New trends in neuronal migration disorders

european journal of paediatric neurology 14 (2010) 1–12

Official Journal of the European Paediatric Neurology Society

Review article

New trends in neuronal migration disorders Alberto Verrottia, Alberto Spaliceb, Fabiana Ursittib, Laura Papettib, Rosanna Marianib, Antonella Castronovob, Mario Mastrangelob, Paola Iannettib,* a

Department of Pediatrics, University of Chieti, Italy Department of Pediatrics, University of Rome, Italy

b

article info

abstract

Article history:

Neuronal migration disorders are an heterogeneous group of disorders of nervous system

Received 27 June 2008

development and they are considered to be one of the most significant causes of neuro-

Received in revised form

logical and developmental disabilities and epileptic seizures in childhood. In the last ten

27 January 2009

years, molecular biologic and genetic investigations have widely increased our knowledge

Accepted 30 January 2009

about the regulation of neuronal migration during development. One of the most frequent disorders is lissencephaly. It is characterized by a paucity of

Keywords:

normal gyri and sulci resulting in a ‘‘smooth brain’’. There are two pathologic subtypes:

Neuronal migration

classical and cobblestone. Classical lissencephaly is caused by an arrest of neuronal

Lissencephaly

migration whereas cobblestone lissencephaly caused by overmigration.

Heterotopia

Heterotopia is another important neuronal migration disorder. It is characterized by

Polymicrogyria

a cluster of disorganized neurons in abnormal locations and it is divided into three main

Schizencephaly

groups: periventricular nodular heterotopia, subcortical heterotopia and marginal glioneural heterotopia. Polymicrogyria develops at the final stages of neuronal migration, in the earliest phases of cortical organization; bilateral frontoparietal form is characterized by bilateral, symmetric polymicrogyria in the frontoparietal regions. Bilateral perisylvian polymicrogyria causes a clinical syndrome which manifests itself in the form of mild mental retardation, epilepsy and pseudobulbar palsy. Schizencephaly is another important neuronal migration disorder whose clinical characteristics are extremely variable. This review reports the main clinical and pathophysiological aspects of these disorders paying particular attention to the recent advances in molecular genetics. ª 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Neuronal migration disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1. Lissencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1.1. Classical lissencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

* Corresponding author. Tel.: þ39 06 49979313; fax: þ39 06 49979312. E-mail address: [email protected] (P. Iannetti). 1090-3798/$ – see front matter ª 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2009.01.005

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european journal of paediatric neurology 14 (2010) 1–12

3.

4.

5.

6. 7.

1.

2.1.1.1. Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1.1.2. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1.1.3. Neuroradiological findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1.2. Cobblestone lissencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1.2.1. Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1.2.2. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1.2.3. Neuroradiological findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.3. Lissencephaly X-linked with agenesis of the corpus callosum (XLAG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.3.1. Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.3.2. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.3.3. Neuroradiological aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.4. Lissencephaly with cerebellar hypoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.4.1. Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.4.2. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.4.3. Neuroradiological findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.5. Microlissencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Heterotopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.1. Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.2. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.3. Neuroradiological findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Polymicrogyria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.1. Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.2. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.3. Neuroradiological findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Schizencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.1. Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.2. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.3. Neuroradiological findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Introduction

Development of central nervous system is a highly complicated process and it is organized in the following steps: I Primary neurulation (3–4 weeks of gestation); beginning of neuronal migration (5th week of gestation); II Prosencephalic development (2–3 months of gestation); III Neuronal proliferation (3–4 months of gestation); IV Neuronal migration (1–5 months of gestation); V Organization (5 months of gestation–after the birth); VI Myelination (after the birth). Neuronal migration consists of nerve cells moving from their original site in the ventricular and subventricular zones to their final location. Regulation of timing and direction of these simultaneous migrations is carried out with extreme precision.1 Neurons originating in the cortical ventricular zone migrate radially to form the cortical plate and mainly become projection neurons.2 Migration of neocortical neurons occurs mostly from the fifth gestational week, when the telencephalic vesicle appears, approximately twenty-two week of gestation.3 The neurons which migrate first, will stop in the deepest cortical layers, those which migrate afterwards passing through the layers formed previously to form the outer cortical layers according to a migration scheme defined ‘‘inside-out’’.1,3 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 cortical plate.

