Neuronal Migration Disorders

C H A P T E R

26 Neuronal Migration Disorders J.J. LoTurco, A.B. Booker University of Connecticut, Storrs, CT, USA

O U T L I N E 26.1 Introduction

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26.2 Types of Malformations in NMD 26.2.1 Pachygyria 26.2.2 Lissencephaly 26.2.3 Cobblestone Lissencephaly 26.2.4 Polymicrogyria 26.2.5 Schizencephaly 26.2.6 Subcortical Band Heterotopia 26.2.7 Periventricular Heterotopia 26.2.8 Microcephaly 26.2.9 Focal Cortical Dysplasia

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26.3 Type 1 Lissencephaly 26.3.1 Miller–Dieker Syndrome and the LIS1 and YWHAE Genes 26.3.2 X-Linked Lissencephaly 26.3.3 ARX Mutations 26.3.4 Mutations in Reelin

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26.1 INTRODUCTION Disorders in neuronal migration cause aberrations in the cellular architecture of the brain including alterations in sulci and gyri, and lamination of the neocortex. The term ‘neuronal migration disorder’ (NMD) has come to encompass a large number of syndromes. The reported alterations that occur in cytoarchitecture and structure in NMDs are diverse in terms of type and severity. Disruptions range from the subtle, only seen with microscopic analysis in isolated regions, to those covering large regions of the brain that are easily apparent with MRI imaging. Genetic studies have now revealed many gene mutations that cause syndromes associated with disorders in neuronal migration. Functional studies of the products of these genes have in turn revealed

Cellular Migration and Formation of Neuronal Connections: Comprehensive Developmental Neuroscience, Volume 2 http://dx.doi.org/10.1016/B978-0-12-397266-8.00038-7

26.4 Mutations in Tubulin Subunits TUBA1A, TUBB2B, and TUBA8

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26.5 Subcortical Band Heterotopia

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26.6 Periventricular Heterotopia 26.6.1 FLNA 26.6.2 ARFGEF2

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26.7 Polymicrogyria

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26.8 Cobblestone Cortical Malformation

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26.9 Focal Cortical Dysplasia 26.9.1 Tuberous Sclerosis Complex and Type II FCD 26.9.2 Type I FCD and CNTNAP2

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26.10 Summary

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Acknowledgments

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proteins and pathways required for distinct stages in brain development. NMDs have come to include any number of early developmental disruptions that may cause a displacement of neurons from the typical pattern. It is, however, important to appreciate that the actual underlying disruption that causes an NMD may not be a direct deficit in the process of neuronal motility or migration during development. For example, changes in cell proliferation, cell death, cellular differentiation, or cellular adhesion, can all cause disruptions in normal cellular patterns. Changes in any of these may alter movements and ultimate positioning of neurons by blocking or changing physical pathways, or by altering a pattern of cellular growth, without any direct change in an immature neuron’s intrinsic ability to move or migrate.

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# 2013 Elsevier Inc. All rights reserved.

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Although NMDs may involve many parts of the brain, they most typically involve the neocortex, hippocampus, and cerebellum. The enrichment of migration disorders involving these areas is likely due to the highly patterned and regular structure of these brain areas. Any disruption in cell placement is more obvious in such structures. The ordered pattern of cell migration required to establish the precise architectures of cortex and cerebellum require coordinated molecular and cellular processes in multiple cell types, and disruption in any of these or in their coordination can result in a migration disorder. The required mechanistic complexity may render these structures more susceptible to both genetic and environmental insults. Consistent with the correlation between complex and ordered cellular architecture and susceptibility to NMDs, the human brain shows a greater variety of distinguishable NMD types compared to the rodent brain. This chapter focuses on defining the categories and underlying mechanisms of NMDs and relating these mechanisms to molecular pathways essential for normal neural development. The chapter focuses primarily on genetically based conditions, including type 1 and type 2 lissencephaly, subcortical band heterotopia (SBH), nodular heterotopia, polymicrogyria (PMG), and focal cortical dysplasia (FCD).

pathological terms remain important components of the newer categories. It is important to recognize, however, that each pathological feature does not represent a single disease or syndrome. For example, distinct categories of NMDs can contain pachygyria to varying degrees, lissencephaly with or without microcephaly, or lissencephaly with or without cerebellar hypoplasia. In fact, the comorbidities of malformation types, even when caused by a single gene mutation, reveal shared and distinct functions of single genes between and within different regions of the brain. The aim of this section is to provide general definitions of the types of major neuropathological features associated with NMDs.

26.2.1 Pachygyria Pachygyria literally means thick or fat gyri. It is characterized by a marked thickening of the gray matter of the neocortex such that the normal cross-sectional thickness is increased typically by 50% or more. The underlying white matter is also often more diffuse and/or thinner than normal. Pachygyria is usually associated with a reduction in the number of gyri and sulci, or agyria, to varying degrees. It is most commonly associated with lissencephaly, but can also occur in isolation.

26.2.2 Lissencephaly 26.2 TYPES OF MALFORMATIONS IN NMD NMDs, initially categorized by descriptive pathological features and inheritance patterns, are now divided into an increasing number of defined syndromes. These syndromes are characterized by combinations of clinical features, malformation types, genetic causes, and predominant locations of malformations. The descriptive

Type 1 or ‘classical’ lissencephaly (LIS), meaning smooth brain from the Greek root ‘lisso,’ is defined by a lack of gyri and sulci in the cerebral neocortex (Figure 26.1(c)). In terms of comparative neuroanatomy, ‘lissencephalic’ refers to species such as mice with neocortices that are smooth and lack sulci or gyri. It is important to distinguish this evolutionary lissencephaly from the human pathology. Human lissencephaly, in addition

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FIGURE 26.1 Normal and lissencephalic brain sections. (a) Illustration of a coronal view of a normal brain. The gray matter is a uniform thickness surrounding the white matter, and the surface shows a convoluted pattern of sulci and gyri. (b) Schematic enlargement of the box in A, showing the cytoarchitecture of typical six-layered cortex. (c) Coronal view of a lissencephalic brain whose lack of gyri and sulci result in a smooth appearance. (d) Magnified schematic depicting the cortical layers of the thicker lissencephalic cortex that consists of just four layers.

