Malformations of cortical development: clinical features and genetic causes

Abstract

Malformations of cortical development are common causes of developmental delay and epilepsy. Some patients have early, severe neurological impairment, but others have epilepsy or unexpected deficits that are detectable only by screening. The rapid evolution of molecular biology, genetics, and imaging has resulted in a substantial increase in knowledge about the development of the cerebral cortex and the number and types of malformations reported. Genetic studies have identified several genes that might disrupt each of the main stages of cell proliferation and specification, neuronal migration, and late cortical organisation. Many of these malformations are caused by de-novo dominant or X-linked mutations occurring in sporadic cases. Genetic testing needs accurate assessment of imaging features, and familial distribution, if any, and can be straightforward in some disorders but requires a complex diagnostic algorithm in others. Because of substantial genotypic and phenotypic heterogeneity for most of these genes, a comprehensive analysis of clinical, imaging, and genetic data is needed to properly define these disorders. Exome sequencing and high-field MRI are rapidly modifying the classification of these disorders.

Figure 1

Axial T2-weighted images at the level of the mid-lateral ventricles showing different malformations of cortical development. Long arrows show representative areas of cortical malformation (A–D, F, I–O), subcortical band heterotopia (H) or periventricular nodular heterotopia (P). The short black arrow shows a small periventricular nodular heterotopia (O). Asterisks denote abnormal white matter (B), focal transmantle dysplasia (D), wide inter hemispheric space due to absent corpus callosum (E), a shunt (I), and an open-lip cleft (M). The malformations of cortical development shown include severe congenital microcephaly with a PMG-like cortical malformation (A), right-sided dysplastic megalencephaly (hemimegalencephaly) (B), megalencephaly and frontal-perisylvian polymicrogyria (C), focal cortical dysplasia type 2b (D), severe lissencephaly with cerebellar hypoplasia and absent corpus callosum (E), PMG-like cortical malformation in a tubulinopathy (F), grade 3 classic lissencephaly (G), diffuse subcortical band heterotopia in a female (H), frontal predominant cobblestone malformation in muscle-eye-brain disease (I), frontal predominant cobblestone malformation in autosomal recessive cutis lax (J), posterior predominant cobblestone mutation in a child with congenital muscular dystrophy (K), peroxisomal cortical malformation in Zellweger syndrome (L), classic schizencephaly with a left frontal open-lip cleft (M), perisylvian polymicrogyria imaged at 7 Tesla (N), posterior periventricular nodular heterotopia with overlying PMG (O), and bilateral diffuse periventricular nodular heterotopia (P).(This is a short form, see Supplementary Text for longer version).

Figure 2

Axial MRI images at 7T showing different morphological aspects of polymicrogyria in five young adult patients. Images ‘A’ and ‘G’ are inversion recovery (IR) weighed (W), image ‘C’ is T1W, images ‘B’, ‘D–F’ are susceptibility (S) W images; image ‘H’ shows a detail of image ‘G’ and is obtained using the tissue border enhancement by IR acquisition technique.¹⁷⁴ ‘A’ shows the pebbled aspects of the grey matter typical of polymicrogyria, with areas of thickening and infoldings, involving the posterior frontal and parietal cortex on both sides, in a young woman. ‘B’, is taken from the same patient as ‘A’, using SW sequences. Detail of the cortex at the parietal lobe level, discloses the underlying structure of the malformed cortex, which is thin and overfolded, with ribbon like aspect. The arrows indicate the areas where these characteristics are more prominent. Note that the cortex has normal thickness and shape in the mesial hemispheric surface. ‘C’ shows gross thickening and abnormal sulcation of the posterior perisylvian and parietal cortex of the left hemisphere in a young adult man. ‘D’, showing a detail of ‘C’ obtained using SW sequences, discloses ribbon like cortical overfolding bordering the abnormal sulci. For comparison, see the normal cortex in the contralateral hemisphere. ‘E’ is obtained using SW in the same patient as in figure 1N. Note the abrupt transition between the abnormally thick and overfolded cortex in the perisylvian borders (arrows) and the normal temporo-parietal cortex (black asterisks). ‘F’ shows abnormal infolding due to abnormal sulcation and cortical thickness in a young man with left unilateral perisylvian polymicrogyria. ‘G’ shows an extensive area of heterotopia involving most of the right frontal lobe in a young man. The macronodular aspect of the heterotopia and the irregular surface of the overlying cortex (black asterisk) make this malformation not easily distinguishable from what is seen, for example, in the left parietal lobe in patients shown in ‘A’ and ‘C’. Tissue border enhancement, used in ‘H’ (showing a detail of ‘G’), helped defining the grey-white matter border and diagnose this malformation as heterotopia even if the overlying cortex contains small gyri and abnormal sulci.

Figure 3

Schematic representation of the PI3K-AKT-mTOR signaling pathway. Genes encoding proteins with activator effects on the downstream signaling components are represented by ellipsis, genes encoding proteins with inhibitory effect are represented by hexagons and AKT gene family and MTORC1, which may have both activating and repressor effect, are represented by decagons. Genes encoding proteins of the PI3K-AKT-MTOR pathway already implicated in malformations of cortical development in human disease are coloured in red. Protein abbreviations are provided in the appendix.

Figure 4

Reelin-LIS1-tubulins pathway. Schematic representation of the reelin-mediated signaling pathway for neuronal migration. Reelin binding to one of three receptors complexes (CNR, VLDLR/LRP8, or β-integrin) activates mDAB, which mediates the binding of LIS1 with NDE1/NDE1L and DYNC1H1. The interaction of the LIS1-NDE1/NDE1L-DYNC1H1 complex with KIF5C mediates the anterograde transport, whereas its interaction with dynactin mediates the retrograde transport. KIF1A mediates the VAMP2 transport through the interaction with DCX, and KIF2A mediates microtubule depolymerisation. Genes encoding proteins of the reelin-LIS1-tubulins pathway already implicated in malformation of cortical development in human disease are coloured in red. Protein abbreviations are provided in the appendix.