Epileptogenic brain malformations: clinical presentation

doi:10.1053/seiz.2001.0650, available online at http://www.idealibrary.com onSeizure 2001; 10: 532–547

Epileptogenic brain malformations: clinicalpresentation, malformative patterns and indications forgenetic testing

RENZO GUERRINI†

& ROMEO CARROZZO‡

†Neurosciences Unit, Great Ormond Street Hospital for Sick Children and Institute of Child Health

University College London, The Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, UK;‡Servizio di Genetica Medica, IRCCS Ospedale San Raffaele, Milano, Italy

Correspondence to: Professor Renzo Guerrini, Neurosciences Unit, Great Ormond Street Hospital for Children andInstitute of Child Health, The Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, UK.E-mail: [email protected]

We review here those malformations of the cerebral cortex which are most often observed in epilepsy patients, for which agenetic basis has been elucidated or is suspected and give indications for genetic testing.

There are three forms of lissencephaly (agyria-pachygyria) resulting from mutations of known genes, which can be distin-guished because of their distinctive imaging features. They account for about 85% of all lissencephalies. Lissencephaly withposteriorly predominant gyral abnormality is caused by mutations of theLIS1gene on chromosome 17. Anteriorly predominantlissencephaly in hemizygous males and subcortical band heterotopia (SBH) in heterozygous females are caused by mutationsof theXLIS(or DCX) gene. Mutations of the coding region ofXLISwere found in all reported pedigrees, and in most sporadicfemale patients with SBH. Missense mutations of bothLIS1 andXLIS genes have been observed in some of the rare malepatients with SBH. Autosomal recessive lissencephaly with cerebellar hypoplasia has been associated with mutations of thereelin gene. With few exceptions, children with lissencephaly have severe developmental delay and infantile spasms early inlife. Patients with SBH have a mild to severe mental retardation with epilepsy of variable severity and type.

X-linked bilateral periventricular nodular heterotopia (BPNH) consists of typical BPNH with focal epilepsy in females andprenatal lethality in males. About 88% of patients have focal epilepsy. Filamin A (FLNA) mutations have been reported in somefamilies and in sporadic patients. Additional, possibly autosomal recessive gene(s) are likely to be involved in causing BPNHnon-linked toFLN1.

Tuberous sclerosis (TS) is a dominant disorder caused by mutations in at lest two genes,TSC1andTSC2. 75% of cases aresporadic. Most patients with TS have epilepsy. Infantile spasms are a frequent early manifestation of TS.

Schizencephaly (cleft brain) has a wide anatomo-clinical spectrum, including focal epilepsy in most patients. Familialoccurrence is rare. Heterozygous mutations in theEMX2gene have been reported in some patients. However, at present, there isno clear indication on the possible pattern of inheritance and on the practical usefulness that mutation detection in an individualwith schizencephaly would carry in terms of genetic counselling.

Amongst several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria had familial occurrence on sev-eral occasions. Genetic heterogeneity is likely, including autosomal recessive, X-linked dominant, X-linked recessive inheri-tance and association to 22q11.2 deletions. FISH analysis for 22q11.2 is advisable in all patients with perisylvian polymicro-gyria. Parents of an affected child with normal karyotype should be given up to a 25% recurrence risk.

c© 2001 BEA Trading Ltd

Key words:epilepsy; lissencephaly; heterotopia; polymicrogyria;LIS1;DCX; FLNA.

INTRODUCTION

Major progress has been made in the diagnosticrecognition of malformations of the cerebral cortexor of cortical development1, especially through the

useof magnetic resonance imaging (MRI). Variationsin distribution and depth of cortical sulci, corticalthickness, boundaries between gray and white matter,and signal intensity allow recognition of differentmalformation patterns.

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Epileptogenic brain malformations 533

Abnormal cortical development represents a majorcause of epilepsy2. More severe malformationsmanifest with profound developmental delay andearly onset seizures, with consequent reproductivedisadvantage. Mild malformations may be detectedafter seizure onset at various ages in otherwise healthyindividuals.

Some malformations have a clear pattern of inher-itance, while others are almost exclusively sporadic.Collection of large series of homogenous clinicaland imaging observations, as well as neuropatho-logical studies3 have helped establish nosologicalsubdivisions1. Linkage studies and candidate gene ap-proacheshave led to the identification of several geneswhich regulate brain development4. In the followingsections,we will review those malformations of thecerebral cortex for which a genetic basis has beenelucidated or is suspected, the types of epilepsy theycan present with and the indications for genetic testing.

