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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISORDERS OF NEURONAL MIGRATION
  5. CONCLUSION
  6. ACKNOWLEDGEMENTS
  7. CONFLICT OF INTEREST
  8. References

Disorders of neuronal migration are a heterogeneous group of disorders of nervous system development.

One of the most frequent disorders is lissencephaly, characterized by a paucity of normal gyri and sulci resulting in a ‘smooth brain’. There are two pathologic subtypes: classical and cobblestone. Six different genes could be responsible for this entity (LIS1, DCX, TUBA1A, VLDLR, ARX, RELN), although co-delection of YWHAE gene with LIS1 could result in Miller–Dieker Syndrome.

Heterotopia is defined as a cluster of normal neurons in abnormal locations, and divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia and marginal glioneural heterotopia. Genetically, heterotopia is related to Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2) genes mutations.

Polymicrogyria is described as an augmentation of small circonvolutions separated by shallow enlarged sulci; bilateral frontoparietal form is characterized by bilateral, symmetric polymicrogyria in the frontoparietal regions. Bilateral perisylvian polymicrogyria results in a clinical syndrome manifested by mild mental retardation, epilepsy and pseudobulbar palsy. Gene mutations linked to this disorder are SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1 and COL18A1.

Schizencephaly, consisting in a cleft of cerebral hemisphere connecting extra-axial subaracnoid spaces and ventricles, is another important disorder of neuronal migration whose clinical characteristics are extremely variable. EMX2 gene could be implicated in its genesis.

Focal cortical dysplasia is characterized by three different types of altered cortical laminations, and represents one of most severe cause of epilepsy in children. TSC1 gene could play a role in its etiology.

Conclusion: This review reports the main clinical, genetical and neuroradiological aspects of these disorders. It is hoped that accumulating data of the development mechanisms underlying the expanded network formation in the brain will lead to the development of therapeutic options for neuronal migration disorders.

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INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISORDERS OF NEURONAL MIGRATION
  5. CONCLUSION
  6. ACKNOWLEDGEMENTS
  7. CONFLICT OF INTEREST
  8. References

Development of central nervous system is a highly complicated process and is organized in the following steps: primary neurulation (3–4 weeks of gestation), prosencephalic development (2–3 months of gestation), neuronal proliferation (3–4 months of gestation), neuronal migration (3–5 months of gestation), organization (5 months of gestation – after the birth), myelination (after the birth) (1).

Neuronal migration consists of nerve cells moving from their sites of origin in the ventricular and subventricular zones to their final location. Regulation of the timing and direction of these simultaneous migrations is highly ordered. Recently it has been focused on the control mechanisms of these signalling which can be altered by inborn genetic errors as well as by exogenous factors (1).

Neurons that originate from the cortical ventricular zone (VZ) migrate radially to form the cortical plate (CP) and mainly become projection neurons (2).

Migration of neocortical neurons occurs mostly between the twelfth and the twenty-fourth weeks of gestation. The first post-mitotic neurons produced in the periventricular germinative neuroepithelium (VZ) will migrate to form a subpialpreplate or primitive plexiform zone. Subsequently produced neurons, which will form the CP, migrate into the pre-plate and split it into the superficial molecular layer (or layer I or the marginal zone [MZ] containing Cajal–Retzius neurons) and the deep subplate. Schematically, the successive waves of migratory neurons will pass the subplate neurons and finish their migratory pathway below layer I, forming successively (but with substantial overlap) cortical layers VI, V, IV, III and II (inside-out pattern) (Fig. 1).

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Figure 1. Top: tangentially and radially neuronal migration (top left), inside-out mechanism of neuronal migration (top centre), normal appereance of the cortex (top right); Bottom: different appereances of cerebral cortex layers in neuronal migration disorders. GE = gangliar eminence; MZ = marginal zone; CP = cortical plate; SCZ = subcortical zone; IZ = intermedial zone; VZ = ventricular zone; WM = white matter.

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Neocortical migrating neurons can adopt different types of trajectories: a large proportion of neurons migrate radially, along radial glial guides, from the germinative zone to the CP.

Radial glia are specialized glial cells present in the neocortex during neuronal migration (Fig. 2).

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Figure 2. Neurons migrate trough periventricular germinal zone by radial glial fibre towards cortical hemisphere.

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Another important group of neuronal precursors initially adopts a tangential trajectory at the level of the ventricular or subventricular germinative zones before adopting a classic radial migrating pathway along radial glia. Tangentially migrating neurons have also been described at the level of the intermediate zone (IZ) (prospective white matter [WM]).

The phenotype of radial glia seems to be determined by both migrating neurons and intrinsic factors expressed by glial cells. Among the latter, the transcription factor Pax6, which is specifically localized in radial glia during cortical development, is critical for the morphology, number, function and cell cycle of radial glia (3).

The cellular and molecular substrates necessary for both radial cell migration and non-radial cell migration have been, and continue to be, the focus of many studies in this field. Studies over the last decade have identified several molecules involved in the control of neuronal migration and targeting of neurons to specific brain regions.