Radial glial cells are specialized glial cells, present in the neocortex during neuronal migration. 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 located at intermediate zone level (prospective white matter). 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 Paired Box Gene (Pax6), which is specifically localized in radial glia during cortical development, is critical for the morphology, number, function, and cell cycle of radial glia.4 Studies over the last decade have identified several molecules involved in the control of neuronal migration and in targeting the exact destination of the neurons. These molecules can be divided into four broad categories: - molecules of the cytoskeleton which play an important role in the initiation and ongoing progression of neuronal migration (i.e. Filamin-A, ARFGEF2 or ADP-ribosylation factor GEF2, doublecortin, LIS1, TUBA1A); - signalling molecules playing a role in lamination (i.e. reelin and some reelin receptors, p35, cdk5, Brn1/Brn2); - molecules modulating glycosylation which seem to provide stop signs for migrating neurons (i.e. POMT1, POMGnT1, fukutin and focal adhesion kinase); - other factors including neurotransmitters (glutamate and GABA), trophic factors (brain-derived neurotrophic factor or

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european journal of paediatric neurology 14 (2010) 1–12

BDNF, and thyroid hormones), molecules deriving from peroxisomal metabolism, and environmental factors (ethanol and cocaine).5

2.1.1.1. Clinical aspects. Isolated lissencephaly sequence (ILS)

Malformations of cortical development are classified by Barkovich et al. according to their clinical and neuroradiologic (MRI, SPECT scan and PET scan) features. Neuronal migration disorders include lissencephaly, heterotopia, focal cortical dysgenesis, polymicrogyria and schizencephaly. Recent laboratory researches have reinforced the hypothesis that polymicrogyria and schizencephaly result from a developmental disorder or injury occurring between the end of the neuronal migration period and the early phase of cortical organization.6,7

(OMIM # 607432) is clinically characterized by early hypotonia which may evolve to limb spasticity, seizures and psychomotor retardation. Seizures develop in the first 6–12 months. They include infantile spasms or akinetic–myoclonic seizures with disordered EEG. Later on most children have a complex epileptic syndrome including atypical absences, drop attacks, myoclonic, partial complex, tonic and tonic–clonic seizures.9,10 Children with Miller–Dieker syndrome (MDS) (OMIM # 247200) have a severe form of LIS associated with facial dysmorphisms including a prominent forehead, bitemporal hollowing, a short nose with upturned nares, and a long and protuberant upper lip with thin vermillion border and small jaw. Other children with MDS might also present cardiac and renal abnormalities, cryptorchidism, sacral dimple, omphaloceles and clinodactyly.9

2.1.

2.1.1.2. Genetics. Three distinct genetic alterations for clas-

2.

Neuronal migration disorders

Lissencephaly

Lissencephaly (LIS), which literally means ‘‘smooth brain’’, consists of a set of rare brain disorders characterized by the lack of normal cortical convolutions. The severity of the malformation ranges from the absence (agyria) to reduction (pachygyria) of normal gyral pattern. On the basis of etiologies and associated malformations, five groups of lissencephaly can be identified: classical lissencephaly, cobblestone lissencephaly, X-linked lissencephaly with agenesis of the corpus callosum; lissencephaly with cerebellar hypoplasia; microlissencephaly (Table 1). The incidence of classical and cobblestone lissencephaly has been estimated to be 1.2 in 100,000 births and 1 in 100,000 births respectively. The onset of lissencephaly is considered to occur no later than the 12th– 16th week of gestation.8

2.1.1.

Classical lissencephaly

Classical lissencephaly previously known as type 1 lissencephaly, causes a combination of agyria and pachygyria. Microscopically, the cortex appears poorly structured with only four immature layers of neurons instead of the normal six highly organized layers present in a well-developed brain.9

sical lissencephaly have been described in various researches.11 The LIS1 gene (PAFAH1B1 on17p13.3) is the first gene that was correlated with human lissencephaly. It controls mitotic spindle orientation in both the neuroepithelial stem cells as well as the radial glial progenitor cells; its deletion causes dysfunction of the dynein, a microtubular cytoplasmic protein involved in neuronal migration processes.12 ILS is caused by intragenic mutations or deletions of the LIS1 gene or by small deletions involving 17p13.3.13,14 In contrast with previous studies,15 Uyanik and colleagues affirm that genotype– phenotype correlation is vague and the clinical setting only correlates with the degree of agyria and cortical thickening.16 Complete deletion of both LIS1 and 14-3-33 YWHAE genes on the chromosome 17p13 causes Miller–Dieker syndrome (MDS). YWHAE belongs to the 14-3-3 family of proteins that can have many effects on phosphoproteins, including protection from dephosphorylation. 14-3-33 binds to CDK5/ p35-phosphorylated NUDEL and this binding maintains NUDEL phosphorylation. NUDEL is a LIS1-binding protein that, together with LIS1, regulates the cytoplasmic dynein heavy chain function through phosphorylation by CDK5/p35,