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to a lack of sulci and gyri, is characterized by a simplification of neocortical lamination. Typically, the neocortex of lissencephalic patients has 3–4 layers instead of 6. Lissencephaly, like pachygyria, does not necessarily occur across the entire cortex and is often restricted to more frontal or occipital regions, depending on the underlying genetic cause.

26.2.3 Cobblestone Lissencephaly Cobblestone lissencephaly, also known as type 2 lissencephaly, is different from classical or type 1 lissencephaly. The lack of sulci and gyri in this malformation type are the result of neurons migrating past the outer limits of normal gray matter to form discrete and interconnected patches. This results in a characteristic bumpy, granular, or ‘cobblestone’ appearance to the surface of the cortex, lacking deep sulci (Figure 26.3(c)). At the cellular level the normal laminar appearance of the cortex is replaced by variable aggregations of cells. There is usually disruption in white matter and myelination, enlarged ventricles, brainstem hypoplasia, and cerebellar hypoplasia. This type of malformation is typically associated with retinal dysplasia and muscular dystrophy.

26.2.4 Polymicrogyria Polymicrogyria (PMG) is a malformation whereby a part of or the entire cortex contains many more sulci and gyria than normal, and these additional convolutions are smaller than usual (Figure 26.3(a)). PMG can be highly localized and bilaterally symmetric, asymmetric, or unilateral. The cortex is thinned as in cobblestone lissencephaly, but, unlike cobblestone lissencephaly, the cortex retains a degree of regular structure and lamination.

At the cellular level, the cortical lamination is reduced to 2–3 layers and the cell-sparse marginal zone is typically intact.

26.2.5 Schizencephaly Schizencephaly, from the Greek schizen ‘to divide,’ is characterized by unilateral or bilateral discontinuities in the cortex. These breaks in continuity create clefts that divide the gray matter from the pia to the ependymal lining of the lateral ventricles. Type I or ‘closed lip’ schizencephaly has a strip of gray matter tissue connecting one of the divided ends of the cortex to the other. In type II or ‘open lip’ schizencephaly, the cleft extends through the hemispheres from the ependyma centrally to the pia peripherally, without a connecting band of gray matter. Familial occurrence of schizencephaly is rare, suggesting a lack of gene mutations that cause this type of malformation.

26.2.6 Subcortical Band Heterotopia Subcortical band heterotopia (SBH), or band heterotopia, are characterized by contiguous groupings of neurons forming a band of gray matter within the white matter just below the neocortical lamina (Figure 26.2(a)). In the most extreme version of SBH, double cortex syndrome, bands of neocortical neurons form bilateral and elongated structures that are as thick or thicker in cross-section than the more superficial ‘normatopic’ cortex. SBH are either partially or completely surrounded by cortical white matter. Utilizing enhanced imaging technologies, small band heterotopia have been identified in the brains of some epileptic patients and nonepileptic individuals.

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FIGURE 26.2 Subcortical band heterotopia (SBH) and periventricular heterotopia (PH). (a) Illustration of a coronal section from a brain with SBH. Note the band of heterotopic neurons in the white matter below the cortical layers. (b) Magnified schematic of the cortical layers showing normal six-layered organization, with the addition of heterotopic neurons sequestered within the white matter. (c) Drawing depicting a brain with PH which harbors multiple nodules lining the surface of the ventricles. (d) Schematic showing cortical layers with normal organization.

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26.2.7 Periventricular Heterotopia Periventricular heterotopia (PH), similar to SBH, are also formed by ectopic aggregates of neurons located medial to or underneath the normal neocortical gray matter (Figure 26.2(c)). Unlike SBH, however, PH abut and extend into the ventricles. They are also known as subependymal heterotopia and can appear in combinations of single to multiple nodes along the surface of the lateral ventricles. When numerous, the nodes merge to form a wavy contiguous mass along the ventricular surface.

26.2.8 Microcephaly Microcephaly is not due to a defect in neuronal migration, and simply refers to a smaller brain, typically 2–3 standard deviations smaller than normal. While not considered an NMD, it is however, a common neuropathological defect that frequently occurs in combination with NMDs.

26.2.9 Focal Cortical Dysplasia Focal cortical dysplasia (FCD) is a broad category of malformation types that are characterized by diverse cellular features. All share the property of a discrete interruption in the normal architecture of the neocortex, and all forms of FCD lead to disorganization of the normal structure of the cerebral cortex in a relatively small and confined region. Several, but not all, forms of FCD are characterized by a distinctly abnormal, elipitically shaped cell type known as balloon cells, and enlarged, or cytomegalic, neurons. In some forms of FCD the lamination of the neocortex is disrupted from the pia into the white matter, while in others small heterotopic arrangements of cells within parenchyma, white matter or the marginal zone are apparent. These focal malformations as a group are more common than all of the above malformation types, and are linked to the majority of pharmacologically intractable epilepsies in children. Tuberous sclerosis (TSC) caused by heterozygous mutations in either TSC1 or TSC2 genes is one well-established genetic cause of FCD.