These molecules can be divided into the following four broad categories:

  • 1
    Molecules of the cytoskeleton which play an important role in the initiation and ongoing progression of neuronal movement (i.e. filamin A (FLNA), ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2) or ADP-rybosylation factor GEF2, doublecortin, Lis1);
  • 2
    Signalling molecules playing a role in lamination (i.e. reelin and some reelin receptors, p35, cdk5, Brn1/Brn2);
  • 3
    Molecules modulating glycosylation which seem to provide stop signals for migrating neurons (i.e. POMT1, POMGnT1, fukutin and focaladhesion);
  • 4
    Other factors including neurotransmitters (glutamate and γ amino-butirric acid (GABA)), trophic factors (brain-derived neurotrophic factor or BDNF and thyroid hormones), molecules deriving from peroxisomal metabolism and environmental factors (ethanol and cocaine) (4). Among these mechanisms the neurotransmitter GABA and glutamate deserve particular attention because they are expressed early in the developing brain, they act as paracrine signalling molecules in the immature brain and they regulate intracellular calcium required for many cellular functions including cytoskeletal dynamic changes (4). According to these data a perturbation of neurotransmitter and neurotransmitter receptor actions results in the genesis of cell migration defects with neurons remaining close to ventricle or stacked in intermediate locations (4).

Malformations of cortical development are classified by some authors on the basis of clinical, neuroradiologic and genetics characteristic (5,6). It should be considered that these classifications are very difficult and with time modifiable. Neuronal migration disorders include:

  • 1
    Lissencephaly
  • 2
    Heterotopia
  • 3
    Polymicrogyria
  • 4
    Schizencephaly
  • 5
    Focal cortical dysgenesis

The malformation of the cerebral cortex delineates a considerable cause of developmental abnormalities and severe epilepsy. It is figured out that up to 40% of children with drug-resistant epilepsy have a cortical malformation.

However, the physiological mechanisms that connect cortical malformation with epilepsy remain undefined.

The most common cause of infantile spasms and intractable epilepsy in children and adult are malformation owing to anomalies of cortical development mainly those associated with disturbances of neuronal and glial cell progenitor migration. Various types of epilepsy are related to the distinct conditions.

DISORDERS OF NEURONAL MIGRATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISORDERS OF NEURONAL MIGRATION
  5. CONCLUSION
  6. ACKNOWLEDGEMENTS
  7. CONFLICT OF INTEREST
  8. References

Disorders of neuroepitelial cell migration and cortical pattering (5) compass:

  • 1
    Lissencephaly:
    • (i) 
      type I also called classical lissencephaly derived from both tangential and radial migration disorders of neurons;
    • (ii) 
      type II lissencephaly with shallow dimpled appearance of the cortex also called cobblestone dysplasia with three genetical different conditions including:
      • - 
        Fukuyama-type congenital muscular dystrophy;
      • - 
        Muscle–eye–brain disease;
      • - 
        Walker–Warburg Syndrome;
  • 2
    Polymicrogyria
  • 3
    Schizencephaly
  • 4
    Neuronal Heterotopia (Periventricular and Subcortical band)
  • 5
    Cortical dysgenesis/Focal cortical dysplasia

Numerous types of epilepsy have been related to the following different conditions.

Lissencephaly

Lissencephaly type I (classical)

Affected children have early developmental delay, mental retardation and spastic quadriparesis.

Seizures are present in almost the totality of children with onset in early age. High prevalence (80%) of infantile spasms with or without typical hypssarrhythmia on EEG has been reported. Consequently multiple seizure types including focal seizures, tonic seizures, atypical absences and atonic seizures are observed (6).

The EEG demonstrates diffused fast rhythms with high amplitude, considered peculiar of this condition.

Lissencephaly type II (cobblestone)

Fukuyama type congenital muscular dystrophy-eyes anomalies.

In this condition, the association of epilepsy and related seizure disorders have been reported in about 50% of the patients. The seizures signalled were febrile and afebrile such as generalized tonic–clonic, complex partial seizure, Lennox–Gastaut syndrome. High percentage (30%) of them were intractable (7).

Polymicrogyria

The typical appearance is an augmentation of small circonvolutions separated by shallow enlarged sulci.

The wide spectrum of clinical manifestations is related to the extension of polymicrogyria, which varies greatly. In fact polymicrogyria may be bilateral perisilvian, bilateral parasagittal, parieto-occipital, bilateral frontal and fronto-parietal, unilateral perisilvian or multilobar.

These different forms may represent distinct entities that reflect influence of regionally expanded developmental genes (8).

Affected children may have continuous general spike-wave complexes during slow-wave sleep and suffer from focal motor seizures, atypical absence seizures, atonic drop attacks, tonic–clonic seizures, Lennox–Gastaut syndrome, appearing in the first decade of life. Epilepsy could arise with different severity and often is drug resistant (9).

Moreover children may present with developmental delay and mild spastic quadriparesis (10).

Schizencephaly

This malformation consists of unilateral or bilateral full-thickness cleft of the cerebral hemispheres with communication between the ventricles and extra-axial subaracnoid spaces. The cleft is often found in perisilvian areas (11). Two anatomical presentation could be distinguished: open (walls of cleft are entirely divided by cerebrospinal fluid) and closed (walls of cleft are incompletely divided) lip; however the spectrum is various, ranging from small, unilateral fused-lip clefts to large, bilateral open lips. Additionally schizencephaly is often associated with septo-optic dysplasia (agenesis of septum pellucidum and optic nerve hypoplasia) (7).