LISSENCEPHALY AND SUBCORTICAL BANDHETEROTOPIA(THE AGYRIA-PACHYGYRIA-BANDSPECTRUM)

The malformative spectrum

Lissencephaly (smooth brain) is a severe abnormalityof neuronal migration characterized by absent (agyria)or decreased (pachygyria) convolutions, producinga smooth cerebral surface with thickened cortex(Figs 1(a) and 1(b))3, 5. Although there are severaltypes of lissencephaly6 we will refer here tothe most frequent and best characterized forms:lissencephaly caused by mutations of theLIS1 gene7

and lissencephaly caused by mutations of theXLIS(orDCX) gene8, 9. Subcortical band heterotopia (SBH)comprisesthe mild end of this group of malforma-tions, which may accordingly be called the agyria-pachygyria-band spectrum10. In SBH, the gyralpatternis usually simplified with broad convolutionsand slightly increased cortical thickness; but may benormal in some patients. Just beneath the corticalribbon, a thin band of white matter separates the cortexfrom a heterotopic band of gray matter of variablethickness and extension11 (Figs 1(c) and 1(d)). Ingeneral,the thicker the heterotopic band, the higherthe chances of finding a pachygyric cortical surface12.XLIS lissencephaly and SBH can be observed indifferent individuals from the same family13, 14.Pathological studies of both lissencephaly and SBHdemonstrate incomplete neuronal migration3, 15.

Several malformation syndromes associated withclassical lissencephaly have been described. The bestknown of these is Miller–Dieker syndrome (MDS),

which is caused by large deletions of theLIS1 gene,mapping to chromosome 17p13.3, and contiguousgenes16. The most frequent form, the X-linkeddominantlissencephaly and SBH, consists of classicallissencephaly in hemizygous males and SBH inheterozygous females. TheDCX gene is locatedon chromosome Xq22.3-q248, 9, 17, 18. Mutations ofthe coding region of DCX were found in allreported pedigrees14 and in 38 to 91% of sporadicfemale patients11. In general while all womenwith DCX mutations have anteriorly predominantband/pachygyria, about 25% of those with anteriorband and all those with posteriorly predominant bandor with unilateral band have shown noDCXmutations,suggesting that other loci or somatic mosaicism maybe responsible for these variable phenotypes11, 19.Maternal germline or mosaic-DCXmutations mayoccur in about 10% of cases of either BH or XLIS19.BH in rare affected boys has been associated withmissense mutations ofDCX or LIS120.

Approximately, 65% of patients with ILS showa mutation involving theLIS1 gene. Among allthe patients with ILS, 40% exhibit a deletioninvolving the entire gene21, and 25% show anintragenic mutation (roughly, 4% gross rearrange-ment, 17% deletion/truncating mutations, 4% mis-sense mutations)22. In general, in patients withmissense mutations the malformation is milder(lissencephaly grade 3 through grade 6, according tothe ‘Lissencephaly grading system’, where grade 1is the most severe)23 than in patients with trunca-ting/deletionmutations22.

Children with XLIS mutations have anteriorlypredominant lissencephaly (Fig. 1(b)) and childrenwith LIS1 mutations have posteriorly predominantlissencephaly (Fig. 1(a))21. This anatomic differenceis usually clearcut24 and of great importance inguidinggenetic testing (See below).

The clinical syndromes and epileptic spectrum

Classical lissencephaly is quite rare with a prevalenceof 11.7 per million births25. Affected children haveearly developmental delay and eventual profoundmental retardation and spastic quadriparesis. Somechildren with lissencephaly have lived more than20 years, but life span may be much shorter in otherpatients. Seizures occur in over 90% of children, withonset before 6 months in about 75%. About 80%of children have infantile spasms, although the EEGmay not show typical hypsarrhythmia. After the firstmonths of life, most children have mixed seizuredisorders including persisting spasms, focal motorand generalized tonic seizures26–29, complex partialseizures,atypical absences, atonic and myoclonic

534 R. Guerrini & R. Carrozzo

(d ) (e)

( g) (h) (i)

(a) (b) (c)

( f )

Fig. 1: (a) Lissencephaly in a boy with LIS1 mutation. Note the mild sparing of the gyral pattern anteriorly and the completelysmooth cortex in the posterior brain. (b) X-linked lissencephaly in a boy with a missense XLIS mutation. The cortex is thicker andsmoother in the frontal lobes, the gyral pattern is partially spared posteriorly. (c) Band heterotopia with thick generalized band in agirl with epilepsy, severe mental retardation, epilepsy and a truncating mutation of the XLIS gene. (d) Band heterotopia withdiffuse band in a boy with epilepsy moderate mental retardation and a missense mutation of XLIS. (e) Bilateral periventricularnodular heterotopia with contiguous nodules in a woman with a truncating mutation of the FLN1 gene. (f ) TS with multiplebilateral cortical tubers. (g) Bilateral open lip schizencephaly. (h) Unilateral closed lip schizencephaly. The cleft spans from thecortical surface to the upper part of the underlying ventricular wall. (i) Bilateral perisylvian polymicrogyria.

seizures. Most children with lissencephaly havecharacteristicEEG changes, including diffuse highamplitude fast rhythms30 which are considered to behighly specific for this malformation31.

