatal exogenous melatonin on behavioral and histopathological changes and antioxidative enzymes in neonate mouse model of cortical malformation

“…The histological analysis in the present study demonstrated dyslamination and heterotopic cells in the MAM and LUZ (as an MT receptor antagonist) groups. Heterotopic cells were recognized by the ectopic position of neurons (Watrin et al, 2015). Furthermore, ectopic cells, as well as dysmorphic cells with a large size and abnormal shape, were detected in these groups.…”

“…Previous studies have shown that the histological signs of cortical malformation include dyslamination and the presence of heterotopic and dysmorphic cells (Fauser et al, 2004; Watrin et al, 2015). Our findings corroborated a previous study reporting delayed neurodevelopment and cortical malformations in the offspring of animals with melatonin deficiency.…”

Neuronal Migration Disorder

“…[1,2,3] Periventricular heterotopia -mutation in FLNA gene on Xq28 were found on 100% of families with X linked bilateral periventricular nodular heterotopia and 26% of sporadic cases with coagulopathy and cardiovascular malformation may be associated. [4] Mutation in the gene locus ARFGEF2 (20q 13.13) present with PNH with microcephaly. Mutation in gene (C6 orf 70 6q27, FAT4 (4q-28.1), DCHS1 (11p15.4) are other genes associated with PNH.…”

“…Heterotopia are most commonly isolated anomalies, but may be part of number of syndromes including chromosamal anomalies and fetal exposure to toxins include alcohol. [4] Subcortical heterotopia may present with epilepsy in both men and women. The more extreme heterotopia, the greater the CNS deficit.…”

Permutation and parametric tests for effect sizes in voxel-based morphometry of gray matter volume in brain structural MRI

“…These provide robust tools for assessing differences in, for example, the proportion of grey matter voxels between two or more groups. Reductions in grey matter volume are a commonly observed feature of normal ageing [10], and are also seen in diseases such as amyotrophic lateral sclerosis [11], epilepsy [12], Alzheimer’s disease [13] and schizophrenia [14]. However, differences in tissue structure can be subtle and difficult to identify consistently between studies [14,15].…”