Genetic malformations of the cerebral cortex are usually charac-terized by malposition and faulty differentiation of gray matter.1

Epilepsy is often present and tends to be severe, although its inci-dence and type vary in different malformations.2 It is estimated thatup to 40% of children with drug-resistant epilepsy have a corticalmalformation.3 Mutations of several genes regulating brain devel-opment have been associated with specific malformations.1

The abnormalities that primarily affect proliferation are usu-ally associated with an alteration in both neuronal and glial cell dif-ferentiation, producing abnormal cell size and morphology.4

Disorders affecting neuronal migration are characterized by abnor-mal neuronal positioning.4 When migration is arrested during latercortical development, abnormal cell position is more likely to berestricted to the cortex. In the following sections, we discuss themost frequent cortical malformations causing epilepsy and thosefor which the causative genes have been cloned.

287

Topical Review

Neuronal Migration Disorders, Genetics,

and Epileptogenesis

Renzo Guerrini, MD; Tiziana Filippi, MD

ABSTRACT

Several malformation syndromes with abnormal cortical development have been recognized. Specific causative genedefects and characteristic electroclinical patterns have been identified for some. X-linked periventricular nodular het-erotopia is mainly seen in female patients and is often associated with focal epilepsy. FLN1 mutations have been reportedin all familial cases and in about 25% of sporadic patients. A rare recessive form of periventricular nodular heterotopiaowing to ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay, and early-onsetseizures. Lissencephaly-pachygyria and subcortical band heterotopia represent a malformative spectrum resulting frommutations of either the LIS1 or the DCX (XLIS) gene. LIS1 mutations cause a more severe malformation posteriorly. Mostchildren have severe developmental delay and infantile spasms, but milder phenotypes are on record, including posteriorsubcortical band heterotopia owing to mosaic mutations of LIS1. DCX mutations usually cause anteriorly predominantlissencephaly in male patients and subcortical band heterotopia in female patients. Mutations of the coding region of DCX

were found in all reported pedigrees and in about 50% of sporadic female patients with subcortical band heterotopia.Mutations of XLIS have also been found in male patients with anterior subcortical band heterotopia and in female patientswith normal brain magnetic resonance imaging. The thickness of the band and the severity of pachygyria correlate withthe likelihood of developing severe epilepsy. Autosomal recessive lissencephaly with cerebellar hypoplasia, accompaniedby severe delay, hypotonia, and seizures, has been associated with mutations of the reelin (RELN) gene. X-linked lissencephalywith corpus callosum agenesis and ambiguous genitalia in genotypic males is associated with mutations of the ARX gene.Affected boys have severe delay and infantile spasms with suppression-burst electroencephalograms. Early death is fre-quent. Carrier female patients can have isolated corpus callosum agenesis. Schizencephaly has a wide anatomoclinicalspectrum, including focal epilepsy in most patients. Familial occurrence is rare. Initial reports of heterozygous mutationsin the EMX2 gene have not been confirmed. Among several syndromes featuring polymicrogyria, bilateral perisylvianpolymicrogyria shows genetic heterogeneity, including linkage to chromosome Xq28 in some pedigrees, autosomal dom-inant or recessive inheritance in others, and an association with chromosome 22q11.2 deletion in some patients. About65% of patients have severe epilepsy. Recessive bilateral frontoparietal polymicrogyria has been associated with muta-tions of the GPR56 gene. (J Child Neurol 2005;20:287–299).

Received Oct 1, 2004. Accepted for publication Nov 2, 2004.

From the Epilepsy, Neurophysiology and Neurogenetics Unit (Drs Guerriniand Filippi), Division of Child Neurology and Psychiatry, University of Pisaand Research Institute, Stella Maris Foundation, Pisa, Italy.

Presented in part at the International Symposium on Neuronal MigrationDisorders and Childhood Epilepsies (7th Annual Meeting of the InfantileSeizure Society), Tokyo, Japan, April 16–17, 2004.

Address correspondence to Prof Renzo Guerrini, Division of Child Neurologyand Psychiatry, University of Pisa, Via dei Giacinti 2, 56018 Calambrone,Pisa, Italy. Tel: 39 050 886280; fax: 39 050 32214; e-mail:renzo.guerrini@inpe.unipi.it.

MALFORMATIONS RELATED TO ABNORMAL

PROLIFERATION OF NEURONS AND GLIA

Hemimegalencephaly

In hemimegalencephaly, one cerebral hemisphere is enlarged andpresents with a thick cortex, wide convolutions, and reduced sulci(Figure 1). Although the abnormality is strictly unilateral in mostcases,4 postmortem examination showed minor abnormalities ofthe apparently unaffected hemisphere in two cases and mild cor-tical dysplastic abnormalities in another.5,6 The potential for struc-tural changes in the seemingly normal hemisphere is of particularimportance with respect to planning surgical treatment of epilepsy.Laminar organization of the cortex is absent, and gray-white mat-ter demarcation is poor. Giant neurons are observed throughoutthe cortex and the underlying white matter. In about 50% of cases,large, bizarre cells are observed, which have been named ballooncells.4,5 In some patients, the structural abnormality is multilobar,usually predominating in the posterior quadrant (posterior temporaland parieto-occipital lobes), but does not affect an entire hemi-sphere.7 Hemimegalencephaly is probably an etiologically hetero-geneous condition. Localization of the abnormality to one cerebralhemisphere and the fact that the malformation has always been spo-radic can indicate somatic mosaicism.4 It has also been suggestedthat a fault in programmed cell death can be a causative factor.8