Table 1 – Classification of lissencephaly. Type of lissencephaly Classical lissencephaly Cobblestone lissencephaly

Lissencephaly X-linked with agenesis of the corpus callosum (XLAG) Lissencephaly with cerebellar hypoplasia (LCH). Microlissencephaly

Subtypes

Genes involved

Isolated lissencephaly sequence Miller–Dieker Syndrome Walker–Warburg syndrome Muscle–Eye–Brain disease Fukuyama congenital muscular dystrophy

LIS1, DCX, TUBA1A LIS1 and YHAWAE co-deletion POMT1, POMT2, FKTN, FKRP, LARGE POMGnT1 FKTN ARX

RELN, VLDLR Norman-Roberts syndrome Barth syndrome Primordial osteodysplastic dwarfism and microcephaly (MOPD type 1)

Undefined Undefined Undefined

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a complex known to be essential for neuronal migration.17 Recently smaller deletion, encompassing the region of LIS1 gene but not the 14-3-33 gene has been associated with a milder phenotype of isolated LIS. The classical or commercial FISH probed, generally used to diagnose MDS, may fail to detect this atypical mutation.18 Mutations of doublecortin (DCX ) gene on chromosome Xq22.3 are also known to cause classical lissencephaly in males while heterozygous mutations in females are associated with subcortical band heterotopia (SBH). However, males with SBH and DCX mutations have rarely been reported.19 Doublecortin is expressed in postmitotic neurons, but neither in proliferating cells of the ventricular zone during the development period and nor in mature neurons of the adult brain. DCX is also a microtubule (MT)-associated protein confirming that regulation of the MT cytoskeleton dynamics is critical for neuronal migration.20,21,22 Recently, mutations in TUBA1A (alpha tubulinic complex) gene located on the chromosome 12q12–q14 have been correlated with the agyria–pachygyria-band spectrum of phenotypes. This gene encodes for alpha tubulin protein which represents one of the major component of microtubule complex required for cell movements.23,24 Mutations in TUBA1A are considered to affect the folding of tubulin heterodimers as well as influence interactions with MT binding proteins (doublecortin and kinesin KIF1A)25 resulting in disorders of microtubular function and deficits in the motility of neuronal progenitor cells.

2.1.1.3. Neuroradiological findings. In addition to pachygyria and agyria, MRI in classical LIS demonstrates poorly developed sylvian and rolandic fissures and failure of opercularization of the insular areas.26 The cortex is moderately thickened (5–10 mm) with white matter signal abnormalities. Associated findings may include dilatation of lateral ventricles, mild hypoplasia of corpus callosum, and persistent cavum septum pellucidum.11,25 A different localization of cortical abnormalities distinguishes the three genetic defects. Mutations in LIS1 are often associated with abnormalities prevalent in the parietal and occipital cortex, whereas DCXlissencephaly is more pronounced in frontal cortex. Mutations in TUBA1A have led to gyral malformations that are more severe in posterior than in anterior regions of the brain (posterior-to-anterior gradient),27 often combined with dysgenesis of corpus callosum, cerebellar and brainstem hypoplasia28 and variable cortical malformation, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule.29 Recently a new type of lissencephaly associated with TUBA1A has been described in four cases, revealing a large neuropathological spectrum in which five features are regularly observed: lissencephaly, severe anomalies of the corpus callosum, the hippocampus, cerebellum and the brainstem. This new form resembles the characteristic of lissencephaly linked to RELN gene mutations (LCH).27 2.1.2.

Cobblestone lissencephaly

Cobblestone lissencephaly (previously type II) is a complex brain malformation characterized by global disorganization of cerebral organogenesis. The cortex displays irregular grooves

imparting a cobblestone pattern and consists of cluster and circular arrays of neurons, with no recognizable layers, separated by glial and vascular septa.21,25