Schizencephaly is also considered a disorder of cortical organization because the cortex surrounding the cleft is polymicrogyric. Clinical findings include focal seizures with early onset. Bilateral cleft are associated with other neurological signs (12).

Neuronal heterotopia

Periventricular nodular heterotopia

The location of the heterotopia is often bilateral and placed along lateral ventricles. The spectrum of clinical presentation is wide. Epilepsy is the main aspect. In fact approximately 90% of patients have epilepsy, which can begin at any time. Patients mainly have partial attacks with temporo-parieto-occipital auras. Surgical removal of the heterotopia cortex led to seizure freedom (7).

Subcortical band heterotopia

The main clinical manifestation is epilepsy. Cognitive function varies from normal to severe retardation and correlates well with the thickness of the band and the degree of pachygyria (13).

Epilepsy, which may be partial and generalized, is intractable in about 65% of patients. Lennox–Gastaut syndrome is another potential presentation. Epilepsy surgery for focal seizures yields poor results while callosotomy has been associated with improvement in drop attacks (6).

Cortical dysgenesis/focal cortical dysplasia

This malformation consists of three main subtypes:

  • 1
    A first type is characterized by architectural dysplasia with abnormal cortical lamination and ectopic neurons in the WM.
  • 2
    A second type defined as cytoarchitectural dysplasia characterized by altered cortical lamination and giant neurofilament-enriched neurons.
  • 3
    A third type is the Taylor-type cortical dysplasia, characterized by giant dysmorphic neurons and balloon cells associated with cortical laminar disruption (7).

Focal cortical dysplasia is generally associated with intractable focal epilepsy, which usually starts in adolescence. Seizures semeiology depends on the location of the lesion. Epilepsia partialis continua has been reported (14).

The continuous epileptiform EEG discharges are characteristic for focal cortical dysplasia. Epilepsy may be intractable and surgical treatment may be required (6).

Neuroradiological (structural and functional) and genetical data in NMDs

Neuroradiologic features in NMDs

Cortical malformations from abnormal migration are increasingly recognized as a cause of both epilepsy and developmental disabilities. Neuronal migration disorders (NMDs) represent one of the conditions associated with intractable epilepsy; particularly, histologically proven developmental brain abnormalities are observed in up to 25% of children with intractable seizures (14). Most of such abnormalities may now be detected with magnetic resonance imaging (MRI), although some cortical malformations remain undetectable even with the best imaging techniques. Sometimes, we can use a specific term in case of suggestive (or even pathognomonic) MRI pattern, but neuroradiological investigations do not always provide a precise indication of the pathological nature of the lesion.

Abnormalities of the cerebral cortex may be diffuse or they may involve discrete cortical areas. Certain NMDs are genetically determined and, for others, a genetic origin has been hypothesized; however, some may be linked to prenatal insult (environmental, chemical or iatrogenic) with a precise gestational age timing-related.

Recognizing in every single patient the type of NMDs represent a very important challenge. It can allow us to formulate more accurate prognostic evaluations, considering that some malformations are more epileptogenic than others, as they occur in specific forms (showing a well-known neuroradiological pattern) in which the epileptogenesis appears to originate from the intrinsic properties of the dysplastic tissue (15).

Most NMDs affected patients, can be well identified by MRI techniques, structural and functional.

To best classify NMDs in these children, imaging studies should be optimized and, as a rule, thin-section T1- and T2-weighted MRI images should be acquired. For T1-weighted images, a volumetric spoiled gradient echo sequence should be acquired with partition size of 1–1.5 mm to allow the data to be reformatted in any plane. At a minimum, sagittal, coronal and axial images are necessary. For T2-weighted images, contrast between grey and WM is best using conventional spin echo images. In neonates and infants less than 10-month olds (before myelination), thin-section (1.5–3 mm) heavily T2-weighted spin echo images are optimal, whereas between the ages of 10 and 24 months, thin partitions of T1-weighted volumetric spoiled gradient echo images with heavy T1 weighting are best. Beyond the age of two years, standard adult protocols should be used.

The imaging findings of lissencephaly vary with the severity of the mutation (16). When very severe, the cortex is markedly thickened and almost no sulci are formed (Fig. 3); when less severe, the cortex is less thickened and a variable number of shallow sulci separate broad gyri. In some cases, a ‘cell-sparse zone’ is identified between the thin outer cortical layer and the thicker inner cortical layer of neurons whose migration has been arrested (17).

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Figure 3. Brain MRI: lissencephaly type I. T1 weighed axial view: slight hypoplasia of the corpus callosum and a small cyst of the septum pellucidum and a cavum vergae (pentagon); agyria in the parietal lobes (arrows); some gyri and sulci in frontal and occipital lobes (arrowheads), colpocephaly (horizontal and bidirectional arrow) and beginning of the silvian fissures.