26.3 TYPE 1 LISSENCEPHALY Type 1 or ‘classical’ lissencephaly (LIS) varies in genetic causes, severity, regions of neocortex most affected, pattern of inheritance, and whether there is associated cerebellar malformation. In this section, different subtypes of lissencephaly (isolated LIS (iLIS), Miller–Dieker syndrome, X-linked lissencephaly (XLIS), X-linked lissencephaly with abnormal genitalia (XLAG), and

lissencephaly with cerebellar hypoplasia (LCH)) (Kumar et al., 2010; Ross et al., 2001) are defined and the functions of the mutated genes that cause them are described. Lissencephaly can follow an autosomal dominant, autosomal recessive, or X-linked pattern of inheritance, but many mutations that cause ‘classical’ lissencephaly are not inherited but are de novo mutations associated with chromosomal rearrangements. The majority of autosomal dominant and X-linked forms are associated with mutations in the genes PAFAH1B, also known as LIS1, and DCX respectively. In fact, mutations in LIS1 and DCX account for 85% of all cases of lissencephaly. The causes of lissencephaly can be explained on a cellular level by a dysregulation in cytoskeletal proteins and cytoskeletal dynamics involving microtubules which are impaired in migrating neurons. Moreover, the observations that there are predictable differences in the regions of cortex affected due to different LIS-causing mutations suggest a model of development in which different cytoskeletal regulatory mechanisms contribute differentially to migration in different areas of the cortex. The cytoarchitecture of the neocortex in lissencephaly shows marked differences in lamination compared to a normal cortex (Dobyns et al., 1993). In addition to pachygyria, or thickened cortex, the lissencephalic cortex is simplified from 6 layers to 2–4 layers (Figure 26.1(d); Dobyns et al., 1984, 1993; Forman et al., 2005). The general pattern of lamination disruption, defined by the size and morphology of neurons present within each layer, appears inverted in type 1 lissencephaly compared to normal cortex. The large pyramidal neurons, typically found in layer V, are in the second most superficial layer. An ectopic layer of white matter with a few scattered small pyramidal cells, typical of layer IV cells, often forms as a middle layer of lissencephalic cortex. The deepest layers often contain small pyramidal neurons and granular neurons more typical of layers II and III in normal cortex. Depending largely upon the genetic mutation there can be variations in this typical lissencepahlic lamination pattern. For example, in PAFAH1B/LIS1 or DCX mutations respectively, the junction between the deepest layers and underlying white matter can differ. The deep white matter layer junction in LIS1 mutation is not clearly demarcated. It is often interrupted by white matter penetrating into lower cellular layers and scattered neurons present in white matter. In lissencephaly associated with DCX mutations, there are prominent heterotopic arrangements of neurons within the vicinity of the gray matter/white matter junction that penetrate into the white matter in a disorganized fashion (Forman et al., 2005). In other lissencephalies, XLAG caused by mutations in ARX and LCH caused by mutations in TUBA1A, neocortical lamination is often further reduced to only

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26.3 TYPE 1 LISSENCEPHALY

two layers: a marginal zone or layer 1 and a single thickened neuronal layer (Forman et al., 2005). In all, the altered lamination patterns in human lissencephaly indicate that there are different patterns of migration disruption that largely correspond to the particular causative mutation (Forman et al., 2005; Jaglin and Chelly, 2009). Neurons typically destined for superficial layers are misplaced. These neurons are either present in deeper laminar positions or spread throughout the cortex. Similarly, neurons destined for deeper layers are often found spread throughout the cortex or in more superficial positions.

26.3.1 Miller–Dieker Syndrome and the LIS1 and YWHAE Genes Miller–Dieker syndrome is a severe neurodevelopmental disorder that involves lissencephaly as well as other disruptions in CNS structure. iLIS, without all the defining features of Miller–Dieker, can be caused by mutation in LIS1 alone. Deletions in 17p are typically de novo deletions, as well as deletion of two genes in this region, LIS1, also known as PAFAH1B1, and YWHAE, also known as 14-3-3epsilon, are responsible for the syndrome. Deletions that involve just YWHAE can cause developmental abnormalities in the brain without significant lissencephaly (Nagamani et al., 2009; Schiff et al., 2010). Miller–Dieker is characterized by pachygyria (Dobyns et al., 1993), and compared to XLIS has a greater degree of agyria in posterior and occipital regions of the cortex (Dobyns et al., 1984, 1999). Miller–Dieker is also associated with enlarged ventricles, hypoplasia of the corpus callosum, and hypoplasia of the cerebral peduncles and cerebral pyramids, further adding to the severity of the neural disruption. In addition to a severe grade of lissencephaly, another feature that distinguishes Miller–Dieker lissencephaly from iLIS is the presence of characteristic dysmorphic facial features (Allanson et al., 1998). Miller–Dieker patients show severe to profound mental retardation and early onset seizures that may lead to intractable epilepsy. Seizures start early in life, near birth to four months of age (Dobyns et al., 1983), and there is a significantly shortened lifespan (Dobyns et al., 1992). The clinical severity of Miller– Dieker syndrome correlates with both the anatomical measures, as well as the nature of the genetic disruption, with large genetic deletions showing more severe phenotypes (Cardoso et al., 2002). The PAFAH1B1 gene codes for a protein initially described as a subunit in the enzyme for processing platelet-activating factor (PAF). It was the first gene to be shown to be involved in lissencephaly when mutated (Hattori et al., 1994). Its role in neuronal migration has not been found to be linked to PAF activity, and instead primarily functions in neurodevelopment