Hemimegalencephaly has been described in the context of dif-ferent disorders, including epidermal nevus syndrome, Proteussyndrome, hypomelanosis of Ito, neurofibromatosis type 1, andtuberous sclerosis, but occurs most frequently as an isolated mal-formation. The clinical and anatomic spectrum of severity is wide,ranging from severe epileptic encephalopathy beginning in theneonatal period5 to patients with normal cognitive function.9,10

Indeed, the milder end of the clinical spectrum includes patientswith well-controlled seizures or no seizures at all.11 However, mostpatients have a severe structural abnormality and almost contin-uous seizures. The most common presentation is asymmetricmacrocrania, hemiparesis, hemianopia, mental retardation, andseizures. The electroclinical features usually include partial motorseizures beginning in the neonatal period, infantile spasms, and oftenan asymmetric suppression-burst pattern on sleep electroen-cephalography (EEG).11,12 Patients with early-onset, severe epilepsyalmost always develop major cognitive and motor impairment.13 Inaddition, there is a high mortality rate in the first months or yearsof life, with status epilepticus being the most important cause ofdeath.4,14–16 Seizure intractability in these patients can usually beestablished within the first year of life.11,17 This is important becausemajor surgical procedures can stop life-threatening seizures andprevent epileptic activity from interfering with physiologic activ-ity of the contralateral, healthy hemisphere.16,17 There are indica-tions that the operation should be performed early18 because inyounger children, transfer of functions to the “normal” hemisphereis greater and a better neuropsychologic outcome is more likely,19

although significantly improved cognitive skills after the procedurehave not been uniformly observed.20

Focal Cortical Dysplasia

Focal cortical dysplasia was originally described in patients whowere treated surgically for drug-resistant epilepsy.21 The histo-logic abnormalities are usually restricted to one lobe or a smallersegment and include local disorganization of the laminar structure,

large aberrant neurons, isolated neuronal heterotopia in subcor-tical white matter, balloon cells, giant and odd macroglia, foci ofdemyelination, and gliosis of adjacent white matter.22 The abnor-mal area is not usually sharply delimited from adjacent tissue.4,23

One or more of the above components might not be present, andthree main subtypes of focal cortical dysplasia are recognized,which might correspond to the different times of embryologic ori-gin.24 A first type is characterized by architectural dysplasia, withabnormal cortical lamination and ectopic neurons in the whitematter. A second type, defined as cytoarchitectural dysplasia, ischaracterized by giant neurofilament-enriched neurons in additionto altered cortical lamination. A third type, corresponding to Taylor-type cortical dysplasia, is characterized by giant dysmorphicneurons and balloon cells associated with cortical laminar dis-ruption. Patients with architectural dysplasia have lower seizurefrequency than those with cytoarchitectural and Taylor-type dys-plasia.24 Focal cortical dysplasia can occur in any part of the cor-tex. The lesion can be quite extensive, rendering complete removalimpossible in many cases.25,26 Magnetic resonance imaging (MRI)can be unrevealing in up to 34% of patients.24,27 Distinctive signalalterations on T2-weighted or fluid-attenuated inversion recoveryimages are present in most patients with Taylor-type dysplasia, oftenassociated with focal areas of cortical thickening, simplified gyra-tion, blurring of the gray-white limit, or rectilinear boundariesbetween gray and white matter (Figure 2).24,28,29 Focal hypoplasiawith MRI abnormalities is often found in architectural dysplasia.24

The histologic characteristics of Taylor-type dysplasia are indis-tinguishable from those of hemimegalencephaly. Some cases pre-sent involvement of more than an entire lobe and probably representa continuum with minor forms of hemimegalencephaly.7

Focal cortical dysplasia usually presents with intractablefocal epilepsy, which can start at any age but generally before theend of adolescence. Seizure semiology depends on the location ofthe lesion, and focal status epilepticus has been reported fre-

288 Journal of Child Neurology / Volume 20, Number 4, April 2005

Figure 1. Hemimegalencephaly in a 3-month-old boy with intractableseizures. Spin-echo magnetic resonance image, coronal section. Theright hemisphere is enlarged, with a thickened cortex and smooth sur-face. There are no digitations between the gray and white matter. Highsignal intensity in the white matter throughout the right hemisphere.

quently.27,30,31 Location in the precentral gyrus is often complicatedby epilepsia partialis continua.32–35 Unless the dysplastic area is large,patients do not suffer from severe neurologic deficits. Interictal EEGshows focal, rhythmic epileptiform discharges in about half of thepatients.36 The ictal EEG abnormalities are highly specific for focalcortical dysplasia, are located over the epileptogenic area, andcorrelate with the continuous epileptiform discharges recorded dur-ing electrocorticography.30,37,38 Electrocorticographic seizure activ-ity shows spatial colocalization with the lesion. Complete resectionof the tissue producing ictal electrocorticographic discharges isessential for good seizure outcome. Intrinsic epileptogenicity of thedysplastic tissue has been confirmed with depth electrode studies.24

The mechanisms underlying the epileptiform activity gener-ated by dysplastic neocortex remain to be elucidated. In the abnor-mal cortical multilaminar organization typical of focal corticaldysplasia, neurons are prevented from establishing normal synap-tic connections with their neighbors and are dysfunctional. Intra-cellular recordings from neurons of a dysplastic human neocortexhave revealed no abnormalities in the membrane properties ofsingle neurons.39,40 However, a dysfunction of synaptic circuitsseems to be responsible for the abnormal synchronization of neu-ronal populations underlying the genesis of epileptiform activity.Abnormalities in the morphology and distribution of local-circuit�-aminobutyric (GABA)ergic inhibitory neurons have been observedusing immunocytochemistry.33,41 Such abnormal circuitry can playan important role in originating and maintaining the epileptiformactivity.