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The imaging characteristics of bilateral frontoparietal polymicrogyria (BFPP) (myelination defects, cerebellar cortical dysplasia with cysts, frequent involvement of the medial aspects of the cerebral hemispheres) resemble more those of the so-called cobblestone malformations (muscle–eye–brain disease and Fukuyama congenital muscular dystrophy) that are also associated with N-glycosylation defects in the developing brain. Therefore, this disorder might be best classified as a cobblestone malformation. The imaging appearance of polymicrogyria varies with the age of the patient (18). In newborns and young infants, the polymicrogyric cortex is very thin, with multiple, very small undulations. After myelination, polymicrogyria appears as slightly thick cortex with a slightly irregular cortex-WM junction. The pial surface might appear paradoxically smooth, as a result of fusion of the molecular layer (cortical layer 1) across adjacent microgyri. Polymicrogyria can be localized to a single gyrus, involve portions of a hemisphere, be bilateral and asymmetrical, bilateral and symmetrical or diffuse (Fig. 4). Sometimes, it is associated with deep clefts that might extend through the entire cerebral mantle to communicate with the lateral ventricle (schizencephaly).

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Figure 4. Bilateral opercular polymicrogyria (arrows) more evident on the right hemisphere.

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Single photon emission computed tomography (SPECT) (ictal and interictal) and positron emission tomography (PET) give additional information about metabolic correlations (19); in specific condition MRI-spectroscopy may give crucial metabolic information too.

Previous studies have shown that interictal and postictal SPECT are well correlated with EEG in partial epilepsy in terms of focal decreasing in cerebral blood flow (rCBF) (19). However, decreased rCBF can be present in cortical dysplasia in both ictal and interictal phases (20).

Functional studies have suggested that NMDs can present with either hypometabolism or preserved perfusion of heterotopia, the so-called ‘displaced grey matter activity (21)’.

In NMDs, the observation of preserved perfusion by SPECT studies in heterotopia has been related to the microscopic finding of a normal six-layered cortex in laminar heterotopia (22), while cerebellar hemispheric hypoperfusion, contralateral to the epileptic focus, has been reported in a variety of unilateral cerebral lesions in patient with focal epilepsy (23). These cerebellar modifications cannot be interpreted as the result of a complication of repetitive seizures, nor the expression of lesions at the ‘morphologic’ level; they are most likely the result of altered corticopontocerebellar input from the contralateral cerebral hemisphere (cerebellar diaschisis) (24).

In addition to MRI and PET/SPECT studies, Proton MRI spectroscopy (MRS) should add information for the identification and characterization of abnormal brain tissue of NMDs. In general N-acetylaspartate (NAA), choline-containing compounds (Cho) and creatine-phosphocreatine (Cr) are expressed in a various concentration throughout the brain, depending on tissue degree of maturation. Furthermore, neuronal tissue may have different spectra profiles depending on technology (single or multiple voxel) (Fig. 5). In fact, giant grey matter heterotopia have been reported to be characterized by normal NAA, Cho, Cr spectra or by increased Cho, Cr peaks and a normal NAA signal. By means of proton MRS at 4.1 T it has been demonstrated that focal cortical dysplasia revealed metabolic abnormalities consistent with the structural lesions, whereas in focal heterotopia and polymicrogyria biochemical abnormalities have not been demonstrated (25).

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Figure 5. (A,B): A: MRI (coronal view-T2 weighted) in the left frontal lobe a diffuse cortical hyperintensity (arrow) with absence of the normal cortical blurring between white and grey matter compatible with cortical dysplasia. B: MRI spectroscopy (single voxel) notes the augmentation of the myoinositol and the marked depletion of the N-acetyl-aspartate in the cortical dysplasia.

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Among new neurodevelopmental technologies, functional magnetic resonance imaging (fMRI) is a recent method to study the sensorimotor cortex in healthy subjects and in patients (7). Bilateral and symmetric band heterotopia have been studied with this methodology in only one child (6); in this patient a bilateral activation of both normal cortical mantle and band heterotopia was observed during a finger-tapping test. In our patient, activation of the normal left sensorymotor cortex together with the facing band heterotopia was observed. In the right hemisphere only the sensorymotor cortex was activated; no involvement of the right band heterotopic tissue was observed (25) (Fig. 6).

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Figure 6. (A, B): A: MRI scan (axial view: IR sequence; TR = 2000 ms, TE = 20 ms). Normal overlying cortical mantle; bilateral band heterotopia (arrows) characterized by a greater thickness in the left hemisphere especially at frontal and occipital levels (arrowheads). B: fMRI activation of both the left band heterotopia (arrow) and the overlying cortex (arrowhead) when right hand is activated.

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Schizencephaly is characterized by full thickness cleft of the cerebral hemisphere from the ependyma to the pial surface of the brain. The cleft is located everywhere, but it is more frequent in the perisylvian regions. (Fig. 7). This malformation can be unilateral or bilateral, symmetric or asymmetric and divided in two types: closed or fused lips, type I (if the cleft walls are in apposition) and open lips, type II (if the cleft walls are separated). Schizencephaly type II is more common than type I (11).

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Figure 7. MRI (IR sequence SE 200 – 38 coronal view) show large left open lip frontotemporoparietal schizencephaly (arrowheads), with a polymicrogyric cortex lining the cleft. On the right-hand side a polymicrogyric opercular malformation is also present (arrows).