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through interactions with Dynein, microtubules, 143-3epsilon protein, and Nudel protein. The genetic evidence for Miller–Dieker and protein interaction evidence for LIS1 and YWHAE are consistent (Wynshaw-Boris, 2007). In addition, LIS1/NDEL1 interaction plays a well-conserved role throughout biology in the movement of nuclei within cells that allows for translocation of the cellular nucleus (Morris, 2000). As mentioned above, neocortical lamination in both Miller–Dieker syndrome and iLIS is reduced to four layers. The four-layered cortex is present throughout occipital regions of cortex, and within the same brains there can be normal six-layered cortex in the inferior temporal and frontal lobes. This shows a degree of regionalization in the requirements of LIS1. Studies in mutant mice have further revealed the functions of Lis1 and Ywhae in migration and cortical development. Both the LIS1 gene and two interacting genes, Ndel1and Ywhae, when mutated in mice, alone or in combination, disrupt proliferation (Yingling et al., 2008), cell fate determination (Pawlisz et al., 2008), as well as neuronal migration (Hirotsune et al., 1998). The cerebellum, hippocampus and olfactory bulb are also deleteriously affected by loss of Lis1 gene function in mice, and the severity of the disruptions are correlated with gene dosage (Gambello et al., 2003; Hirotsune et al., 1998). Mutation of Ywhae in mice causes disruption in neuronal migration as well (Toyo-oka et al., 2003). Lis1 and Ywhae appear to be multifunctional in neurodevelopment as mutations disrupt several stages of development including nuclear movement during migration, neurite process outgrowth (Youn et al., 2009), and spindle dynamics during proliferation (Yingling et al., 2008). Recent mosaic mutation analysis in mice by the mosaic analysis with double markers technique further shows that Lis1 and Ndel1 loss of function in isolated cells in the cortex and cerebellum can create a surprising degree of noncellautonomous disruption of migration in surrounding cells (Hippenmeyer et al., 2010).

26.3.2 X-Linked Lissencephaly Mutations in the X-linked gene, DCX, result in lissencephaly (XLIS) in males hemizygous for the mutant gene (des Portes et al., 1998a; Gleeson et al., 1998; Pilz et al., 1998), while females with a single copy of the mutated gene can have a genetically related but phenotypically different syndrome, double cortex syndrome with prominent SBH (see below; des Portes et al., 1998a; Gleeson et al., 1998). The lissencephaly syndrome XLIS is similar, but not identical, to isolated lissencephaly caused by mutation in the LIS1 gene. First, the lissencephaly in XLIS is more predominant in the frontal cortex, while mutations in LIS1 are more prevalent in occipital regions (Pilz et al.,

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1998). At the architectonic level, there are also differences in lissencephaly caused by DCX mutations and those caused by LIS1 mutations. The LIS1 mutant cortices have what appears to be a largely inverted cortical lamination, while the lamination disruption in XLIS appears as more of a dispersion of cells and thickening and blurring of lamina. In addition, aggregates of cells similar to small SBH malformations are prevalent in DCX mutations but not in LIS1-related cases (Forman et al., 2005). The protein product of the DCX gene is a microtubulebinding protein that promotes polymerization of microtubules in cell-free polymerization assays (Gleeson et al., 1999; Moores et al., 2004). Both Dcx and Lis1 functions are linked through interaction of complexes with microtubules, and there is evidence in migrating granule cells of the cerebellum that the two genes have at least partial redundancy in migration (Tanaka et al., 2004). Similarly, both Dcx and Lis1 are important to the extension of neurites (Bai et al., 2003; Friocourt et al., 2003; Tsai et al., 2005). RNAi of both Lis1and Dcx also delay migrating neurons in the rat neocortex from extending a leading process and transitioning from a multipolar neuroblast to a bipolar migrating neuron stage of differentiation (Bai et al., 2003; Tsai et al., 2005). Interestingly, the genetic deletion of Dcx alone in mice has only modest effects on the migration of neocortical neurons that are most apparent early in development (Pramparo et al., 2010), and migration abnormalities in the cortex are exacerbated by concomitant mutation of Lis1 or Dclk (Deuel et al., 2006; Koizumi et al., 2006; Pramparo et al., 2010).

26.3.3 ARX Mutations XLAG is a rare genetic disorder that is caused by mutations in the gene ARX (Kato et al., 2004). It is the only known transcription factor to be causative to lissencephaly. XLAG is also distinct from classical LIS in that affected males display abnormal genitalia, and a neocortical lamination pattern that is clearly different from aberrant cortical lamination associated with mutations in either LIS1 or DCX. Specifically, the neocortex in individuals with ARX mutations appears to show a threelayered cortex with an abnormal number of neurons in the marginal zone, and lacking an internal fiber layer seen in the brains of individuals with DCX or LIS1 mutations (Forman et al., 2005). ARX mutations are associated with a wide spectrum of neurodevelopmental disorders with striking pleiotropy (Kato et al., 2004). The clinical features associated with mutation of ARX range from severe lissencephaly with microcephaly and seizures, to mild mental retardation and autism without lissencephaly (Kato et al., 2004). The phenotypes of mice with different Arx mutations, similar to the human phenotypes, reveal disorders in

neuronal migration with a range of phenotype severity depending on the specific mutation in the gene (Kitamura et al., 2002, 2009; Marsh et al., 2009). The phenotypes range from embryonic death to learning and seizure disorders with only subtle disruption in neurodevelopment. Migration of GABAergic interneurons are consistently affected by mutations in Arx (Marsh et al., 2009). RNAi knockdown of Arx in both migrating neocortical pyramidal neurons and migrating GABAergic interneurons further show that Arx has noncell-autonomous functions, as predicted for a transcription factor (Friocourt et al., 2006, 2008). The genes that are downstream of the Arx transcription factor include genes important to neurogenesis, migration, and axonal growth. Genes previously associated with clinical features identified in patients with ARX mutations including autism, epilepsy, and mental retardation are also downstream of ARX (Fulp et al., 2008).