The interictal EEG shows focal, often rhythmic epileptiformdischarges in about half of the patients.36 Most patients with elec-trocorticographic ictal discharges who had complete removal ofthe discharging tissue were seizure free or had over 90% reductionin major seizures. None of the patients with persistence of dis-charging tissue had a favorable outcome.30 The different histo-logic subtypes of focal cortical dysplasia can carry different chancesof seizure freedom after surgery. According to Tassi et al, who useddepth electrodes in most cases, patients with Taylor-type dyspla-sia had the best outcome, with 75% being seizure free (Engel classIa) compared with 50% with cytoarchitectural dysplasia and 43%with architectural dysplasia.24 In fact, the area of resection couldbe better defined in patients with Taylor-type dysplasia, possiblyowing to the distinctive interictal epileptiform discharges,30 whichcan be captured by depth electrodes.42

Most descriptions of focal cortical dysplasia and hemimega-lencephaly are based on studies from epilepsy surgery centers. Thus,the clinical and electrophysiologic features described are likely to

be typical only of the most severe cases. Our experience indicatesthat there are some patients with well-controlled seizures in whomMRI shows focal abnormalities identical to those present in patientswith histologically proven focal cortical dysplasia.43

MALFORMATIONS OWING TO ABNORMAL

NEURONAL MIGRATION

Periventricular Nodular Heterotopia

Periventricular nodular heterotopia, which is often bilateral, con-sists of confluent nodules of gray matter located along the lateralventricles. Although most patients with periventricular nodular het-erotopia are brought to medical attention because they have epilep-tic seizures without additional neurologic abnormalities, thespectrum of clinical presentations is wide. There is some correla-tion between the size of periventricular nodular heterotopia andthe severity of clinical impairment. However, the degree of anatomicand functional impairment of the cerebral cortex overlying thearea(s) of heterotopia is variable and can, in turn, contribute todetermining the clinical picture.

Periventricular nodular heterotopia occurs much more fre-quently in women as X-linked bilateral periventricular nodularheterotopia (Figure 3A) (Mendelian Inheritance in Man #300049),which is associated with prenatal lethality in almost all men44,45 anda 50% recurrence risk in the female offspring of affected women.Almost 100% of families with X-linked bilateral periventricularnodular heterotopia and about 20% of sporadic patients (19% of spo-radic women and 9% of sporadic men) harbor mutations of the fil-amin 1 gene (FLN1).44–47 The low percentage of FLN1 mutationsin sporadic cases could be explained by low somatic mosaicism,48

as well as the viability of some affected males. FLN1 maps tochromosome Xq28, is composed of 48 exons, spans a 26 kb genomicregion, and codes for filamin 1, a 280 kDa protein with three majorfunctional domains, allowing homodimerization and binding toactin and a wide range of cytoplasmic signaling proteins.46

Heterozygous females have normal to borderline intelligenceand epilepsy of variable severity. Coagulopathy and cardiovascu-lar abnormalities have been observed in some patients.46 A few liv-ing male patients with bilateral periventricular nodular heterotopiaowing to FLN1 mutations are on record.46,47 Mild missense muta-tions or mosaic mutations, probably causing limited functionaldefect of the FLN1 protein, account for survival of affected men,47

who can, in turn, transmit their genetic defect. Rare patients of bothgenders with FLN1 mutations had unilateral periventricular nodu-lar heterotopia.47,49

Neuronal Migration Disorders, Genetics, and Epileptogenesis / Guerrini and Filippi 289

Figure 2. Left, Focal cortical dysplasia ina girl with epilepsia partialis continua. T2-weighted magnetic resonance image, axialslice. Dysplastic cortex involving the rightfrontal lobe with thickened gyri, increasedwhite-matter signal below the malformedcortex, unclear distinction between grayand white matter, and mild enlargementof the right frontal horn. Right, Histologicpreparation from the same patient: silver-stained section showing irregular arrange-ment of large neurons and pale brownballoon cells.

Other genes can cause bilateral periventricular nodular het-erotopia in both genders. A rare recessive form of periventricu-lar nodular heterotopia owing to mutations of the adenosinediphosphate–ribosylation factor guanine nucleotide exchangefactor 2 (ARFGEF2) has been reported in two consanguineouspedigrees.50 This gene encodes for the protein brefeldin A–inhibited guanine nucleotide exchange factor 2 (BIG2), which isrequired for vesicle and membrane trafficking from the trans-Golginetwork. Impaired vesicle trafficking prevents transport to the cellsurface of polarized molecules, such as E-cadherin and �-catenin,thereby disrupting proliferation and migration during cortical devel-opment. Affected children had microcephaly (Figure 3B), severedevelopmental delay, and early-onset seizures, including infantilespasms. Several other sporadic syndromes with periventricularnodular heterotopia and mental retardation have been described,almost exclusively in boys.51–53 In some such syndromes, the mal-formation can result from small chromosomal rearrangementsinvolving the FLN1 gene54 and other unknown genes.55