The main clinical manifestations of SBH aremental retardation and epilepsy. Cognitive level rangesfrom normal to severely retarded, and correlates

with MRI parameters, above all band thickness andseverity of pachygyria12. Patients with pachygyriahave significantly earlier seizure onset. The moresevere the pachygyria and the thicker the heterotopicband, the higher the chances of developing Lennox–Gastaut syndrome or some other generalized symp-tomatic epilepsy form. Very early seizure onset is


uncommon. About 90% of patients with SBH haveepilepsy12, 28, 32–36which is generalized in about 50%.Overall, 65% of the patients studied had intractableseizures. Using depth electrodes, Morrellet al.,37

demonstrated that epileptiform activity may originatedirectly from the heterotopic neurons, independentlyof the activity of the overlying cortex. Persistentseizures causing drop attacks have been treated withcallosotomy in a few patients33, 36 with worthwhileimprovement. On the other hand, focal resections andmultiple subpial transections yielded poor results in amulticenter series38.

Laboratory investigations

Chromosome analysis. A standard blood chromo-some analysis (400–550 bands resolution) is war-ranted in all patients with classical lissencephaly.Three cases have been reported of patients with clas-sical lissencephaly due to a chromosomal reciprocaltranslocation39–41. About 60% of patients with MDSshow a cytogenetically visibile deletion, and a fewof them show a different chromosome rearrangement(translocation, ring chromosome).

FISH. Fluorescentin situ hybridization with com-mercial probes containing theLIS1gene is required inall patients in whom a chromosome 17 lissencephalyis suspected on the basis of the appearance of the MRIscan, especially when a more severe lissencephaly inseen in the posterior brain regions24. About 40% ofpatientswith ILS show a deletion at 17p13.3. Sincethese deletions are not observed under a standardchromosome banding analysis, they are referred toas ‘submicroscopic’. A submicroscopic deletion isdetected in MDS patients with normal chromosomeanalysis.

LIS1 gene sequencing and southern blot analysis.The analysis consists of the direct sequencing of theLIS1 gene, following the PCR amplification of theentire coding region. About 25% of patients withclassical lissencephaly show an intragenic mutation ofLIS1. Gene sequencing is not 100% sensitive, since thepromoter and the transcription regulatory regions ofthe gene are not routinely investigated, and a mutationin these regions could be missed. The Southern blotanalysis reveals gross rearrangements of theLIS1gene, which can be detected in about 4% of patients.

DCX gene sequencing. This analysis is indicatedin male individuals with classical lissencephaly inwhom an X-linked pattern of inheritance is suspected,on the basis of either pedigree analysis or MRIevidence of a more severe malformation in the frontal

brain regions24. Both female and male patients withSBH should be tested forDCX mutations whenevera genetic counselling is advisable. This analysis isperformed on the coding exons of theDCX geneand although, similarly to theLIS1 gene sequencing,it does not detect all the potential causing diseasemutations, it has a high yield42.

Laboratory testing strategy

In patients with classical lissencephaly, the cytoge-netic and molecular investigations are part of thediagnostic process, which relies, in addition, on thepedigree analysis, the experience of the examiner ofbrain MRI, and the syndromic evaluation of the child,which might rule out a known syndrome.

When MDS is suspected, a standard chromosomeanalysis and FISH assay on 17p13.3 are indicated. Ifboth tests are normal, the patient is very likely not tobe affected with MDS. When non-syndromic isolatedlissencephaly is diagnosed, careful assessment of theantero-posterior gradient of gyral pattern abnormalityand cortical thickness, will be suggestive of theinvolvement of either theLIS1or theDCXgene. Whenlissencephaly is more severe posteriorly, it is worthperforming the chromosome analysis with a FISHassay on 17p13.3. If a deletion is not found,LIS1genesequencing and the southern blot analysis should beperformed consequently.

In male patients in whom MRI shows more severelissencephaly in the frontal lobes, sequencing of theDCX gene is indicated.