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NMDs genetic aspects

NMDs are frequently caused by defects in molecules that are essential for neuronal migration (26). For example, among the identified genes currently associated with PH, the most cited are ARFGEF2 and FLNa (8). FLNa is tightly regulated both temporally and spatially during cortical development, where normal expression appears to be low in the VZ and is higher in the IZ and CP. This reflects enrichment of FLNa in post-mitotic migrating neurons, an expression pattern that might be maintained in part by FILIP (Filamin-A-interacting protein), a potent degrader of FLNa (27). Although FILIP is expressed in the developing forebrain, whether it is present and active in both neurons and radial glia is unknown. It is conceivable that FILIP activity is high in neuronal progenitors and is subsequently lost or inactivated in post-mitotic neurons, allowing FLNa to initiate migration.

FLNa is believed to drive migration by reorganizing the actin cytoskeleton to generate the forces necessary for cell mobility (28). This is supported by the finding that in mice, expression of FLNa lacking the actin-binding domain (FLNa-actin binding domain [ABD]) arrests the migration of post-mitotic neurons, albeit in the IZ. FLNa mutations resulting in PH often involve truncation or disruption of the actin-binding domain, indicating that FLNa's ability to cross-link actin may be necessary for migration. Nevertheless, FLNa might play additional developmental roles during corticogenesis.

Genetics in lissencephaly

Lissencephaly (including both agyria and pachygyria) is the most severe of the known malformations from abnormal neuronal migration. Most cases of lissencephaly occur without any associated malformation outside the brain (isolated lissencephaly sequence – ILS), and some belong to more complex malformation syndromes, explaining the difficulty in Lissencephaly classification (Table 1).

Table 1.  Types of lissencephaly classification (new proposed 2008 classification is based on the gradient [anterior/posterior] and size of the altered cerebral structure and on the association with anomalies of extra-cerebral structures; this classification in not completely defined)
Types of lissencephaly classificationLissencephaly groupsSub-groups
Dobyns and Leventer 2003 (43)Classic (or Type I)Isolated lissencephaly sequence (ILS)
Subcortical band heterotopia (SBH)
Miller–Dieker syndrome (MDS)
Isolated lissencephaly without known genetic defects
Cobblestone (or Type II)Walker–Warburg syndrome (WWS)
Muscle–eye–brain disease (MEB)
Fukuyama type congenital muscolar dystrophy
Lissencephaly (mild) with cerebellar hypoplasia ‘GROUP B’ (LCH) or Disequilibrium syndrome 
X-linked lissencephaly with abnormal genitalia (XLAG) 
Microlissencephaly 
 
New (2008) proposed lissencephaly classification (8,44)Lissencephaly variants 4,3,2 layersVariant 4 layers (classical lissencephaly; Miller–Dieker syndrome):
1. Isolated lissencephaly sequence (ILS);
2. Subcortical band heterotopia (SBH);
3. Lissencephaly with cerebellar hypoplasia (LCH) ‘group A’;
4. Baraitser–Winter syndrome
Variant 3 layers: XLAG
Variant 2 layers: lissencephaly with cerebellar hypoplasia (LCH) ‘group C’;
Other lissencephalies (autosomal recessive)1. Lis with mild frontal pachygyria;
2. Lissencephaly with cerebellar hypoplasia (LCH) ‘group B’;
Microlissencephaly spectrum (severe congenital microcephaly with lis)1. Barth microlissencephaly syndrome;
2. Norman–Roberts syndrome (NRS);
3. Microcephalic osteodysplastic primordial dwarfism I (MOPD 1);
Cobblestone cortical malformation1. Walker–Warburg syndrome (WWS);
2. Muscle-eye-brain disease (MEB);
3. Fukuyama type congenital muscolar dystrophy;
4. Gpr56-related bilateral fronto-parietal cobblestone-like malformation;
5. Debre' type cutis laxa with cgd type II glycosylation defect and cobblestone-like dysgenesis

Less severe defects in the same genes and developmental processes result in subcortical band heterotopia. In this group of malformations, neurons begin migration but are unable to complete it. To date, mutations of six genes have been associated with lissencephaly including LIS1, DCX, TUBA1A, RELN, VLDLR and ARX, whereas co-deletion of YWHAE with LIS1 appears to act as a modifier locus. The associated phenotypes include isolated lissencephaly sequence (DCX in males, LIS1 and rarely TUBA1A), subcortical band heterotopia (DCX in females and rare males, and LIS1), Miller–Dieker syndrome (co-deletion of LIS1 and YWHAE), mild lissencephaly with cerebellar hypoplasia ‘group b’ or the ‘disequilibrium syndrome’ (RELN and VLDLR) and X-linked lissencephaly with abnormal genitalia (ARX) (Table 2). Mutations of LIS1 (including deletions), DCX and TUBA1A account for 65%, 12% and an unknown but small percent of patients with lissencephaly. In contrast to previous reports, recent data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity (29). The proteins coded by these genes all regulate microtubule and cytoplasmic dynein function and – at least for LIS1– interfere with neuronal migration by blocking microtubule-directed nuclear movement in VZ neuroblasts, conversion of nascent post-mitotic neurons to multipolar pre-migratory cells and conversion of multipolar to bipolar migratory cells. Mutations of these three genes lead to the classic form of lissencephaly in which cortical thickness is increased fourfold (3.5–4 mm to 12–20 mm) and produce a recognizable gradient in which the malformation is more severe anteriorly (DCX) or posteriorly (LIS1 and TUBA1A).