Genetic counseling is relatively easy in familial cases with aclear X-linked pattern of inheritance. Classic periventricular nodu-lar heterotopia with cerebellar hypoplasia and no dysmorphic fea-tures is much more frequent in women and more likely to be dueto FLN1 mutations than in atypical cases. Among carrier women,about half have de novo mutations of FLN1, whereas the remain-ing half have inherited mutations. Although maternal transmis-sion is much more likely, father-to-daughter transmission ispossibile,47 implying that either parent can transmit the mutationto a female proband. An affected man with periventricular nodu-lar heterotopia caused by the FLN1 mutation would be expectedto transmit the mutation to all of his daughters, unless somaticmosaicism is present. If none of the parents has epilepsy or cog-

nitive impairment, the proband’s mother should be studied first toconfirm the mutation or the brain abnormality. If the mother is muta-tion negative and the proband is a female, the father should alsobe studied. Given that germline mosaicism of FLN1 has neverbeen reported in periventricular nodular heterotopia, the recurrencerisk (for other children) seems to be very low when a mutation isfound in the proband but neither parent is a carrier.

Approximately 90% of patients with periventricular nodu-lar heterotopia have epilepsy,56 which can begin at any age.Dubeau et al56 studied 33 patients with periventricular and sub-cortical nodular heterotopia, 29 (88%) of whom had seizures,mainly partial attacks with temporoparieto-occipital auras.Seizures began between the age of 2 months and 33 years andwere intractable in 27 patients (82%). Bilateral periventricularnodular heterotopia was observed in nine patients. Temporallobectomy, which did not include the area of heterotopia inseven patients, did not result in any significant improvement,despite EEG findings in the temporal area.57 Studies with depthelectrodes have provided evidence that seizure activity can arisesimultaneously from periventricular heterotopic cortex58 andfrom distantly located cortical areas.42,59 Surgical removal of theheterotopic cortex, as well as the normal-appearing epileptogeniccortex, led to seizure freedom.

Early fluorodeoxyglucose–positron emission tomographic(PET) studies had shown that heterotopia has the same metabolicactivity as normal gray matter. Functional MRI studies suggestthat periventricular nodular heterotopia caused by FLN1 mutationscan also be functionally integrated in motor circuits, suggesting thatneurons that have failed to migrate have maintained the informa-tion that allows them to assemble in functionally active aggre-gates and to participate in integrated networks.60

290 Journal of Child Neurology / Volume 20, Number 4, April 2005

Figure 3. A, Bilateral periventricular nodular matter heterotopia in a girl with the FLN1 mutation. B, Bilateral periventricular nodular hetero-topia, with a simplified gyral pattern, ventriculomegaly, and microcephaly in a boy with the ARGEF2 mutation.

A B

Classic Lissencephaly and Subcortical Band Heterotopia

(Agyria-Pachygyria-Band Spectrum)

Lissencephaly (smooth brain) is characterized by absent (agyria)or decreased (pachygyria) convolutions, producing a smooth cere-bral surface.7 The most frequent forms are caused by mutations ofthe LIS1 gene (Mendelian Inheritance in Man #601545)61 (Figure4) and of the DCX (or XLIS) gene (Mendelian Inheritance in Man#300121) (Figure 5).62,63 Subcortical band heterotopia is a slightlydifferent malformation that is now included within the agyria-pachygyria-band spectrum.7 In subcortical band heterotopia, thegyral pattern is normal or simplified with broad convolutions andincreased cortical thickness. Just beneath the cortical ribbon, a thinband of white matter separates the cortex from a heterotopic bandof gray matter of variable thickness and extension (Figure 6). Mostcases of subcortical band heterotopia are caused by mutations ofthe DCX gene64 and a minority by mutations of the LIS1 gene.65,66

Lissencephaly and subcortical band heterotopia caused by muta-tions of the LIS1 and DCX genes have distinct anatomic featuresthat can help in choosing the diagnostic strategy and are illus-trated below.

Several malformation syndromes associated with lissencephalyhave been described. The LIS1 gene is the first gene that wasassociated with human lissencephaly.61 A morphologic feature thatis common to the malformative spectrum caused by LIS1 mutationsis a posteriorly predominant brain abnormality. The LIS1 is the generesponsible for all cases of Miller-Dieker lissencephaly, which iscaused by large deletions of LIS1 and contiguous genes,67 forapproximately 65% of cases of isolated lissencephaly sequence, andfor almost all cases in which the gyral disorder is more severe pos-teriorly. Among all of the patients with isolated lissencephalysequence, 40% exhibit a deletion involving the entire gene68 and 25%show an intragenic mutation (4% gross rearrangement, 17% dele-tion or truncating mutations, 4% missense mutations).69 Patientswith missense mutations generally have less severe malforma-tions and can, accordingly, present with much milder neurologicand cognitive impairment.69 Severe truncating mutations causesevere lissencephaly, whereas milder mutations, usually missensemutations, cause pachygyria and rare cases of subcortical band het-erotopia.65 Mosaic mutations of LIS1 cause subcortical band het-erotopia in the posterior brain.66