2.1.2.1. Clinical aspects. Cobblestone lissencephaly has been described in three syndromes: the Walker–Warburg syndrome (WWS or HARDS syndrome OMIM # 236670) (see Table 2), Muscle–Eye–Brain disease (MEB OMIM # 253280) and Fukuyama congenital muscular dystrophy (FCMD OMIM # 253800). WWS is the most severe of these small groups of syndromes. It has a worldwide distribution while FCMD has been found in Japan and MEB primarily in Finland. The overall incidence is unknown but a survey in North-eastern Italy has reported an incidence rate of 1.2 for every 100,000 live births.30 The current diagnostic criteria for WWS and related syndromes are summarized in Table 1; some of these features explain the acronym HARD  E which is used for this syndrome (hydrocephalus, agyria, retinal dysplasia with or without encephalocele).31 WWS is associated with generalized hypotonia and vision impairment, mental retardation and severe seizures. Eye abnormalities include cataracts, microcornea and microphthalmia, lens defects, hypoplasia or atrophy of the optic nerve and macula. The median life expectancy is only four months, although some patients may live for more than five years. MEB disease results in a severe form of congenital muscular dystrophy with mental retardation. Ocular disorders include progressive myopia, retinal dystrophy and optic atrophy. Patients often die for respiratory failure during the first or second decade, others survive to adulthood in spite of the severe clinical disturbances.32 FCMD is the mild form of cobblestone lissencephaly and it is characterized by severe hypotonia, progressive weakness and developmental delay. The association of epilepsy and seizurerelated disorders in FCMD is widely accepted: febrile seizures and epilepsy with generalized tonic-convulsions appear in about 50% of children but they are usually not severe.33 Ocular involvement includes retinal dysplasia leading to myopia, nystagmus and chorioretinal degeneration less severe than in WWS and MEB. In many cases, patients affected manage to lead a normal life apart from the recurring seizures.

2.1.2.2. Genetics. Several genes have been implicated in the etiology of WWS. Different mutations were found in the Proteins O-mannosyltransferase 1 and 2 (POMT1 at 9q34 and

Table 2 – Major clinical features of Walker–Warburg Syndrome Data from Dobyns, W.B.: the neurogenetic of lissencephaly. Macrocephaly Type II lissencephalya Cerebellar malformationa Ventricular dilation/hydrocephalus Retinal malformationa Anterior chamber abnormality Congenital muscular dystrophya a Necessary for diagnostic criteria.

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POMT2 genes), and one mutation was found in each of the fukutin (FKTN at 9q31–33) and fukutin-related 9 protein (FKRP at 19q13–32) genes34,35 In two Saudi siblings with WWS, born from consanguineous parents, van Reeuwijk et al identified a monozygous 63-kb intragenic deletion in the LARGE gene on chromosome 22q12.36 The MEB gene has been localized on the chromosome 1p32–p34 (POMGnT1 gene for protein O mannose beta-1,2-Nacetylglucosaminyltransferase).37 FCMD is associated with mutations of the gene FKTN on chromosome 9q31, which encodes a novel 461-aminoacid protein termed ‘‘fukutin’’.38 All these genes are involved in the glycosylation of a-dystroglycan, an extracellular protein capable of binding to components of extracellular matrix such as laminin, agrin, neurexin and perlecan.39 Mutations in these genes compromise the integrity of the superficial marginal zone of the cortex, so that neurons overmigrate beyond this structure into the pial surface, forming the typical cobblestone.25

2.1.2.3. Neuroradiological findings. Brain MRI demonstrates the typical cobblestone lissencephaly with varying degrees of severity. MRI in WWS and MEB reveals pontine hypogenesis with a distinct dorsal ‘‘kink’’ at the mesencephalic–pontine junction; a ‘‘Z-shaped’’ hypoplastic brainstem is considered a key feature.25,40 Other findings include agenesis or hypogenesis of corpus callosum, cerebellar vermis hypoplasia, hydrocephalus and hypomyelination. Occipital encephalocele may be found in WWS.30,41 FCMD shows frontal polymicrogyria with temporo-occipi tal cobblestone lissencephaly, mild cerebellar polymicrogyria and partial obstruction of the subarachnoid space.11,42

2.1.3. Lissencephaly X-linked with agenesis of the corpus callosum (XLAG) XLAG (OMIM # 300215) includes thickened cortex with gyral malformations that are more severe in posterior than anterior brain regions, agenesis of corpus callosum (ACC) and ambiguous genitalia.43

2.1.3.1. Clinical aspects. XLAG is associated with neonatalonset epilepsy, temperature instability, probably due to a hypothalamic dysfunction, and abnormal genitalia with micropenis and cryptorchidism.44 To date the syndrome has only manifested itself in genotypic males whereas related females may have mental retardation and epilepsy and, in some cases, ACC.