Table 2.  Classic Lissencephaly (type I): involved genes with protein products, functions and associated phenotipes (8)
GeneFull name/protein productLocusProtein functionAssociated phenotype
LIS1 or PAFAH1B1Alpha subunit of the intracellular 1b isoform of the platelet activating factor acetylhydrolase17 p13.3Initiation and progression of neuronal movement through regulation of microtubule and dynein functionIsolated Lissencephaly Sequence (ILS) (OMIM #607432)
 
DCX or XLISDoublecortinXq22.3q23Initiation and progression of neuronal movement through regulation of microtubule and dynein functionX-Linked Lissencephaly (in males); Subcortical Band Heterotopia (in females); (OMIM #300067)
TUBA1AAlpha 1a tubulin12q12-q14Initiation and progression of neuronal movement through regulation of microtubule and dynein functionIsolated Lissencephaly Sequence (ILS) (OMIM #611603)
 
VLDLRVery low density lipo-protein receptor9p24Part of the reelin signalling pathwayLissencephaly with cerebellar hypoplasia "group b" (LCH) (OMIM #224050)
 
RELNReeler mutant mouse/Reelin7q22Cell–cell interactions and neuronal migration (secreted by Cajal–Retzius cell 1)Lissencephaly with cerebellar hypoplasia "group b" (LCH) (OMIM #257320)
 
ARXAristaless related homeobox (trascription factor)Xp22.13Proliferation/development of neuronal precursor; tangential migration of interneuronsX-linked Lissencephaly with Abnormal Genitalia (XLAG) (OMIM #300215)
 
YWHAE (with LIS1)Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein17p13.314-3-3 family of proteins; mediate signal transduction by binding to phosphoserine-containing proteinsMiller–Dieker syndrome (MDS) (OMIM #247200)

Other patients with classical ILS or subcortical band heterotopia (SBH) (about 20%) have mutations of the DCX gene (Xq22.3), resulting in X-linked lissencephaly (LISX1) or double cortex (DC) syndrome; mutations of DCX gene and is its product, doublecortin, a cytoplasmic protein which appears to direct neuronal migration by regulating the organization and stability of microtubules, cause a complete lissencephaly in males and a double cortex syndrome in females; this difference is caused by the physiological random inactivation of the X chromosome (lyonization) occurring in females. If the abnormal DCX gene is not compensated by its normal homologous copy, a normal neuronal migration is prevented: consequently, the mutated neurons in the non-inactivated X chromosome are unable to complete the migration and reach their final destination; in reverse, the neurons with a normal copy of the gene (whose abnormal counterpart is contained in the inactivated X-chromosome) can normally migrate to the brain cortical surface. The above reported mutations in females result in two bands of cortex separated by a layer of WM (double cortex), while in males it results in a complete lissencephalic phenotype (30).

Mutations of ARX are a rare cause of lissencephaly (16) although less severe mutations result in a more common developmental disorder, cryptogenic infantile spasms. This gene is a transcription factor expressed in forebrain that regulates non-radial migration of interneurons from ventral regions (ganglionic eminence) to the developing cortex (31) and has other unknown functions in the dorsal cortex. Severe seizures are presumably related to a severe deficiency of inhibitory interneurons and suggest a novel developmental mechanism for some forms of early onset severe epilepsy. Patients with ARX mutations have abnormalities of the basal ganglia and absence of the corpus callosum, whereas those with RELN and VLDLR mutations have less cortical thickening, absence of a cell-sparse zone and profound cerebellar hypoplasia (32). The cerebral cortex of the newly described two-layered lissencephaly (17) has only a slightly thickened cortex with few sulci, thinning of the cerebral WM and, often, absence of the corpus callosum.

ARX's role in nervous system development is confirmed by numerous syndromes genetically related: X-linked infantile spasms (West syndrome), X-linked myoclonic epilepsy with spasticity and mental retardation, X-linked mental retardation, Partington syndrome (mental retardation, dystonic movements of the hands and dysarthria), Proud syndrome (acquired microcephaly, mental retardation, agenesis of the corpus callosum and peculiar facies), hydranencephaly with ambiguous genitalia, XLAG syndrome. XLAG is a syndrome described in 1999, presenting with lissencephaly (more severe than LIS1 or DCX-related lissencephaly), agenesis of the corpus callosum, refractory epilepsy (with tonic, multifocal myoclonic or generalized tonic–clonic seizures) of neonatal onset, acquired microcephaly and male genotype with ambiguous genitalia; all patients show intractable epilepsy and lacked psychomotor development, and the most of cases die before the age of 18 months (33).

The main genes involved in Lissencephaly type II are summarized in Table 3.