DCX mutations usually cause classic lissencephaly in hem-izygous males and subcortical band heterotopia in heterozygousfemales.62 Mutations of the coding region of DCX were found inall reported pedigrees and in 38% to 91% of sporadic femalepatients.70 Rare carrier women harboring missense mutationsshow normal brain MRI owing to either favorable X-inactivationskewing or to mutations with mild functional consequences.71 Allwomen with DCX mutations and abnormal MRIs have an anteri-orly predominant band or pachygyria. About one fourth of thosewith an anterior band and all of those with a posteriorly pre-dominant band or a unilateral band have not shown DCX muta-tions, suggesting that other loci or somatic mosaicism might beresponsible for these variable phenotypes.62 Maternal germline ormosaic DCX mutations can occur in about 10% of cases of eithersubcortical band heterotopia or XLIS.64 In boys, the rare cases ofsubcortical band heterotopia that have been described wereassociated with missense mutations of DCX when anteriorly pre-dominant71 or with either missense or mosaic LIS1 mutationswhen posteriorly predominant.66,72

Neuronal Migration Disorders, Genetics, and Epileptogenesis / Guerrini and Filippi 291

Figure 4. A 2-year-old boy with severe developmental delay, infan-tile spasms, and an intragenic mutation of the LIS1 gene. There is dif-fuse, posteriorly predominant pachygyria with a thickened cortex,broad gyri, and shallow sulci.

Figure 5. Magnetic resonance image of a boy carrying a DCX muta-tion. Severe pachygyria in the frontal lobes (upward pointing arrows)and subcortical band heterotopia in the parietal lobes (downwardpointing arrows).

Classic lissencephaly has a prevalence of 11.7 per millionbirths (1 in 85,470),73 but the prevalence of milder phenotypes isunknown. Affected children have early developmental delay andeventual profound mental retardation and spastic quadriparesis.Some children with severe lissencephaly have lived more than 20years, but their life span is often shorter. Seizures occur in over 90%of children, with onset before 6 months in about 75%. About 80%have infantile spasms,9 although the EEG might not show typicalhypsarrhythmia. Most children subsequently have multiple seizuretypes, including persisting spasms, focal seizures, tonic seizures,atypical absences, and atonic seizures.74 The EEG demonstrates dif-fuse, high-amplitude, fast rhythms, which are considered to behighly specific for this malformation.75

The main clinical manifestations of subcortical band hetero-topia are mental retardation and epilepsy. Cognitive functionranges from normal to severe retardation and correlates with thethickness of the band and the degree of pachygyria.76 Epilepsy ispresent in almost all patients with subcortical band heterotopia andis intractable in about 65%.51 About 50% of epilepsy patients havefocal seizures and the remaining 50% have generalized epilepsy, oftenLennox-Gastaut syndrome. Those with more severe MRI abnor-malities have significantly earlier seizure onset and are more likelyto develop Lennox-Gastaut syndrome.76 Depth electrode studiesdemonstrated that epileptiform activity can originate directly fromthe heterotopic neurons.77 Callosotomy has been associated withworthwhile improvement in drop attacks in a few patients.25,78

Epilepsy surgery for focal seizures yields poor results.79

Laboratory Investigations in LIS1 and XLIS

Lissencephaly-Pachygyria-Band Heterotopia

Chromosome Analysis A standard blood chromosome analysis(400–550 band resolution) is warranted in all patients with classiclissencephaly. A few cases have been reported of patients withclassic lissencephaly owing to a chromosomal reciprocal translo-cation.80–82 About 60% of patients with Miller-Dieker syndrome showa cytogenetically visible deletion, and a few of them show a differ-ent chromosome rearrangement (translocation, ring chromosome).

Fluorescent In Situ Hybridization Fluorescent in situ hybridiza-tion with commercial probes containing the LIS1 gene is requiredin all patients in whom a chromosome 17 lissencephaly is suspectedon the basis of the appearance of the MRI.83 About 40% of patientswith isolated lissencephaly sequence show a deletion at chromo-some 17p13.3. Because these deletions are not observed under astandard chromosome banding analysis, they are referred to as “sub-microscopic.” In particular, it is recommended that a fluorescentin situ hybridization study be performed using the LIS1-specificprobe PAC 95H6.

LIS1 Gene Sequencing and Southern Blot Analysis The analy-sis consists of the direct sequencing of the LIS1 gene, followingpolymerase chain reaction amplification of the entire coding region.About 25% of patients with classic lissencephaly show an intragenicmutation of LIS1. Gene sequencing is not 100% sensitive becausethe promoter and the transcription regulatory regions of the geneare not routinely investigated, and a mutation in these regionscould be missed. The Southern blot analysis reveals gross rearrange-ments of the LIS1 gene, which can be detected in about 4% ofpatients. The recent demonstration of mosaic mutations of the LIS1

gene in individuals with posterior band heterotopia-pachygyriasuggests that a highly sensitive technique, such as denaturing high-pressure liquid chromatography, can be useful in identifying low-level mosaicism, which can escape recognition by direct sequencingor other standard techniques.66

DCX Gene Sequencing This analysis is indicated in male indi-viduals with classic lissencephaly in whom an X-linked pattern ofinheritance is suspected, on the basis of either pedigree analysisor MRI evidence of a more severe malformation in the frontalbrain regions.83 Both female and male patients with subcortical bandheterotopia should be tested for DCX mutations whenever geneticcounseling is advisable. This analysis is performed on the codingexons of the DCX gene that has a high yield,84,85 although, similarlyto the LIS1 gene sequencing, it does not detect all of the potentialcausative disease mutations. When a mutation in the DCX gene isfound in a child of either gender with XLIS, mutation analysisshould be extended to the proband’s mother, even if her brainMRI is normal.71 The report of relatively mildly affected malepatients carrying missense DCX mutations71 makes father-to-daugh-ter transmission theoretically possible, although not yet reported.