Mutations in theLIS1 and in theDCX gene havebeen reported in patients with SBH. The pedigreeanalysis and assessment of the distribution of theheterotopic band and areas of pachygyria are helpful topredictDCX involvement vs. the rare cases due toLIS1mutations.DCX mutations should be searched for bydirect sequencing.

Mutation analysis with direct sequencing of therelevant exons is also indicated in the mothers ofpatients harbouring aDCXmutation, or other potentialfemale carriers in the family who are in reproductiveage. Normal brain MRI scan does not excludeDCXmutations in female carriers43.

Genetic counselling

Miller–Dieker syndrome. About 80% of MDSpatients have ade novo deletion, and 20% haveinherited a deletion from a parent who carries abalanced chromosome rearrangement. For this reasona karyotype and FISH assay should be obtainedfrom both parents of children with MDS. If the


mutation event is ‘de novo’, the recurrence risk islow (about 1%). If one of the parents is a carrier of achromosomal imbalance, the recurrence risk will becalculated accordingly.

LIS1 lissencephaly. All reported mutations in theLIS1 gene (deletion, intragenic, submicroscopic) are‘de novo’. Nevertheless, if aLIS1mutation is found, itis correct to perform the mutation analysis on both par-ents. Given the theoretical risk of germline mosaicismin either parent (which has been demonstrated forother diseases but never forLIS1 lissencephaly) acouple with a child with chromosome 17 lissencephalyis usually given a 1% recurrence risk in the offspring.

XLIS lissencephaly. When a mutation in theDCXgene is found in a boy with lissencephaly, mutationanalysis ofDCX should be extended to the proband’smother, even if her brain MRI scan is normal43. Ifthe mother is a mutation carrier, the mutation will betransmitted according to the mendelian inheritance.If the mother is not a carrier, she is at risk to be agermline mosaic19, and the risk of transmitting themutationto her offspring might roughly be estimatedaround 5%. For this reason, a prenatal diagnosis mightbe indicated in every pregnancy of a woman who hasa child with aDCX mutation.

Classical lissencephaly without a detected mutation.If a mutation is not found in theLIS1 or DCX gene,the anteroposterior lissencephaly gradient detected onMRI might still be helpful in distinguishing the Xlinked vs. the 17 linked forms, and can be used in thecounselling session with the parents of a patient withclassical lissencephaly.

AUTOSOMAL RECESSIVE LISSENCEPHALYWITH CEREBELLAR HYPOPLASIA

Mutations in the reelin gene are responsible for thereeler mouse mutant, characterized by impaired motorcoordination, tremors and ataxia. A recent report44,describedtwo recessive pedigrees with three affectedsibs each, showing moderately severe pachygyria andsevere cerebellar hypoplasia. Affected children inone family had congenital lymphoedema, hypotonia,severe developmental delay and generalized seizureswhich were controlled by drugs. Severe hypotonia,delay and seizures were reported also in the otherpedigree. A splice acceptor site mutation and adeletion of exon 42 in the reelin gene (approvedgene symbolRELN) were reported for these families,respectively.

Mutations in the reelin gene can be searched for inselected research laboratories.

BILATERAL PERIVENTRICULAR NODULARHETEROTOPIA

The malformation

The term ‘heterotopia’ designates agglomerates ofmorphologically normal neurons in an abnormal site.These neurons may assemble in a pattern suggestiveof laminar organization15. Collection of heterotopicneuronscan be unilateral or bilateral, diffuse or local-ized, subependimal or subcortical, or may extend fromthe subependymal region to the subcortex. Heterotopiacan readily be diagnosed with MRI, showing the samesignal as the normal cortex at every impulse sequence.On FDG-PET imaging, heterotopia has the samemetabolic activity as normal gray matter45. Seizureactivity may originate both within the heterotopiccortex and the overlying cerebral cortex46.

Bilateral periventricular nodular hetero-topia (BPNH) consists of confluent and symmetricsubependymal nodules of gray matter located alongthe lateral ventricles, particularly along the ventricularbody (Fig. 1(e)). Extent of the heterotopia and severityof associated clinical symptoms is variable.

Genetic basis

BPNH is far more frequent in females, resultingin the syndrome of classical X-linked BPNH withprenatal lethality in males10 and a 50% recurrencerisk in the female offspring of women with BPNH.X-linked BPNH and BPNH occurring in sporadicwomen has been associated with mutations of thefilamin A (FLNA) gene (approved gene symbolFLNA,also indicated asFLN1, andABP-280)47.