Table 3.  Cobblestone Lissencephaly (type II): involved genes with protein products, functions and associated phenotypes (8)
GeneFull name/protein productLocusProtein functionAssociated phenotypes
POMT1Protein-O-mannosyltransferase 19q34Cell integrity and cell wall rigidityWalker–Warburg syndrome (WWS) (OMIM #236670)
 
Muscle-eye-brain disease (MEB) (OMIM #253280)
 
POMT2Protein-O-mannosyltransferase 214q24.3Interaction with the product of the POMT1 gene for enzymatic functionMEB WWS
 
FKTN (or FCMD)Fukutin9q31–33Glycosilation of alpha–destro-glycan carbohydrates in the skeletal muscleFukuyama type congenital muscular dystrophy (FCMD) (OMIM #253800)
WWS
 
FKRPFukutin related protein19q13.32Co-operates with FukutinMEB
WWS
 
POMGnT1Protein O-linked mannose beta1, 2-N-acetylglucosaminyltransferase1p34Conversion of the mannose beta 1–2 acetylateMEB
 
LARGEAcetylglucosaminyltransferase-like protein22q-12.3–13.1Glycosilation of the alpha-destro-glycansMEB
Genetics in heterotopia

Heterotopia are clusters of normal neurons in abnormal locations. The most common type, periventricular nodular heterotopia (PNH), are the neurons that never begin migration, remaining adjacent to the lateral ventricles. To date, 15 distinct PNH syndromes have been described (34). The most common of these is classic bilateral PNH, which is much more frequent in females; more than 50% have mutations of the X-linked FLNA gene. Autosomal recessive microcephaly with PNH is a very rare phenotype caused by mutations of ARFGEF2. PNH has also been associated with copy number variations including duplication 5p15.1 or 5p15.33 (35) and deletion 6q26-q27 or 7q11.33 (36).

Some patients with PNH have also been described with Chiari I and Amniotic Band Syndrome (37,38). No genetic insights into other forms of heterotopia have been gleaned. Heterotopia are divided into three main groups, PNH, subcortical heterotopia and leptomeningeal heterotopia, but only the first two can be detected by imaging (so called subcortical band heterotopia or ‘double cortex’ is a mild form of lissencephaly and classified in that group). PNH might be isolated – usually presenting with seizures – or part of a multiple congenital anomaly syndrome. When isolated they are often X-linked, and affected patients develop normally until the onset of epilepsy, which appears in 72% and at variable ages. Subcortical heterotopia are sporadic, irregular, curvilinear accumulations of grey matter nodules that course from the ventricular surface to the cortex, which is often thin and microgyric. The ipsilateral hemisphere is typically small and the basal ganglia are small and irregular. Affected patients have epilepsy and might have accompanying neurologic signs/symptoms.

Genetics in polymicrogyria

The term polymicrogyria defines an excessive number of abnormally small gyri that produce an irregular cortical surface. It is a very common cortical malformation and is associated with a dizzying array of patterns and syndromes (Table 4).

Table 4.  Polymicrogyric syndromes (45)
Polymicrogyric syndromesClinical signs/symptomsCerebral or other associated malformationInheritance
Bilateral generalized polymicrogyria (BGP)Motor and cognitive delay; spastic haemi- or quadriparesis; SeizuresVentriculomegaly and reduced WMvolume; macrocephaly, scalp and limb defects, low set ears, macrostomia, hypothyroidism and sensorineural hearing lossAR
 
Bilateral frontal polymicrogyria (BFP)Motor and language delay; spastic haemi- or quadriparesis; Mild/moderate mental retardation; seizures (38%)UndefinedAR
 
Bilateral perisylvian polymicrogyria (BPP) (4 grades) (OMIM #300388)Pseudo-bulbar palsy (facio-pharyngo-glosso-masticatory paresis) and dysarthria (100%); seizures (85%); piramidal signs; mental delay (50–80%)Arthrogryposis, club feet and micrognathiaAR or AD Xq28 (X-linked)
 
Bilateral fronto-parietal polymicrogyria (BFPP) (OMIM #606854)Motor and mental delay; dysconjugate gaze (esotropia); seizures (>90%); cerebellar and piramidal signs;Bilateral WM abnormalities atrophy of the brain stem and cerebellum16q12.2-21 (GPR56 gene) AR
 
Bilateral parasagittal parieto-occipital polymicrogyria (BPOP)Seizures; mild/moderate mental retardationUndefinedUndefined
 
Unilateral polymicrogyria (OMIM%610031)Spastic haemiparesis; mental delay; seizures; electrical status epilepticus during sleep (ESES)UndefinedAR or AD or X-linked

Extent and location of the polymicrogyric abnormality influence the severity of neurologic manifestations. Polymicrogyric cortex in language-related areas, around the left perisylvian fissure, was identified by means of autopsy in individuals with developmental dysphasia or dyslexia (39) and is considered to be an important cause of the developmental language disorder. Mutations of the SRPX2 gene have been associated with bilateral perisylvian polymicrogyria, which is regularly accompanied by oral and speech dyspraxia, but also with oral and speech dyspraxia and seizures in individuals with normal brain MRI. These observations, and the finding that the orthologous gene SRPX2 is not detected during murine embryogenesis, suggest a major role for SRPX2 in the development and functioning of language-related areas in humans.