Laboratory Testing Strategy

In patients with classic lissencephaly, the cytogenetic and molec-ular investigations are part of the diagnostic process, which relies,in addition, on the pedigree analysis, the experience of the exam-iner of brain MRI and the syndromic evaluation of the child. WhenMiller-Dieker syndrome is suspected, a standard chromosome

292 Journal of Child Neurology / Volume 20, Number 4, April 2005

Figure 6. A 16-year-old girl with moderate mental retardation and mul-tiple seizure types within the spectrum of the Lennox-Gastaut syn-drome. Subcortical band heterotopia owing to a DCX gene mutation.Note the thick heterotopic band and the associated microgyric appear-ance of the cortical surface.

analysis and fluorescent in situ hybridization assay on chromosome17p13.3 are indicated.85 If both tests are normal, the patient is verylikely not to be affected with Miller-Dieker syndrome. When non-syndromic isolated lissencephaly is diagnosed, careful assessmentof the anteroposterior gradient of gyral pattern abnormality and cor-tical thickness will be suggestive of the involvement of either theLIS1 or the DCX gene. When lissencephaly is more severe poste-riorly, it is worth performing the chromosome analysis with a flu-orescent in situ hybridization assay on chromosome 17p13.3. If adeletion is not found, LIS1 gene sequencing and the Southern blotanalysis should be performed consequently. In boys whose MRIshows more severe pachygyria in the frontal lobes, sequencing ofthe DCX gene is indicated.

Mutations of LIS1 and DCX have been reported in patients withsubcortical band heterotopia. The pedigree analysis and assessmentof the distribution of the heterotopic band and areas of pachygyriaare helpful to predict DCX involvement versus the rare casesowing to germline or mosaic LIS1 mutations. DCX mutationsshould be searched for by direct sequencing. Mutation analysis withdirect sequencing of the relevant exons is also indicated in the moth-ers of patients harboring a DCX mutation or other potential femalecarriers in the family who are of reproductive age. Normal brainMRI does not exclude DCX mutations in female carriers.71,86,

Genetic Counseling

Miller-Dieker Syndrome About 80% of patients with Miller-Dieker syndrome have a de novo deletion and 20% have inheriteda deletion from a parent carrying a balanced chromosomerearrangement. For this reason, a karyotype and fluorescent in situhybridization assay should be obtained from both parents of chil-dren with Miller-Dieker syndrome. If the mutation event is denovo, the recurrence risk is low (about 1%). If one of the parentsis a carrier of a chromosomal imbalance, the recurrence risk willbe calculated accordingly.

LIS1 Lissencephaly All reported mutations in the LIS1 gene(deletion, intragenic, submicroscopic) are de novo. Nevertheless,if a LIS1 mutation is found, it is correct to perform the mutationanalysis on both parents. Given the theoretical risk of germlinemosaicism in either parent (which has been demonstrated forother diseases but never for LIS1 lissencephaly), a couple with achild with chromosome 17 lissencephaly is usually given a 1%recurrence risk in the offspring.

XLIS Lissencephaly When a mutation in the DCX gene is foundin a boy with lissencephaly, mutation analysis of DCX should beextended to the proband’s mother, even if her brain MRI is normal.If the mother is a mutation carrier, the mutation will be transmit-ted according to mendelian inheritance. If the mother is not a car-rier, she can still be at risk of harboring germline mosaicism,64 andthe risk of transmitting the mutation to her offspring might roughlybe estimated at around 5%. For this reason, a prenatal diagnosismight be indicated in every pregnancy of a woman who has a childwith a DCX mutation.85

Classic Lissencephaly Without a Detected Mutation If a muta-tion is not found in the LIS1 or DCX gene, the anteroposteriorlissencephaly gradient detected on MRI might still be helpful in dis-tinguishing the X-linked versus the chromosome 17–linked forms

or other forms with different anatomic patterns and can be usedin the counseling session with the parents of a patient with clas-sic lissencephaly.

Autosomal Recessive Lissencephaly

With Cerebellar Hypoplasia

Two recessive pedigrees, each with three affected sibs showing mod-erately severe pachygyria and extremely severe cerebellar hypopla-sia, have been associated with a mutation and a deletion of the reelingene.87 Affected children in one family had congenital lymphedema,hypotonia, severe developmental delay, and generalized seizuresthat were controlled by drugs. Severe hypotonia, delay, and seizureswere also reported in the other pedigree.

X-LINKED LISSENCEPHALY WITH CORPUS

CALLOSUM AGENESIS AND AMBIGUOUS

GENITALIA

X-linked lissencephaly with absent corpus callosum and ambigu-ous genitalia is a severe malformation syndrome that is observedonly in boys. The anatomoclinical spectrum includes lissencephalywith a posterior-to-anterior gradient and only a moderate increasein the cortical thickness (only 6 to 7 mm in X-linked lissencephalywith corpus callosum agenesis and ambiguous genitalia versus 15to 20 mm seen in classic lissencephaly associated with mutationsof LIS1 or DCX) (Figure 7), an absent corpus callosum, poorly delin-eated and cavitated basal ganglia, postnatal microcephaly, neonatal-onset epilepsy, hypothalamic dysfunction including defi-cient temperature regulation, chronic diarrhea, and ambiguousgenitalia with micropenis and cryptorchidism.83,88 Early death is notuncommon.89 Brain neuropathology reveals an abnormally lami-nated cortex exclusively containing pyramidal neurons, with apattern suggesting disruption of both tangential and radial migra-tion, dysplastic basal ganglia, hypoplastic olfactory bulbs and opticnerves, abnormal gliotic white matter containing numerous het-erotopic neurons, and complete agenesis of the corpus callosumwithout Probst bundles.88