2.1.3.2. Genetics. XLAG results from defects in ARX gene (Aristaless-related homeobox gene) located at Xp22. ARX is specifically expressed in interneurons of the forebrain and in the interstitium of the male gonad. It is involved in differentiation of the testes and the embryonic forebrain, especially in proliferation of neural precursors and tangential migration of interneurons.45 Mutations of ARX cause a wide range of phenotypes that correlate closely with the type of mutation.46,47

2.1.3.3. Neuroradiological aspects. Imaging studies show a thick cerebral cortex (5–6 mm) with anterior pachygyria and posterior agyria. Other findings include abnormal signal of

5

white matter, absence of corpus callosum and cystic or fragmented basal ganglia.43

2.1.4.

Lissencephaly with cerebellar hypoplasia

Lissencephaly with cerebellar hypoplasia (LCH) (OMIM # 257320) has been recently defined as a different group of lissencephaly, which is included in neither classical nor cobblestone types. It is characterized by cerebellar underdevelopment, ranging from vermian hypoplasia to total aplasia with either classical or cobblestone lissencephaly.10

2.1.4.1. Clinical aspects. Affected children show a motor, language and cognitive delay, they do not sit or stand unsupported, nor do they develop linguistic skills. Hypotonia and severe ataxia are frequent; in addition, generalized epilepsy begins at an early age.48

2.1.4.2. Genetics. LCH has been associated with mutations of the reelin (RELN ) gene mapping to chromosome 7q22. RELN encodes an extracellular matrix-associated glycoprotein (reelin) that is secreted by Cajal–Retzius cells in the developing cerebral cortex and appears critical for the regulation of neuronal migration during cortical development.48 In the spontaneous mouse mutant reeler, the usual lamination pattern of the cerebral cortex is essentially inverted, and the cerebellum is hypoplastic with a decreased number of Purkinje cells. LCH is also correlated with mutations of the gene which encodes for the Very Low Density Lipo-protein Receptor (VLDLR). VLDLR binds to reelin and activates downstream signalling cascade that is thought to influence cell migration.49,50,51 2.1.4.3. Neuroradiological findings. MRI demonstrates diffuse pachygyria, hippocampal dysplasia and hypoplastic brainstem. Cerebellar manifestations range from midline hypoplasia to diffuse volume reduction and disturbed foliation.52 2.1.5.

Microlissencephaly

Microlissencephaly differs from other variants of LIS by the presence of a severe microcephaly. It is caused by an abnormal neuronal proliferation or survival combined with neuronal migration disorders. Two main types of Microlissencephaly are recognizable: type A (Norman-Roberts syndrome (OMIM # 257320)) with no infratentorial anomalies and type B (or Barth syndrome), which is associated with a severe hypoplasia of the cerebellum and corpus callosum.8 A recent form has been reported, in which primordial osteodysplastic dwarfism is associated to a severe microcephaly (MOPD type 1).53 In 1993 we described a case of Norman-Roberts syndrome: a 7-year-old boy with microcephaly, bitemporal hollowing, a low sloping forehead, slightly prominent occiput, widely set eyes, a broad and prominent nasal bridge and severe postnatal growth deficiency. Neurologic features included hypertonia, hyperreflexia, seizures, and severe mental retardation. The brain MRI showed changes consistent with lissencephaly type I. Molecular studies did not demonstrate deletion in the Miller–Dieker/isolated lissencephaly critical region on 17p (Fig. 1).54

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thickness of the band and the overlying cortex. The cortex may be normal or associated with pachygyria.56 In some cases SBH may occur with mild epilepsy and normal intellect or a minor degree of cognitive impairment.60 Partial or generalized seizures often begin in the first decade of life and are refractory to pharmacological therapy. The clinical spectrum of SBH in male subjects overlaps with that in females in terms of seizure type representation, epilepsy syndromes and response to antiepileptic therapy. However, there is increased heterogeneity with respect to cognitive function, neuroimaging and molecular genetic data in males compared with females.61

2.2.2.

Fig. 1 – (a and b) Brain MRI: Lissencephaly type I. a: T2 weighted axial view: slight hypoplasia of the corpus callosum; some gyri and sulci in frontal regions, agyria in the parietal lobes and occipital lobes (arrows); b: T2 weighted axial view agyria in the frontal and temporal lobes, some gyri and sulci in occipital regions.

2.2.