26.3.4 Mutations in Reelin As presented earlier, in Chapter 24, patterned migration in the cortex and cerebellum critically depends upon signaling in the Reelin pathway. Consistent with this role identified in mouse mutants, autosomal recessive mutations in the RELN gene in humans has been linked to a lissencephaly (Hong et al., 2000). Lissencephaly caused by RELN mutations is rare, and causes LCH. LCH can also be caused by some, but not all DCX and LIS1 mutations (Ross et al., 2001), indicating that LCH is a genetically heterogeneous class of NMD, and that DCX and LIS1 may act partially in a shared genetic pathway with Reelin signaling. Consistent with this interaction, Reelin and Lis1 have been shown to genetically interact with mouse mutants (Assadi et al., 2003; Zhang et al., 2007).

26.4 MUTATIONS IN TUBULIN SUBUNITS TUBA1A, TUBB2B, AND TUBA8 Most cases of type 1 lissencephaly are caused by mutation in either of two microtubule associated proteins LIS1 or DCX. From this observation, one prediction would be that there should be corresponding mutations in tubulin subunits which cause malformations of cerebral cortex and cerebellum. In the past few years, mutations in three tubulins, TUBA1A, TUBB2B, and TUBA8, have been identified that cause a range of malformation types, including lissencephaly with cerebellar hypoplasia and PMG (Abdollahi et al., 2009; Jaglin and Chelly, 2009; Tischfield and Engle, 2010).

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The malformation types created by mutations in tubulin genes are surprisingly diverse. Both lissencephaly with pachygyria and PMG occur with mutations in a- and b-subunits. This coincidence of two seemingly opposite phenotypes, a lack of sulci and gyria in LIS and an abundance of extra sulci and gyri in PMG, both originating from mutations in the core components of microtubules, indicates that these types of malformation may be mechanistically related at the molecular level. One possibility for the differences in malformation after mutations in different tubulins may be cell-specific functions and expression of different tubulin isoforms. For example, in one region the loss of function of one tubulin in radial glia could result in PMG, while decreased function of a different tubulin in migrating neurons could cause lissencephaly (Abdollahi et al., 2009; Jaglin and Chelly, 2009). Mutations in the gene TUBA1A, tubulin a-subunit one A, cause malformations of the brain that include lissencephaly, cerebellar hypolasia, agenesis of the corpus callosum, and brain stem anomalies (Keays et al., 2007; Poirier et al., 2007). Mice with mutations in the same gene show a similar impairment in migration of neurons in the neocortex and hippocampus (Keays et al., 2007). Mutations in the TUBA1A gene in humans cause a wide spectrum of neuronal malformations that range in severity from isolated pachygyria in the perisylvian cortex to widespread lissencephaly with cerebellar hypolasia (Bahi-Buisson et al., 2008; Kumar et al., 2010; MorrisRosendahl et al., 2008; Poirier et al., 2007). Moreover, mutations in TUBA1A account for 1–4% of lissencephaly cases and nearly 30% of LCH cases (Kumar et al., 2010; Morris-Rosendahl et al., 2008). At the level of protein function, missense mutations in TUBA1A interfere with the ability of microtubule-binding proteins (MAPs) to associate with microtubules (Kumar et al., 2010). Autosomal recessive mutations in the TUBA8 gene that render this tubulin subunit not susceptible to acetylation at lysine 40 creates a syndrome with generalized PMG and hypoplasia of the optic nerve (Abdollahi et al., 2009). De novo mutation in TUBB2B causes asymmetrical PMG, which can occur in different locations in each hemisphere. Neurons in TUBB2B-related PMG migrate past the normal limits of the most superficial layer through breaks in the basement membrane (Jaglin et al., 2009). This pattern of migration past the basement membrane is an abnormal migration pattern more typical of type 2 than type 1 lissencephaly.

26.5 SUBCORTICAL BAND HETEROTOPIA The class of malformation that is most clearly a direct consequence of stalled migration is subcortical band heterotopia (SBH) (Barkovich et al., 1994; Dobyns et al.,

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1996; Palmini et al., 1991). In its extreme, a large band of cells can form a separate mass of gray matter throughout the cortex, and the presence of such SBH has been referred to as ‘double cortex syndrome’ (Figure 26.2(a); Palmini et al., 1991). During the formation of SBH malformations, many neurons fail to migrate through the intermediate zone and into normally forming cortical lamina, and thereby become embedded within the white matter of neocortex (Figure 26.2(b)). Heterotopia of any type in which subsets of neurons attain abnormal positions while others migrate and pattern normally within the same area suggests somatic mosaicism in migration disruption. How such mosaicism occurs is clear for two major genetic causes of heterotopia: PH (see below) and SBH. Heterozygous mutation in the DCX gene in females is the most common cause of SBH. Random X-inactivation in somatic cells naturally creates a cellular mosaic. Heterozygous DCX mutations then combined with X-inactivation will result in some cells with an active copy of the mutant gene, and these cells fail to migrate into normotopic cortex (des Portes et al., 1998b; Gleeson et al., 1998). Somatic mosaicism may also occur from somatic mutations in early stages of embryonic development that creates a mixture of cells with functional and nonfunctional copies of genes critical to migration. Evidence for this type of mosaic pattern has been found by genotyping hair follicles in some SBH cases and finding a mosaic pattern of DCX or LIS1 mutation (Gleeson et al., 2000; Sicca et al., 2003). Such somatic mosaicism in DCX mutations can be a cause of SBH in males (Poolos et al., 2002). The clinical features of double cortex syndrome show a wide range of severity, but typical deficits are mental retardation with a high incidence of seizures (Barkovich et al., 1994; Guerrini and Carrozzo, 2001a,b). The size of heterotopia is generally correlated with the severity of phenotypes (Guerrini and Carrozzo, 2001a,b). However, some cases of subcortical heterotopia have been discovered in nonsymptomatic mothers of sons with XLIS. The primary reason for a range in the size of SBH in different cases may be due to the natural variation of random X-inactivation. However, the severity of the SBH malformation also correlates with the specific DCX mutation, with some mutations generally causing larger malformations than others. Some milder mutations can even cause SBH in males instead of lissencephaly which would typically be the result of a DCX mutation. Thus, some migrating cortical neurons may be able to migrate normally even with a defective copy of the DCX gene. Animal models of SBH have been developed and, similar to the human condition, the animal models display seizures and more excitable neocortex (Ackman et al., 2009; Bai et al., 2003; Lapray et al., 2010; Manent et al., 2009). A spontaneous mutation in an as