Mutations of the X-linked aristaless-related homeobox gene(ARX) (Mendelian Inheritance in Man #300382) were identified inindividuals with X-linked lissencephaly with corpus callosum agenesisand ambiguous genitalia and in some female relatives.90 Females car-rying abnormal ARX usually have a normal cognitive level and caneither have normal brain MRI or show partial or complete agenesisof the corpus callosum. However, mild mental retardation andepilepsy have been reported in rare female carriers.88 Mouse Arx andhuman ARX are expressed at high levels in both dorsal and ventraltelencephalon, including the neocortical ventricular zone and ger-minal zone of the ganglionic eminence, with less intense signals inthe subventricular zone, cortical plate, hippocampus, basal ganglia,and ventral thalamus.90,91 Arx-deficient mice show deficient tan-gential migration and abnormal differentiation of interneurons con-taining GABAergic interneurons in the ganglionic eminence andneocortex. These characteristics recapitulate some of the clinical fea-tures of X-linked lissencephaly with corpus callosum agenesis andambiguous genitalia in humans90 and might account for the severeneonatal epileptic encephalopathy with infantile spasms and suppression-burst EEG that is often observed in affected boys.

The mutations of the ARX gene in patients with X-linkedlissencephaly with corpus callosum agenesis and ambiguous geni-

Neuronal Migration Disorders, Genetics, and Epileptogenesis / Guerrini and Filippi 293

talia were primarily premature termination mutations (large dele-tions or frameshift, nonsense, or splice-site mutations). Missensemutations are less common and are essentially located in the home-obox domain.89 Patients carrying nonconservative missense muta-tions within the homeobox showed less severe X-linked lissencephalywith corpus callosum agenesis and ambiguous genitalia, whereas con-servative substitution in the homeodomain caused Proud syndrome(corpus callosum agenesis with abnormal genitalia). A nonconser-vative missense mutation near the C-terminal aristaless domaincaused unusually severe X-linked lissencephaly with corpus callo-sum agenesis and ambiguous genitalia with microcephaly and mildcerebellar hypoplasia. ARX mutations are also associated withmilder phenotypes without malformations, including X-linked infan-tile spasms, Partington’s syndrome, and X-linked nonsyndromicmental retardation.92 Most patients with nonmalformation syn-dromes have polyalanine tract expansion mutations.92

MALFORMATIONS OWING TO ABNORMAL

CORTICAL ORGANIZATION

Schizencephaly

Schizencephaly (cleft brain) consists of a unilateral or bilateral full-thickness cleft of the cerebral hemispheres with communicationbetween the ventricle and extra-axial subarachnoid spaces. Theclefts are most often found in the perisylvian area.93 Because thecortex surrounding the cleft of the fissure is polymicrogyric,94

schizencephaly is considered a disorder of cortical organization.7

However, a severe abnormality of neuronal precursor proliferationis also possible, especially when open lip clefts with absence ofdevelopment of a large part of one cerebral hemisphere are con-sidered. The walls of the clefts can be widely separated (Figure 8)

or closely adjacent (Figure 9). Bilateral clefts are usually sym-metric.94 Septo-optic dysplasia (agenesis of the septum pellucidumand optic nerve hypoplasia) is seen in up to one third of patients.93

Schizencephaly can be due to regional absence of proliferation ofneurons and glia or to abnormal cortical organization. Local fail-ure of induction of neuronal migration or focal ischemic necrosiswith destruction of the radial glial fibers during early gestation hasbeen hypothesized. Schizencephaly is usually sporadic, but famil-

294 Journal of Child Neurology / Volume 20, Number 4, April 2005

Figure 7. A 1-year-old boy with X-linked lissencephaly with corpus cal-losum agenesis and ambiguous genitalia and a mutation of the ARXgene: callosal agenesis and severe pachygyria.

Figure 8. A 12-year-old boy with focal epilepsy and right hemipare-sis: left open lip perisylvian schizencephaly.

Figure 9. A 14-year-old boy with focal epilepsy: right perisylvianclosed lip schizencephaly.

ial occurrence has been reported.95 Several sporadic patients andtwo siblings of both genders harboring germline mutations in thehomeobox gene EMX2 have been described.96,97 However, the roleof the EMX2 gene is still unclear, as are the possible pattern of inher-itance and the practical usefulness that mutation detection in anindividual with schizencephaly would carry in terms of genetic coun-seling. Clinical findings include focal seizures in most patients(about 80% of cases in one large review),98 usually beginning beforeage 3 years in bilateral cases. Bilateral clefts are associated withmicrocephaly, severe delay, and spastic quadriparesis, whereaspatients with unilateral schizencephaly most often have hemi-paresis or can be brought to medical attention after seizure onsetwithout having any other neurologic abnormality.99

Polymicrogyria

Polymicrogyria is characterized by an excessive number of smalland prominent convolutions spaced out by shallow and enlargedsulci, giving the cortical surface a lumpy appearance.100 Corticalinfolding and secondary, irregular thickening owing to packing ofmicrogyri are visible on MRI (Figure 10), although mild forms aredifficult to recognize on neuroimaging.101 Two histologic types arerecognized. In unlayered polymicrogyria, the molecular layer is con-tinuous and does not follow the profile of the convolutions, andthe underlying neurons have radial distribution but no laminarorganization.94 In four-layered polymicrogyria, there is a layer ofintracortical laminar necrosis with consequent impairment of latemigration and postmigratory disruption of cortical organization.102