Heterotopia

Heterotopia is a neuronal migration disorder characterized by a cluster of disorganized neurons in abnormal locations and it includes three main groups: periventricular nodular heterotopia (PNH), subcortical heterotopia (SBH) and marginal glioneural heterotopia (Table 3). Periventricular nodular heterotopia (PNH) is a rare malformation in which primary neuronal cells never begin migration and remain adjacent to the lateral ventricles (Fig. 2). PNH may involve both sides of the brain or less frequently be restricted to a single hemisphere.55 Subcortical band heterotopia (SBH; OMIM 600348) or ‘‘double cortex’’ syndrome is characterized by a diffuse laminar band of gray matter located below the cerebral cortex and separated from it by a thin band of white matter (Fig. 3).56 Marginal zone heterotopias (MZH) or leptomeningeal glioneuronal heterotopias (LGH) are one form of dysplasia in which ectopic nests of glial and neuronal cells are observed in the cortical MZ or overlying leptomeninges, respectively.57

2.2.1.

Clinical aspects

About 90% of patients with PNH have epilepsy which can begin at any age and it is usually intractable. Patients mainly have partial attacks with temporo-parieto-occipital auras. Studies with depth electrodes have provided evidence that the onset of seizures can begin simultaneously from periventricular heterotopic cortex and from distantly located cortical areas. Other symptoms include severe developmental delay, microcephaly and infantile spasms. Surgical removal of the heterotopia cortex is generally successful.58,59 Individuals with SBH have variable degrees of mental retardation and intractable epilepsy, which seem to correlate with the

Genetics

PNH can be caused by genetic mutations or extrinsic factors, such as infections or prenatal injuries25; PNH has previously been identified with amniotic band syndrome in a clinical case.62 Mutation of the FLNA gene (X q28;) causes bilateral PNH (OMIM # 300049) in the majority of patients; this form is often fatal for males, therefore explaining the female preponderance. This gene encodes for Filamin-A (FLNA), an actinbinding protein that stabilizes the cytoskeleton and mediates focal adhesions along the ventricular epithelium.63 The autosomal recessive form of PNH (OMIM # 608097) is caused by mutations in the ARFGEF2 gene localized at 20q13.13, which encodes for the protein brefeldin-inhibited GEF2 (BIG2). Previous studies suggest that mutations in ARFGEF may impair the targeted transport of FLNA to the cell surface within neural progenitors along the neuroependyma. These studies also suggest that disruption of these cells could contribute to PNH formation with microcephaly.63 PNH has also been associated with chromosomopathies including duplication of chromosome 5 (OMIM # 608098) and deletion on chromosome 6 or 7.64 SBH is caused by alterations in two genes: LIS1 at 17p13.3265 and DCX at Xq22.3–q23.3. Mutations of the DCX gene have been found in all familial cases and in 53–84% of patients with sporadic, diffuse, or anteriorly predominant band heterotopia, which represent the most common forms of SBH. Other genetic causes for SBH remain unexplained; large deletions or

Table 3 – Classification of heterotopia (from Barkovich Neurology 2005). 1. Heterotopia subependymal (periventricular) heterotopia a. Periventricular nodular heterotopia (PNH) i. Bilateral PNH with FLN1 mutations ii. PNH with mutations of chromosome 5 iii. PNH with bilateral polymicrogyria-perisylvian and posterior subtypes b. Periventricular linear heterotopia (unilateral or bilateral) 2. Subcortical heterotopia (other than band heterotopia) a. Large subcortical heterotopia with cortical infolding, abnormal cortex, hypogenetic corpus callosum b. Pure subcortical heterotopic nodules c. Columnar heterotopia d. Ribbon heterotopia e. Excessive single neurons in white matter 3. Marginal glioneuronal heterotopia

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Fig. 2 – Axial (A) and coronal (B) T1-weighted (TR/TE 400/40 ms) brain images obtained at age 5 years, showing isointense tissue with gray matter lining bilaterally the ventricular walls (arrows) compatible with nodular heterotopia. Note the preserved architecture of the rest of the cerebral structures, including the cerebral cortex and the subcortical white matter: the corpus callosum (A) and the cerebellum (B). duplications and cryptic chromosomal involving DCX might still be implicated.66

2.2.3.

abnormalities

Neuroradiological findings

MRI in patients with X-linked dominant mutation shows bilateral symmetric nodules lying adjacent to the lateral ventricular walls; additional findings include hypoplasia of corpus callosum and of cerebellum. Unilateral PNH is commonly located in the posterior paratrigonal zone of the lateral ventricles and may involve the adjacent white matter. Patients with autosomal recessive mutations of ARFGEF2 gene present microcephaly, slightly enlarged ventricles and delayed myelination. MRI of the brain in SBH demonstrates two parallel layers of gray matter, a thin outer ribbon and a thick inner band, separated by a very thin layer of white matter.25

2.3.