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of yet unidentified gene in rats (the Tish gene) causes an autosomal recessive form of SBH (Chen et al., 2000; Lee et al., 1997, 1998). Mice mutant for the Dcx gene or related Dclk gene do not show the development of SBH, though these mice do show disruptions in neuronal lamination and migration (Deuel et al., 2006; Kerjan et al., 2009; Koizumi et al., 2006). This indicates a species difference in the DCX dependent mechanisms and SBH formation in mice, rats, and humans (Ramos et al., 2006). This species difference is further shown by the difference in the effects of RNAi knockdown of Dcx in mice and rats. In rats, but not in mice, targeting of Dcx expression in a subpopulation of migrating neocortical neurons results in formation of SBH (Bai et al., 2003; Ramos et al., 2006). The variability in SBH sizes and the correlation between malformation size and severity of seizure phenotypes in humans inspired an effort to regress heterotopia sizes in an animal model. In studies using RNAi of Dcx to induce formation of heterotopia, and then subsequent conditional reexpression of Dcx, it was shown that reexpression of Dcx in stalled neurons is sufficient to restart migration out of SBH malformations (Manent et al., 2009). The resulting decrease in SBH size is associated with a decrease in susceptibility to pharmacologically induced seizures (Manent et al., 2009).

26.6 PERIVENTRICULAR HETEROTOPIA PH is a heterogeneous disorder characterized by heterotopic organizations of cells and nodules at the surface of the ventricles that may be isolated or occur in combination with other neuronal malformations, (Figure 26.2(c)) (Dobyns et al., 1997; Fox and Walsh, 1999; Guerrini and Carrozzo, 2001b). In postmortem human PH brains, periventricular nodules are composed of later-born neurons that would normally migrate into upper layers. Also these brains show disruption in the neuroependyma (Ferland et al., 2009). These late-born neurons in nodules are thought to be neurons that failed to start migration away from the ventricular zone at the point of their origin. The clear misplacement of neurons in the neocortex place PH in the category of NMD, but the malformation may result primarily from a deficit in proliferation and cell adhesion in neural progenitors.

26.6.1 FLNA Bilateral PH malformations, similar to SBH malformations, represent cellular mosaics with most cells migrating normally and others not. The cellular mosaicism and skewed incidence in females indicated a pattern

consistent with a causative mutation location of the X chromosome (Dubeau et al., 1995; Fink et al., 1997; Guerrini and Dobyns, 1998). In fact, the first mutant gene related to bilateral periventricular nodular heterotopia (BPNH) was the gene FLNA on Xq28 (Fox et al., 1998). More than 40 different mutations in FLNA have been identified in individuals with bilateral PH, and such mutations in FLNA account for 50% of cases with classical bilateral PH (Parrini et al., 2006). Mutations in other regions of the same gene cause a variety of developmental disruptions, many of which have no apparent neurological involvement. The high degree of specificity for the type of mutation in FLNA in terms of the organ and cell type affected suggests that different domains of the filamin A protein are engaged by distinct signaling mechanisms in different cell types (Robertson, 2004, 2005). The FLNA gene codes for the protein filamin A, an actin-binding protein which promotes the formation of branched networks of actin filaments. Actin filaments when bound to filamin A can interact with a large number of proteins including ion channels and membrane proteins involved in cell adhesion (Nakamura et al., 2011). Knockdown by RNAi resulting in a loss of filamin a and b expression interferes with the initiation of migration and cell spreading in nonneuronal cells (Baldassarre et al., 2009). Mouse mutants of the Flna gene have not been produced that recapitulate the PH phenotype; however, a mouse mutant of the Mekk4 gene, a regulator of FLNA protein function, forms PH in the fetal mouse brain. Similarly, either RNAi knockdown of Flna or expression of Flna dominant negative protein in the mouse ventricular zone impairs proliferation and movement away from the ventricular surface (Ferland et al., 2009).

26.6.2 ARFGEF2 A rare autosomal recessive form of PH with microcephaly is caused by mutation of the ARFGEF2 gene (Sheen et al., 2004). Patients with such mutations in ARFGEF2 show severe developmental delay, seizures beginning in infancy, and microcephaly. The microcephaly phenotype is the primary feature that distinguishes PH caused by ARFGEF2 mutations from PH caused by FLNA mutations, suggesting that the ARFGEF2 gene may play a larger role in the control of proliferation than the FLNA gene. Arfgef2 is highly expressed in neural progenitors in the mouse neocortex. The Arfgef2 gene codes for a protein known as BIG2 which is essential to vesicle trafficking in cells. BIG2 catalyzes guanine diphosphate (GDP) to guanine triphosphate (GTP) and activates ADP-ribosylation factors that trigger vesicle trafficking. BIG2 function is inhibited by BREFELDIN A, and expression of BREFELDIN A inhibits cellular proliferation and the transport of E-cadherin and b-catenin to the cell surface (Sheen et al., 2004).