The two subtypes do not necessarily have a distinct origin becauseboth can coexist in contiguous cortical areas.102

The extent of polymicrogyria varies greatly, and there is a broadrange of clinical manifestations, from severe encephalopathy withintractable epilepsy31,101 to individuals with only selective impair-ment of cognitive functions.103 Several syndromes featuring bilat-eral polymicrogyria have been described, including bilateralperisylvian polymicrogyria104 (Figure 11), bilateral parasagittalparieto-occipital polymicrogyria105 (Figure 12), bilateral frontal106

and frontoparietal (Figure 13) polymicrogyria, and unilateral peri-sylvian or multilobar polymicrogyria.31 These different forms mightrepresent distinct entities that reflect the influence of regionallyexpressed developmental genes. In some children with unilateralor bilateral perisylvian polymicrogyria, electrical status epilepti-cus during sleep can develop.107 Affected individuals have contin-uous generalized spike-wave complexes during slow-wave sleepand suffer from focal motor, atonic, and atypical absence seizuresin the age range between 2 and 10 years. Epilepsy outcome is not

Neuronal Migration Disorders, Genetics, and Epileptogenesis / Guerrini and Filippi 295

Figure 10. Right perisylvian polymicrogyria:right (A and left (B) sagittal T1-weighted mag-netic resonance images. Polymicrogyricappearance of the perisylvian cortex on theright. C, Curvilinear reformation bettershows abnormal cortical ribbon and sulcalarrangement on the right side.

Figure 11. Bilateral perisylvian polymicrogyria with asymmetric thick-ening of the sylvian cortex in a young woman with focal epilepsy.

different from that seen in patients with cryptogenic electricalstatus epilepticus during sleep, that is, the seizures and EEG abnor-malities disappear after a period of variable duration, but cogni-tive and behavioral disturbances, which are especially prominentin those children with longer electrical status epilepticus duringsleep duration, often last.

Bilateral perisylvian polymicrogyria involves the gray matterbordering the sylvian fissure bilaterally. Both four-layered polymi-crogyria and unlayered polymicrogyria have been observed.51,34 Itis unclear whether these cases represent a spectrum of changeswithin a single malformation with the same etiology or differentmalformations, with different etiologies, with the same topography.Although most patients are sporadic, several familial cases havebeen reported, with possible autosomal recessive, autosomal dom-inant, X-linked dominant, and X-linked recessive inheritance.108 Alocus for X-linked bilateral perisylvian polymicrogyria maps tochromosome Xq28 in some families.109 Bilateral perisylvian polymi-crogyria has also been reported in some children with the chro-mosome 22q11.2 deletion110,111 and in children born frommonochorionic biamniotic twin pregnancies that were compli-cated by twin-twin transfusion syndrome,112,113 confirming causalheterogeneity.

Affected patients have faciopharingoglossomasticatory diple-gia34 and dysarthria. Most have mental retardation and epilepsy.Those with more extensive damage can have spastic quadripare-sis.101 Seizures usually begin between age 4 and 12 years and arepoorly controlled in about 65% of patients. The most frequentseizure types are atypical absence seizures, tonic seizures, atonicdrop attacks, and tonic-clonic seizures, often occurring as Lennox-

Gastaut–like syndromes.101,114 A minority of patients (about 25%)have focal seizures only, predominantly involving the perioral orfacial muscles. Infantile spasms have also been reported in aminority of patients.34 Patients with tonic or atonic seizures causingdisabling drop attack can be amenable to anterior callosotomy, withinteresting results.101,114 Lateralization of seemingly generalizedseizures has been clearly documented after callosotomy in bilateralperisylvian polymicrogyria.40

Bilateral frontal polymicrogyria was described in childrenwith developmental delay, mild spastic quadriparesis, and epilepsy.106

Although most reported cases were sporadic, occurrence in off-spring of consanguineous parents and in siblings was consideredpossibly suggestive of autosomal recessive inheritance. Indeed, fron-toparietal polymicrogyria, a malformation extending only a few cen-timeters further back in the pariental lobes, was reported in severalconsanguineous and nonconsanguineous families, suggesting arecessive pattern of inheritance, and was initially mapped to chro-mosome 16q12.2-21115 and subsequently associated with mutationsof the G protein–coupled receptor gene 6 (GPR56).116 GPCR56

belongs to the G protein–coupled receptor family, which is thelargest gene family in the human genome, representing about 1%of all genes. The pattern of expression of mouse Gpr56, as well asthe topography of the cortical abnormailty in patients harboringhomozygous mutations, strongly suggests that Gpr56 regulatescortical patterning.116 The fact that the N-terminus domain thatdefines GPCR56 is unique to animals that have a cerebral cortexalso suggests that this gene might have been a target in the evolu-tion of the cerebral cortex.116 Epilepsy, seen in the majority ofpatients, was mainly accompanied by partial seizures and atypicalabsences and was of variable severity.

296 Journal of Child Neurology / Volume 20, Number 4, April 2005

Figure 12. Bilateral parasagittal polymicrogyria. T1-weighted magneticresonance image, axial section. Irregular thickening and infolding ofthe cortex at the mesial parieto-occipital junction. A young girl withintractable partial epilepsy.

Figure 13. Bilateral frontal polymicrogyria in a boy with the GPR56gene mutation.

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