Polymicrogyria

Polymicrogyria (PMG) is a cortical malformation characterized by an irregular brain surface with an excessive number of small and partly fused gyri separated by shallow sulci (Fig. 4). PMG can be focal or diffused, unilateral or bilateral. It can be an isolated lesion associated with other brain malformations such as heterotopia, white matter lesions or a part of several multiple congenital anomaly/mental retardation syndromes.67 Two types of polymicrogyria can be identified under a histopathological viewpoint: a simplified four layered form (in which there is a layer of intracortical laminar necrosis with subsequent alterations of late migration and postmigratory disruption of cortical organization) and an unlayered form (in which the molecular layer is continuous and

does not follow the borders of convolutions and the neurons below have radial distribution while laminar organization is absent).68 The incidence of polymicrogyria is unknown because of its clinical and aetiological heterogeneity. PMG is the end point of different etiological processes, not necessarily occurring at the same time of cortical development such as congenital CMV infection, placental hypoperfusion in the second trimester, perinatal cerebral hypoxia–ischemia, twin– twin transfusion, loss of twin in utero or maternal drug ingestion.69

2.3.1.

Clinical aspects

Almost all children with PMG have a high risk of developing epilepsy. Seizures usually begin between 4 and 12 years of age and they are drug-resistant in approximately 65% of patients. A small number of children present with focal epilepsy while the most frequent seizure types are atypical absences, tonic or atonic drop attacks or tonic–clonic convulsions.70,71 In the bilateral frontal type the most common symptoms include delayed motor and language milestones, spastic hemiparesis or quadriparesis, and mild to moderate mental retardation. Seizures were present in 38% of patients and varied in type, age at onset, and severity. In the bilateral frontoparietal (OMIM # 606854) form the clinical presentation is characterized by global developmental delay, esotropia, pyramidal and cerebellar signs and seizures, which occur in 94% of patients and are mostly generalized.72 Bilateral perisylvian PMG (OMIM # 300388) affected patients can present pseudobulbar palsy with diplegia of the facial, pharyngeal, and masticatory muscles, pyramidal signs, and seizures. The pseudobulbar involvement results in restricted tongue movements, drooling, feeding problems and dysarthria. Voluntary and emotional facial movements can be dissociated. Developmental language disorder and pyramidal signs can be associated and their severity depends on the

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Fig. 3 – MRI scan (axial view: IR sequence; TR [ 2000 ms, TE [ 20 ms). Normal overlying cortical mantle; bilateral band heterotopia characterized by a greater thickness in the left hemisphere especially at frontal and occipital levels.

extent of the cortical damage. Epilepsy was found in almost 90% of cases in the reported series in literature. Infantile spasms may be the presenting seizure type even if seizures develop only before the end or after the first decade. Most patients develop multiple seizure types and seizure control is poor in more than half of the cases.73 Other forms of PMG such as bilateral parasagittal parieto-occipital, bilateral generalized and unilateral ones can produce various kinds of seizures and EEG abnormalities (including electrical status epilepticus during sleep or ‘‘ESES’’) cognitive slowing, motor delay and cerebral palsy.74–77

2.3.2.

Genetics

The genetic role in the etiopathogenesis of PMG is also supported by its association with Aicardi syndrome, Zellweger and Walker–Warburg syndromes or with chromosomal abnormalities such as 22q11 deletion, 1p36 monosomy and trisomy of chromosome 13. The familial transmission of PMG has been identified in bilateral frontoparietal, bilateral perisylvian, and bilateral generalized forms.78 Bilateral frontoparietal PMG seems to be related to the mutation of the gene GPR56 on chromosome 16q12.2–21 with an autosomic recessive inheritance. This gene encodes for a G protein coupled receptor, a regulator of cellular cycle signalling in neuronal progenitor cells at all ages and plays an essential

role in regional patterning of the human cerebral cortex. To date bilateral perisylvian PMG is mainly attributed to different patterns of inheritance, including X-linked dominant, X-linked recessive, autosomal recessive, autosomal dominant with reduced penetrance, autosomal recessive with pseudodominance, and autosomal dominant. A locus for X-linked bilateral perisylvian PMG maps on the distal long arm of the X chromosome (Xq28) but the linkage has not yet been confirmed and no gene has been identified. It is still unclear if the remaining families with X-linked inheritance map to the same locus, or if additional loci are concerned. Mutations in the gene SRPX2 at Xq22 have been found in one family with bilateral perisylvian PMG. SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. Bilateral generalized PMG is considered to be transmitted through an autosomal recessive mechanism but no specific responsible genes have been identified.79 A new gene involved in the genesis of polymicrogyria, associated with microcephaly and corpus callosum agenesis, is T-box-brain2 (TBR2) on chromosome 3p. This gene, also called eomesodermin transcript (EOMES ), encodes a transcription factor, a member of the Tbox family, that is critical in invertebrate embryonic development of the central nervous system and mesoderm. Some data suggest that EOMES is involved in neuronal division and migration.80