FLNA was originally cloned by Gorlinet al.48 andindicatedas actin-binding protein 28048. FLNA mapsto Xq2849, it is composed of 48 exons, and spans a26 kb genomic region47. FLNA is a 280 kDa protein,with three major functional domains48, allowing thehomodimerizationof FLNA and the heterodimeriza-tion of FLNA with actin and membrane receptors.

Classical BPNH in an X-linked dominant disorder.The disease was mapped to Xq28 by linkage analysis,andFLNA was demonstrated to be the BPNH gene bythe finding of loss-of-function mutations in affectedfamilies and sporadic patients47. FLNA mutationshave been reported in five out of six BPNH pedigrees(83%), and in six of 31 sporadic females with BPNH(19%). RecentlyFLNA mutations have also beenreported in 2/24 males with BPNH (9%), indicatingthat mutations in the hemizygous male are notinvariably associated with death during the fetal orearly neonatal period50.


The clinical syndromes

Heterozygousfemales with classical BPNH linked toFLNA mutations, show epilepsy and coagulopathy.They usually have normal intelligence to borderlinemental retardation. Epilepsy has variable severity.Several syndromes featuring BPNH and mentalretardation have been described always occurringsporadically, almost exclusively in boys51–53. Oneboy with the syndrome of BPNH with severe mentalretardation and syndactily51 was found to harbour aduplication of Xq2854. In this case, a gene dosageimbalancewas felt to be responsible for the disease47.BPNH with frontonasal dysplasia (FND) and mildmental retardation has been described in two boys52

and a girl53 showing similar severity. This syndromecould therefore be recessive and unrelated toFLNAmutations. Mutation screening of theFLNA gene inthe two boys with BPNH/FND was negative (Moro,Carrozzo and Guerrini, unpublished data).

About 88% of patients with periventricular and sub-cortical nodular heterotopia have epilepsy55 beginningat any age between the first months of life andadulthood. Seizure intractability is observed in mostpatients (82%). However, it is not yet known whetherclassical BPNH is accompanied by a homogeneousepilepsy phenotype.

Laboratory testing and genetic counselling

In front of a patient with BPNH, the laboratorytests are part of the diagnostic tools, along withthe dysmorphologic and neurological examination.The FLNA gene can be screened for mutationsthrough SSCP analysis, with the highest chance offinding a mutation in familial cases. This analysiscan be performed in selected research laboratories.FISH analysis with probes containing theFLNAgene might be indicated in BPNH associated withmultiple congenital abnormalities/mental retardationsyndromes, to rule out a duplication at Xq28.

The genetic counselling will be relatively easy infamilial cases with an X-liked pattern of inheritance,when aFLNA mutation is found. The recurrence riskin isolated cases appears to be low when the mother ofthe affected individual is not a carrier of the mutation,since germline mosaicism ofFLNA has never beenreported in BPNH. However, BPNH may also beinherited as an autosomal recessive trait, as stronglysuggested by pedegrees where affected siblings ofboth sexes were born from consanguineous parents(Sebire and Guerrini, unpublished data). RecessiveBPNH appears to be more severe than classical X-linked BPNH.

TUBEROUS SCLEROSIS

The malformation

Tuberous sclerosis (TS) or tuberous sclerosis complex(TSC) is a multi-systemic disorder involving primarilythe central nervous system, the skin, and the kidney56.A prevalence of 1:30000–50000 has been reported.

In the brain, the characteristic features are corticaltubers, subependymal nodules and giant cell tumors.The cortical tubers are the lesions that are moredirectly related to epileptogenesis. They are identi-fied by their nodular appearance, firm texture, andvariability in site, number and size. Microscopically,the tubers consist of subpial glial proliferation withorientation of the glial processes perpendicular to thepial surface, and an irregular neuronal lamination withgiant multinucleated cells that are not clearly neuronalor astrocytic. These pathologic changes are similar tothose seen in focal cortical dysplasia57, 58, a highlyepileptogenic lesion without familial distribution.Cortical tubers are usually well visualized by MRIscan as enlarged gyri with atypical shape andan abnormal signal intensity, mainly involving thesubcortical white matter59. In the newborn they arehyperintense with respect to the surrounding whitematter, on T1 weighted images and hyperintenseon T2 weighted images. Progressive myelinationof the white matter in the older infant gives thetubers an hypointense center on T1 and high signalintensity on T2 (Fig. 1(f)). In the adult the lesionstend to become isointense with the white matteron T1 weighted images but maintain hyperintensityon T2. Tubers may have a tendency to calcify, whichincreases with age. The MRI appearance of corticaltubers and of focal cortical dysplasia are sometimessimilar, but tubers are usually multiple while focalcortical dysplasia is always an isolated lesion.