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26.8 COBBLESTONE CORTICAL MALFORMATION

26.7 POLYMICROGYRIA PMG is a heterogeneous cortical malformation that can occur to varying degrees, and is characterized by multiple small sulci and gyri and a thinned cortex (Figure 26.3(a)). The cortex generally shows a simplification from the normal 6 to 2–3 layers and in some cases complete loss of layering (Figure 26.3(b)). The neurological deficits associated with PMG range from no apparent effects or selective impairment of cognitive function to patients with severe encephalopathies and intractable epilepsy (Guerrini et al., 2008). A remarkable feature of PMG malformations is the high degree of regional specificity that it can exhibit. Malformations in different cases can be completely restricted bilaterally to perisylvian cortex, and others to discrete regions of frontal parietal or occipital cortex. The regionalization of PMG is correlated with the specific gene mutation associated with the malformation. PMG has been associated with mutations in several genes including GPR56, SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1, TUBA8, and COL18A1 (Abdel-Salam et al., 2007; Baala et al., 2007; Borck et al., 2011; Brooks et al., 2005; Menzel et al., 2004; Mitchell et al., 2003; MorrisRosendahl et al., 2010; Piao et al., 2004; Roll et al., 2006). The mutations identified so far involve genes that code for proteins with a diverse set of molecular and cellular functions. PMG can thus arise from any number of cellular disruptions. Such mutations still account for a minority of the cases of PMG. The 22q11.2 deletion syndrome may be the most common genetic cause of PMG, typically causing unilateral right hemispheric PMG. The particular gene, within or near the critical deleted region, which causes PMG is not currently known. Interestingly, the TUBA8 gene is the closest to the 22q11.2 critical region. There are likely many nongenetic causes of PMG including in utero ischemia and viral infection

(Antonov et al., 2003; Marques Dias et al., 1984). Experimentally induced injury or ischemia to the surface of cortex in rodent models creates microgyria with similar structure to microgyria in human PMG (Humphreys et al., 1991; Rosen et al., 1992). Autosomal recessive mutations in the GPR56 gene located on chromosome 16q13 can cause a PMG syndrome in which PMGs are bilaterally localized to frontoparietal regions of the cortex (Bahi-Buisson et al., 2010; Piao et al., 2004). Several mutations in the GPR56 gene have now been associated with bilateral frontoparietal PMG with cerebellar disruption (Bahi-Buisson et al., 2010; Piao et al., 2004). In mouse mutants of GPR56 breaks in the pial basement membrane appear to be the major cause of disruptions in cortical lamination (Li et al., 2008). GPR56 may regulate both neural progenitor cell migration via the g-protein G alpha 12/13 (Iguchi et al., 2008), and cell adhesion between granule neurons in the cerebellum (Koirala et al., 2009). The predominant neocortical phenotype in the mouse mutant, breaks in the pial basement membrane, suggests that GPR56related PMG is mechanistically related to cobblestone lissencephaly. In humans, cellular pathology and clinical analysis further show shared features with cobblestone lissencephaly (Bahi-Buisson et al., 2010).

26.8 COBBLESTONE CORTICAL MALFORMATION Cobblestone lissencephaly, also known as type 2 lissencephaly, is caused almost exclusively by breaks in the basement membrane at the pial surface (Figure 26.3(c)). As a consequence neurons migrate into and beyond the marginal zone of the cortex. The result of this over-migration is a near complete loss of normal cortical lamination with heterotopic organizations of cells in the marginal 1

1 2

2

3 4 3

5

6

Polymicrogyria

(a)

Cobblestone lissencephaly (b)

WM

(c)

(d)

WM

FIGURE 26.3 Polymicrogyria (PMG) and cobblestone lissencephaly. (a) Illustration of a coronal section from a brain with PMG whose sulci and gyri are more numerous and smaller than normal. (b) Schematic enlargement of (a) showing disorganized cortex with fewer layers than normal. (c) Drawing of a coronal section of a brain with cobblestone lissencephaly. The surface of the brain is smooth but has small extrusions of neurons that dimple the cortical surface. (d) Magnified schematic of the cortex depicting a protrusion of neurons through the normal cortical boundaries giving rise to the cobblestone appearance of the brain surface.

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zone (Figure 26.3(d); Muntoni and Voit, 2004; Olson and Walsh, 2002). Because the surface of the cortex loses sulci and gyri as a result of this malformation, it is classified as a type of lissencephaly. Cobblestone lissencephaly is typically associated with hypoplasia and/or malformation of the cerebellum. Cobblestone lissencephaly is a feature of a set of syndromes that include dysgenesis of the retina, and muscular dystrophy including muscle eye brain disease (MEB), Walker– Warburg syndrome (WWS), and Fukuyama-type congenital muscular dystrophy (Muntoni and Voit, 2004; Olson and Walsh, 2002). Patients with cobblestone lissencephaly typically have severe psychomotor retardation, seizures, visual loss, and congenital muscular dystrophy. The genetic causes of cobblestone lissencephaly are typically autosomal recessive mutations in any of six genes involved in the glycosylation of a-dystroglycan: POMT1, POMT2, POMGNT1, FCMD, FKRP, and LARGE (Manzini et al., 2008; Satz et al., 2010). Studies using mouse models show that during cortical development a-dystroglycan stabilizes the glial limitans basement membrane (Satz et al., 2010), and thereby prevents neuronal migration into the marginal zone.

26.9 FOCAL CORTICAL DYSPLASIA Focal cortical dysplasia (FCD) is a heterogeneous NMD. It is the most common NMD, and the most common cause of intractable epilepsy in children (Fauser et al., 2006; Krsek et al., 2008; Palmini et al., 2004b). The causes of FCD, for the most part, are poorly understood. Mutations in either the TSC1 or TSC2 gene that cause tuberous sclerosis complex (TSC) also cause FCD, but most cases are sporadic. FCD is generally characterized by focally thickened cortex containing some level of disordered cytoarchitecture that may include large, abnormally oriented neurons, hypertrophic astrocytes, or other dysmorphic cell types. There have been several categorization schemes proposed for FCD (Chamberlain et al., 2009; Palmini et al., 2004a), and the basic scheme describes type 1 FCD as mild disruption in lamination with hypertrophic neurons, and type 2 FCD as severe lamination disruption with cytomegalic or greatly enlarged neurons and/or balloon cells.