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Fig. 4 – MRI: Axial view T1 weighted: right insular abnormal cortex resembling polymicrogyria; small cavum vergae.

2.3.3.

Neuroradiological findings

MRI in PMG demonstrates small irregular gyri and an indistinct gray and white matter junction. Polymicrogyric cortex often appears mildly thickened (6–10 mm) due to cortical overfolding. T2 signals within the cortex are usually normal although there may be delayed myelination.26

2.4.

Schizencephaly

Schizencephaly (SCZ; OMIM # 269160) is a structural abnormality of the brain, characterized by congenital clefts spanning the cerebral hemisphere from the pial surface to the lateral ventricle and lined by cortical gray matter (Fig. 5).81 Cleft localization varies widely but perisylvian region is more frequently involved.82 The cortex overlying the cleft is often polymicrogyric; for this reason SCZ is classified within the same group as polymicrogyria.25 This malformation can be unilateral or bilateral, symmetric or asymmetric and may be divided in two subtypes: ‘‘closed or fused lips’’ or Type I (if the cleft walls are in apposition) and ‘‘open lips’’ or Type II (if the cleft walls are separated). Type II SCZ is more common than Type I.52 To date the etiology of this disorder is not clearly established and several causes including genetic, vascular, toxic, metabolic and infectious factors might be involved. Some data support the idea that the clefts are induced by

exogenous environmental factors acting during early gestation, such as the relationship between cases of schizencephaly and the exposure in utero to toxins and cytomegalovirus infections.81,83,84

2.4.1.

Clinical aspects

Patients with unilateral closed-lipped SCZ generally have mild hemiparesis and seizures but no impairment of normal developmental milestones. When the cleft is open, patients have mild to moderate developmental delay and hemiparesis. Patients with bilateral clefts show severe mental deficits and severe motor abnormalities including spastic quadriparesis. Blindness due to optic nerve hypoplasia can be common. Language development is more likely to be normal in patients with unilateral schizencephaly compared to patients with bilateral clefts. Several types of seizure have been reported including generalized tonic–clonic, partial motor, and sensorial ones. Infantile spasms have been described in a few children. Seizures are usually resistant to medical therapy and stabilization may be achieved through surgery.84

2.4.2.

Genetics

Previous reports suggest that EMX2 gene mutations may be correlated with type II SCZ.85,86 EMX2 is an homeotic gene,

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Fig. 5 – MRI (IR sequence SE 200-38 coronal view) shows large left open lip frontotemporoparietal schizencephaly, with a polymicrogyric cortex lining the cleft. On the right side a polymicrogyric opercular malformation is also present (arrows).

expressed in proliferating neuroblasts and is probably involved in controlling cortical migration and structural patterning of the developing rostral brain.86 However recent studies criticize the true role of EMX2 in SCZ.87 No further EMX2 mutations were reported in patients with schizencephaly after those two articles. Finally, it should be considered that the causal relationship between EMX2 mutations and schizencephaly is not supported by experimental models.84

2.4.3.

relationship between the fashion of neuronal migration and the fate of the neurons, as well as what makes neurons migrate differently, is foreseen 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. Moreover, the clarification of new gene by means of new genetic techniques may give new insights in this fascinating field.

Neuroradiological findings

references In addition to polymicrogyria, MRI may demonstrate agenesis of the septum pellucidum and agenesis or thinning of the corpus callosum, hippocampal malformations, posterior fossa abnormalities, ventricular diverticula and arachnoid cysts and multiple calcifications. Periventricular heterotopic nodules have also been found in a minority of cases. The malformations associated with schizencephaly may also involve extracerebral structures.84

3.

Concluding remarks

Neuronal migration disorders are considered to be one of the most significant causes of neurological and developmental disabilities and epileptic seizures in childhood. In the last ten years, molecular biologic and genetic investigations have widely increased our knowledge about the regulation of neuronal migration during development. In the near future, the

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