The epileptic spectrum

Epileptic seizures are frequent in TS. They usuallybegin before the age of 15, mostly in the first 2 yearsof life: 63.4% before 1 year56, 70% before 2 years.Infantile spasms are the most common manifestationof epilepsy in the first year of life, sometimes precededby partial seizures60. In their study of 126 patients61,found 63 (50%) with infantile spasms and 63 (50%)with other types of epilepsy [35 partial, 11 Lennox–Gastaut syndrome, four symptomatic generalized, sixoccasional seizures and seven unclassifiable). Forty-two of the latter 63 patients had their first seizurebefore 2 years and the prognosis was strongly relatedto this early onset. Almost all patients were cognitivelyimpaired and the course of epilepsy was severe


in about one third. MRI studies have establishedthat there may be a correlation between tubers andepilepsy. In children with partial epilepsy or withinfantile spasms the largest tuber was found in the areacorresponding to the main EEG focus62. However,MRI may fail to show all the tubers in infants ifmyelination is not complete63. Patients with TS mustbecarefully investigated in order to determine whetherthere is a single epileptogenic area in that its surgicalremoval can yield good control of seizures64, 65. Thenumberand size of tubers seems to be correlated withthe severity of epilepsy and of mental disturbances66.

Genetic basis and genetic testing

TSC is transmitted as an autosomal dominant trait,with variable expression seen among families andreported among patients within the same family.Recurrence in sibship of non-affected parents hasrarely been reported and is thought to be related tolow expressivity or gonadal mosaicism. There is noclear evidence of non-penetrance for TSC. Thereforecareful clinical and diagnostic evaluation of apparentlyunaffected parents is indicated before counselling thefamilies. Between 50 to 75% of all cases are sporadic.

Linkage studies have allowed the identification oftwo loci for TSC, mapping to chromosome 9q34(TSC1) and 16p13.3 (TSC2)67. About 50% of thefamilies are linked toTSC168. A classical positionalcloning approach has led to the isolation of theTSC1gene69 named ‘hamartin’. A mutation in theTSC1genehas so far been identified in about 80%of the families linked to chromosome 9q3470. Thepredictedamino acid sequence does not show an overthomology to other known proteins. The identificationof the gene mapping to 16p13.3 has been facilitatedby the identification of interstitial deletions in fiveunrelated TSC patients. A gene (TSC2) was found tobe disrupted by all the deletions and was demonstratedto harbor intragenic mutations in other non-deletedTSC patients, and named tuberin71.

Clinical assessment indicated that sporadic patientswith TSC1 mutations had, on average, a milderdisease than did patients withTSC2mutations. Theyhad a lower frequency of seizures and moderateto severe mental retardation, fewer subependymalnodules and cortical tubers, less severe kidneyinvolvement, no retinal hamartomas, and less severefacial angiofibroma72.

Both germline and somatic mutations in theTSC2genes have been demonstrated in tumors derived frompatients with TS. According to Knudson’s two-hithypothesis, this finding supports the view indicatingthat TSC genes act as tumor suppressors73, 74.

The search for mutations inTSC1andTSC2genesis only available on a research basis and performed

in selected laboratories. About 50% of familial casesare due to a mutation in theTSC1gene. Among thesporadic cases,TSC2mutations are found in over ahalf of patients, whereasTSC1mutations account forabout 10%.

SCHIZENCEPHALY

The malformation

Schizencephaly (cleft brain) consists of a unilateralor bilateral full thickness cleft of the cerebral hemi-spheres with consequent communication between theventricle and pericerebral subarachnoid spaces. Thewalls of the clefts may be widely separated and thus becalled open-lip schizencephaly (Fig. 1(g)), or closelyadjacent and known as closed-lip schizencephaly(Fig. 1(h)). The clefts may be located anywhere inthe hemispheres, but are most often found in theperisylvian region75. Bilateral clefts are usually sym-metric in location, but not necessarily in size. Septo-optic dysplasia (agenesis of the septum pellucidumand optic nerve hypoplasia) is observed in one third ofpatients76. Schizencephaly is a malformation which isdifficult to classify. At the origin of this disorder couldbe regional absence of proliferation of neurons andglia. However, schizencephalic clefts are covered bypolymicrogyric cortex and unilateral clefts are oftenaccompanied by contralateral polymicrogyria, whichcould indicate a disorder of cortical organization1, 6.