Polymicrogyria pathogenesis is not understood; brain pathology demonstrates abnormal development or loss of neurons in middle and deep cortical layers (40), variably associated with an unlayered cortical structure. Today, polymicrogyria has been associated with mutations of only a few genes including (8) SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1 and COL18A1, with all but SRPX2 found in rare syndromes (Table 5). Developmental studies are available for only PAX6 and TBR2, but these suggest one potentially interesting mechanism. The SRPX2 gene maps to band Xq23, and does not account for X-linked forms of perisylvian polymicrogyria that map to Xq27 and Xq28.

Table 5.  Polymicrogyria:involved genes with protein products, functions and associated phenotipes (45)
GeneFull name/protein productLocationProtein functionAssociated phenotype
  1. *uPAR is urokinase-type plasminogen activator (uPA) receptor; ADAMTS4 is a metalloproteinase; CTSB is cysteine protease cathepsin B.

SRPX2Sushi-repeat-containing protein, X-linked 2Xq21.33-q23Involved in the proteolytic remodeling of the extracellular matrix (partner of uPAR, ADAMTS4, CTSB*) in the development and functioning of the speech cortexBilateral Perisylvian Polymicrogyria (BPP)
 
PAX6Paired box 611p13DNA binding protein and regulator of gene transcription, expressed in the developing nervous systemUnilateral Polymicrogyria
 
TBR2Eomesodermin homolog (EOMES)3p21.3-p21.2Conserved protein family that shares a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processesUndefined
 
KIAA1279Kinesis like family 1 protein (KIF1) binding protein10q21.3KIF1 is an axonal transporter of synaptic vesiclesBilateral Generalized Polymicrogyria
 
RAB3GAP1RAB3 GTPase activating protein subunit 1 (catalytic)2q21.3Involved in regulation of RAB3 protein family, implicated in regulated exocytosis of neurotransmitters and hormonesUndefined
 
COL18A1Alpha 1 type XVIII collagen21q22.3Extracellular matrix proteins with an important role in neural tube closureUndefined
 
GPR56G protein-coupled receptor 5616q12.2-q21Expressed in neuronal progenitor cells of the ventricular and subventricular germinal zones during neurogenesisBilateral Fronto-Parietal Polymicrogyria (BPFF)

BFPP is associated with mutations of a gene named GPR56. GPR56 codes for a G-protein-coupled receptor that is expressed in neuronal progenitor cells of the ventricular and subventricular germinal zones during periods of neurogenesis. It appears that mutations in GPR56 result in impaired trafficking of the mutant protein to the plasma membrane.

Genetics in schizencephaly

To date the etiology of this disorder is not established because it is associated with several causes that include genetic, vascular, toxic, metabolic and infectious factors. It is supposed that a focal ischemic necrosis or focal damage can destroy radial glial fibres during the early development of the cerebral cortex (6).

Another hypothesized cause is that CMV infection during third and fourth month of gestation can involve disruption the radial glial cells guide (41).

An important role in the genesis of schizencephaly is played by mutation in the omeobox gene EMX2, a gene encoding for a transcription factor involved in the expression of the gene. Several studies evidenced data suggesting that EMX2 gene may be involved in the modulation of cell proliferation of cortical neuroblasts and/or cell migration of postmitotic neurons, as it is known that these cells reach their final destination in the mature cortex according to their generation date. On the other hand recent data demonstrate that EMX2 gene has no major role in schizencephaly (42).

Genetics in focal cortical dysplasia

According to the prevailing hypothesis, focal cortical dysplasia (FCD) originates from abnormal migration, maturation and cell death during ontogenesis (3,4,5). A developmental lineage model has been proposed in which balloon cells and dysplastic neurons are derived from radial progenitor cells in the telencephalic VZ (7). The close cytoarchitectural similarities between FCD and the cortical tubers of tuberous sclerosis prompted the hypothesis of a common pathogenetic basis (8). In one study, mutation analysis in patients with FCD showed a higher frequency of mild and not clearly pathogenic sequence changes in the TSC1 (but not TSC2) gene in FCD compared to controls, as well as loss of heterozygosity of markers surrounding the TSC1 gene in dysplastic compared to control tissue (8). These results support some role for TSC1 in the pathogenesis of FCD, although this might be small and has yet to be confirmed.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISORDERS OF NEURONAL MIGRATION
  5. CONCLUSION
  6. ACKNOWLEDGEMENTS
  7. CONFLICT OF INTEREST
  8. References

Over the past decade, molecular biologic and genetic investigations of cortical development have widely increased our knowledge about the regulation of neuronal migration during development. Recently stated techniques, which consent direct observation of the conduct of migrating neurons, combined with molecular biologic trials, are further accelerating progress in this field. In the near future, the relationship between the fashion of neuronal migration and the fate of the neurons, as well as what makes neurons migrate differently, is foresee to be clarified by these techniques and other novel technologies. It is hoped that accumulating data of the development mechanisms underlying the expanded network formation in the brain will lead to the development of therapeutic options for neuronal migration disorders.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISORDERS OF NEURONAL MIGRATION
  5. CONCLUSION
  6. ACKNOWLEDGEMENTS
  7. CONFLICT OF INTEREST
  8. References

We are grateful to Dr. Maria Vincenza Catania (Catania, Italy) for providing Figure 1.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISORDERS OF NEURONAL MIGRATION
  5. CONCLUSION
  6. ACKNOWLEDGEMENTS
  7. CONFLICT OF INTEREST
  8. References