26.9.1 Tuberous Sclerosis Complex and Type II FCD TSC is caused by mutations in either the TSC1 or TSC2 genes. TSC often results in intractable seizures and intellectual disability, and some affected children have characteristic features of autism. It affects approximately 1 in

5000 people. FCD present in the cortex of TSC patients are of Type IIB: severe focal disruption in cortical lamination with characteristic giant cells called balloon cells. Autosomal dominant mutations in the TSC genes result in an over-activation of the mammalian target of rapamycin complex (mTOR). Aberrant activation results from decreased suppression of mTOR signaling due to a decrease in either hamartin or tuberin function, the two proteins coded for by the TSC1 and TSC2 genes respectively. With constitutive activation of mTOR comes a dysregulation in cell growth control and aberrant phosphorylation of S6 kinase and S6 (Baybis et al., 2004; Crino, 2007). Sporadic type II FCD has also been linked to changes in the same activation of mTOR pathways seen in TSC-related FCD (Crino, 2007; Orlova et al., 2010). The similarity in both the lamination and cellular disruptions and in the molecular signatures of cells in all type II FCDs indicates that they may arise from similar developmental disruptions (Crino, 2007). The mechanism leading from constitutive activation of mTOR to type II FCD is not entirely clear. One hypothesis is that FCD represents clonal expansion of an aberrant neural progenitor with dysregulated growth. Support for such a model comes from both the observation that cells within FCD are more likely to be clonally related (Hua and Crino, 2003), and that giant cells and balloon cells in type II FCDs, both sporadic and TSC mutation related, express markers characteristic of pluripotent and neural stem cells (Orlova et al., 2010). These large aberrant cells may therefore be vestiges of a population of stem cells from an earlier clonal expansion that produced the focal malformation. Additional evidence for a causal connection between activated mTOR and cortical malformations leading to seizures comes from results in mouse mutants in which mutation of Tsc1or Pten result in mTOR activation, disrupted cortical development and seizures (Fraser et al., 2004; Kwon et al., 2001, 2003; Zeng et al., 2008).

26.9.2 Type I FCD and CNTNAP2 Type I FCD is the most enigmatic NMD. The variety of forms, essentially any subtle disruption in lamination, makes type I FCD difficult to categorize accurately (Chamberlain et al., 2009). Surgical resection of type I FCD may also have a poorer outcome in terms of relieving seizures (Fauser et al., 2006; Krsek et al., 2008). The mechanism(s) that causes type I FCD could be varied and does not seem related to those responsible for type II FCD. Cells in type I FCD do not share the molecular hallmarks of mTOR signaling shared by cells in type II FCD (Orlova et al., 2010). FCD type I malformation may also result from prenatal and perinatal brain injury (Krsek et al., 2010).

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26.10 SUMMARY

Homozygous recessive mutations of CNTNAP2 discovered in a cohort of Old Amish Order children revealed the first mutation to cause Type I FCD, and cortical dysplasia-focal epilepsy syndrome (CDFES) (Jackman et al., 2009; Strauss et al., 2006). Affected individuals manifest cortical dysplasia, focal epilepsy, and macrocephaly. Pharmacologically intractable focal seizures begin in early childhood. Soon after the onset of seizures, language regression, hyperactivity, impulsive and aggressive behavior, and mental retardation develop. CNTNAP2 codes for a large scaffolding protein that had previously been shown to be involved in the clustering of the potassium channel Kv1.1. The protein is a member of the neurexin family of cell adhesion molecules and contains epidermal growth factor repeats and laminin G domains. The large protein contains many other domains as well, including an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, thrombospondin N-terminal-like domains, and a putative PDZ-binding site. The expression of CNTNAP2 is regulated by the FOXP2 transcription factor previously linked to language production (Vernes et al., 2008). CNTNAP2 has been implicated in multiple neurodevelopmental disorders, including schizophrenia, impaired language development, and autism (Alarcon et al., 2008; Arking et al., 2008; Poot et al., 2010; Zweier et al., 2009). Additional studies are required to determine whether the function of CNTNAP2 is related to cellular mechanisms involved in neuronal migration.

26.10 SUMMARY NMDs have been related to several untreatable or difficult to treat neurological deficits in children. The most common and nearly universal symptom of NMD is pharmacologically intractable epilepsy. The causes of NMD vary significantly by the type of malformation predominating in a particular syndrome, but there are significant similarities in gene functions associated with specific NMD types. Genetic disruption in microtubule associated proteins or microtubules commonly causes lissencephaly and PMG. Mutations in genes related to the extracellular matrix involving a-dystroglycan almost uniformly cause cobblestone lissencephaly malformations. PH, on the other hand, are related to disruptions in proteins linked to the actin cytoskeleton and cell adhesion. PMG malformations are associated with genetic mutations in the most varied class of genes, and this may be partially due to this malformation type sharing features and causes with both lissencephaly, simplified lamination, and cobblestone lissencephaly, breaks and increased physical disruption of the pial surface. Future challenges in the field of NMD research include increasing the number of identified gene mutations, and

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understanding the relationship between environmental insults and genetic susceptibility of NMDs. In addition, existing and new animal models need to be used to provide new insights into possible treatment of NMDs and their deleterious effects.

Acknowledgments The authors would like to thank Virge Kask for her help in preparing the illustrations for this chapter.

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26.10 SUMMARY

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