The clinical and epileptic spectrum

Since schizencephaly has a wide spectrum of anatomicpresentations, the associated clinical findings likewisecover a broad range. Patients with bilateral clefts,usually have microcephaly and severe developmentaldelay with spastic quadriparesis75, 77. Open lip cleftsresultin more severe impairment. Seizures, present inmost patients, usually begin before 3 years of age.Unilateral clefts are accompanied by a much lesssevere clinical phenotype. Small, unilateral closed lipclefts may be discovered on MRI performed after theonset of seizures in otherwise normal individuals75.Epilepsyis estimated to occur in 81% of patients, inequal proportion with unilateral or bilateral clefts77.Early seizure onset and seizure intractability aremore frequent when the malformation is bilateral.All reported patients had partial epilepsy, with nodistinctive electroclinical patterns.


Genetic basis and genetic testing

Yakovlev and Wadsworth78 proposed a pathogenetictheorybased on local failure of induction of neuronalmigration from the ventricular zone, which should oc-cur at 30–60 days of gestation. Barkovich and Kjos75,held that ischemic damage occurring during earlygestation (before the 25th week, as there are no signsof gliosis) could cause focal necrosis with destructionof the radial glial fibers and therefore abnormalities ofneuronal migration such as unlayered polymicrogyriaand gray matter heterotopia. Such causes would beexogenous, and occur with non-familial distribution.However, recent reports indicate that schizencephalymay have familial occurrence79–81, suggesting apossiblegenetic origin. A candidate gene approachled to identification of germline mutations in thehomeobox geneEMX2 in some sporadic and familialcases81, 82. The mouseEMX2 geneis homologous tothe Drosophila ems(empty spiracles) gene, which,when mutated, is responsible for developmental defectin fly-brain segmentation83. Similarly to the otherhomeotic genes,EMX2 is a transcription factor. Itacts as a regulatory gene, and its mouse analog isspecifically expressed in proliferating neuroblasts ofthe developing cerebral cortex84. The humanEMX2gene maps to chromosome 10q26.1. Heterozygousmutations in theEMX2 gene were reported in 13patients with schizencephaly85. All mutations whichhave been described, including those observed in twobrothers, werede novo, as they were not observedin their healthy parents. Severe mutations (frameshiftor splicing mutations) were associated with severebilateral schizencephaly, whereas missense mutationswere associated with a milder cortical abnormality85.The molecular analysis relies on the sequencing ofthe coding region of theEMX2 gene, which canbe performed in research laboratories. However, atpresent, there is no clear indication on the possiblepattern of inheritance of schizencephaly (althoughmutations are assumed to be dominant) and on thepractical usefulness that mutation detection in anindividual with schizencephaly would carry in termsof genetic counselling.

POLYMICROGYRIA

The term polymicrogyria designates an excessivenumber of small and prominent convolutions spacedout by shallow and enlarged sulci, giving the corticalsurface a lumpy aspect3. Although it may be difficultto recognise mild forms of polymicrogyria on MRIscan86, cortical infolding and secondary, irregular,thickening due to packing of microgyri represent quitedistinctive MRI characteristics6, 87.

Microscopically two histological patterns ofpolymicrogyria are recognized. In unlayeredpolymicrogyria, the external molecular layer iscontinuous and does not follow the profile of theconvolutions, and the underlying neurons haveradial (or vertical) distribution but no laminarorganization88. Its aspect suggests an early disruptionof normal neuronal migration with subsequentdisordered cortical organization. By contrast, four-layered polymicrogyria is believed to result fromperfusion failure, occurring between the 20th and 24thweeks of gestation. The two types of polymicrogyriamay co-occur in contiguous cortical areas89,indicatingthat they may comprise a single spectrum.

Polymicrogyria may have a focal or regionaldistribution or involve the whole cortical mantle.There is consequently a wide spectrum of clinicalmanifestations which includes children with severeencephalopathies and intractable epilepsy or normalindividuals with selective impairment of cognitivefunctions in whom the mild cortical abnormality isonly detected on pathological brain study90.

Several malformation syndromes featuring bilat-eral polymicrogyria have been described, includingbilateral perisylvian polymicrogyria91 (Fig. 1(i)), bi-lateralparasagittal parietooccipital polymicrogyria92,bilateral frontal polymicrogyria93 and unilateralperisylvian or multilobar polymicrogyria86. Severaldistinct entities might exist with regional distributionin which contiguous, non-overlapping areas of thecerebral cortex are involved, possibly under the in-fluence of regionally expressed developmental genes.Consistent familial recurrence has been reported onlyfor bilateral perisylvian polymicrogyria94, which issporadicin the great majority of patients. A geneticbasis is also possible for unilateral polymicrogyria, atleast in some cases95.

Bilateral perisylvian polymicrogyria

This malformation involves bilaterally the gray matterbordering the sylvian fissure, which is almost verticaland in continuity with the central or postcentral sulcus.Neuropathologic studies have been performed in foursporadic cases91, 96, 97. It is unclear whether thesepathologicallydocumented cases represent a singlemalformative spectrum with the same etiology ordifferent malformations with the same topography.

Patients have facio-pharingo-glosso-masticatorydiplegia91, 98 with dysarthria. Most have mentalretardation and epilepsy. Seizures usually beginbetween age 4 and 12 years and are poorly controlledin about 65% of patients. The most frequent seizuretypes are atypical absences, tonic or atonic dropattacks and tonic–clonic seizures, often occurring


as Lennox–Gastaut-like syndromes99. A minority ofpatients(26%) have partial seizures.

Bilateral perisylvian polymicrogyria has beenreported in children born from monochorionic bi-amniotic twin pregnancies which were complicated bytwin–twin transfusion syndrome100.

Several families with multiple affected membershave been reported, indicating genetic heterogeneitywith possible autosomal recessive94, X-linked domi-nant101 and X-linked recessive102 inheritance.

Recently, four cases of polymicrogyria and deletionat 22q11.2 have been reported103–105. However, asseveral series of MRI scans of patients with 22q11.2deletion did not show a brain abnormality106, perisyl-vian Polymicrogyria is probably a rare manifestationof the 22q11 deletion spectrum.

The possible association with 22q11.2 deletions,makes FISH chromosome analysis for 22q11.2 anessential investigation in all patients with perisylvianpolymicrogyria. In view of the causal heterogeneityincluding the potential for recessive and X-linkedinheritance, parents of an affected child should begiven 25% recurrence risk. The possibility of anX-linked inheritance should be discussed in the caseof a male offspring with a recurrence risk up to 50%.

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Self-assessment questions

Whichof the following statements are true?

Question 1. Lissencephaly:

(a) Has an unknown etiology in most cases.

(b) May recur in the same family.

(c) Is related to mutations of known genes in most cases.

(d) Can usually be classified according to MRI parameters.

(e) Has a stereotyped malformative pattern irrespective from the cause.

Question 2. Genetic testing in children with lissencephaly:

(a) Should always include high resolution chromosome banding.

(b) Should be performed using direct gene sequencing first.

(c) Does not have any practical implication.

(d) Should be guided by MRI parameters.

(e) Is negative in most cases.

Question 3. Band heterotopia:

(a) Only occurs in female patients.

(b) Occurs in both sexes.

(c) Is an autosomal dominant disorder.

(d) Is an X-linked disorder in most patients.

(e) May be due to mutations of the same gene causing lissencephaly.

Question 4. Bilateral periventricular nodular heterotopia:

(a) Only occurs in the female sex.

(b) Is genetically heterogeneous.

(c) Is always sporadic.

(d) Is never sporadic.

(e) May be X-linked dominant and occur in both sexes.

Question 5. Tuberous sclerosis:

(a) Is an autosomal recessive disorder.

(b) May be caused by mutations of several different genes.

(c) Is an autosomal dominant disorder with variable expressivity.

(d) Causes late onset epilepsy.

(e) Is a major cause of infantile spasms.

Question 6. Schizencephaly:

(a) Is always unilateral.

(b) Often causes epilepsy and neurological deficits.

(c) Is always inherited.

(d) Can be diagnosed with cytogenetic analysis.

(e) Has an as yet unclear pattern of inheritance.


Question 7. Polymicrogyria:

(a) Is always bilateral.

(b) Is histologically heterogeneous.

(c) Is sporadic in most patients.

(d) May be caused by a chromosomal abnormality.

(e) May recur in the same family.


Answers

Question 1. Lissencephaly:

(a) is false.

(b) is true.

(c) is true.

(d) is true.

(e) is false.

Question 2. Genetic testing in children with lissencephaly:

(a) is true.

(b) is false.

(c) is false.

(d) is true.

(e) is false.

Question 3. Band heterotopia:

(a) is false.

(b) is true.

(c) is false.

(d) is true.

(e) is true.

Question 4. Bilateral periventricular nodular heterotopia:

(a) is false.

(b) is true.

(c) is false.

(d) is false.

(e) is true.

Question 5. Tuberous sclerosis:

(a) is false.

(b) is false.

(c) is true.

(d) is false.

(e) is true.

Question 6. Schizencephaly:

(a) is false.

(b) is true.

(c) is false.

(d) is false.

(e) is true.


Question 7. Polymicrogyria:

(a) is false.

(b) is true.

(c) is true.

(d) is true.

(e) is true.

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