Periventricular nodular heterotopia with overlying polymicrogyria

doi:10.1093/brain/awh658 Brain (2005), 128, 2811–2821

Periventricular nodular heterotopia withoverlying polymicrogyria

Gretchen Wieck,1 Richard J. Leventer,5 Waney M. Squier,6 An Jansen,7,8 Eva Andermann,7,8,9

Francois Dubeau,7,8 Anna Ramazzotti,10 Renzo Guerrini10 and William B. Dobyns2,3,4

1Department of Pediatrics, Baylor College of Medicine, Houston, TX, Departments of 2Human Genetics, 3Neurology and4Pediatrics, The University of Chicago, Chicago, IL, USA, 5Department of Neurology and Murdoch Children’s ResearchInstitute, Royal Children’s Hospital, University of Melbourne, Victoria, Australia, 6Department of Neuropathology, RadcliffeInfirmary, Oxford, UK, 7Neurogenetics Unit, Montreal Neurological Hospital and Institute and Departments of 8Neurologyand Neurosurgery and 9Human Genetics, McGill University, Montreal, Quebec, Canada and 10Division of Child Neurologyand Psychiatry, University of Pisa and IRCCS Fondazione Stella Maris, Pisa, Italy

Correspondence to: William B. Dobyns, MD, Department of Human Genetics, The University of Chicago,Room 319 CLSC, 920 E. 58th Street, Chicago, IL 60637, USAE-mail: [email protected]

Polymicrogyria (PMG) and periventricular nodular heterotopia (PNH) are two developmental brainmalformations that have been described independently in multiple syndromes. Clinically, they present withepilepsy and developmental handicaps in both children and adults. Here we describe their occurrence togetheras the twomajor findings in a group of at least three corticalmalformation syndromes.We identified 30 patientsas having both PNH and PMG on brain imaging, reviewed clinical data and brain imaging studies (or neuro-pathology summary) for all, and performed mutation analysis of FLNA in nine patients. The group was dividedinto three subtypes based on brain imaging findings. The frontal-perisylvian PNH–PMG subtype included eightpatients (seven males and one female) between 2 days and 10 years of age. It was characterized by PNH liningthe lateral body and frontal horns of the lateral ventricles and by PMGmost severe in the posterior frontal andperisylvian areas, occasionally with extension to the parietal lobes beyond the immediate perisylvian cortex.The posterior PNH–PMG subtype consisted of 20 patients (15 male and 5 female) between 5 days and 40 yearsof age. It was characterized by PNH in the trigones, temporal and posterior horns of the lateral ventricles, andPMG most severe in the temporo-parieto-occipital regions. The third type was found in 2 females aged 7months and 2 years, and was characterized by severe congenital microcephaly and more diffuse corticalabnormality. The PNH–PMG subtypes described here have distinct imaging and clinical phenotypes thatsuggest multiple genetic aetiologies involving defects in multiple genes, and a shared pathophysiological mech-anism for PNH and PMG. The frontal-perisylvian and posterior subtypes both had skewing of the sex ratiotowards males, which suggests the possibility of X-linked inheritance. Delineation of these syndromes will alsoaid in providing more accurate diagnosis and prognostic information for patients with these malformations.

Keywords: heterotopia; microcephaly; periventricular nodular heterotopia; polymicrogyria; epilepsy; X-linked

Abbreviations: MIC = microcephaly; PMG = polymicrogyria; PNH = periventricular nodular heterotopia

Received March 8, 2005. Revised September 2, 2005. Accepted September 12, 2005

IntroductionPeriventricular nodular heterotopia (PNH) consist of bilateral

subependymal nodules of grey matter found along the walls of

the lateral ventricles that typically protrude into the lumen.

They result from the failure of clusters of neurons to migrate

away from the embryonic ventricular zone to the developing

cortex. Polymicrogyria (PMG) is a cortical malformation

characterized by numerous small 2–3 mm gyri (microgyri)

separated by shallow sulci with fusion of adjacent molecular

layers, excessive cortical folding and abnormal cortical cyto-

architecture. On brain imaging studies, PMG appears as

thickened and irregular cortex with variably visible microgyri.

Submicroscopic heterotopia have been associated with PMG

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(Battaglia, 1996), but grossly visible heterotopia are uncom-

mon, although this association has rarely been reported

(Dubeau et al., 1995).

We reviewed clinical and imaging or pathological data on

48 patients, who had both PNH and PMG, and found

30 patients with one of three distinct malformation subtypes

distinguished by (i) frontal-perisylvian predominant PNH

and PMG, (ii) posterior predominant PNH and PMG, or

(iii) severe congenital microcephaly (MIC) with PNH and

PMG. As many patients with PNH have had mutations in

the Filamin-A (FLNA) gene, mutation analysis of FLNA was

carried out on nine of these patients.

Patients and methodsPatientsPatients were identified through our Brain Malformation Research

Project database, which contains data on 3776 patients with various

brain malformations as of January 7, 2005. Referrals came from

physicians, genetic counsellors and directly from parents, typically

based on abnormal brain imaging obtained during investigations of

infants and children for developmental delay, mental retardation or

seizures. This includes 166 patients with PNH and 765 with PMG.

We reviewed MRI studies on all patients previously classified as

having either PMG or PNH, and identified 48 whose brain imaging

showed both PNH and PMG. Many had other brain abnormalities as

well, especially, of the hippocampus, corpus callosum or cerebellum.

MethodsThe clinical records and brain imaging studies of these patients were

reviewed with attention to age at last follow-up (or death, if

deceased), developmental course, exam findings, seizure history,

family history and specific genetic testing.

Mutation screening and when indicated sequencing of all coding

exons and surrounding intronic regions of FLNA were performed as

previously described (Guerrini et al., 2004). In brief, WAVE dHPLC

with patient DNA was carried out according to the manufacturer’s

specifications (Transgenomic, La Jolla, CA). The 47 exons covering

the coding region of FLNA and their respective intron–exon bound-

aries were amplified by PCR. Primer sequences, PCR conditions and

dHPLC analysis temperatures are available on request. Amplicons

from male subjects were mixed with half volume of PCR product of

the same FLNA region amplified by the same conditions using DNA

from an unaffected female. PCR products that showed an altered

dHPLC elution profile were purified using the GenElute PCR clean-

up kit (Sigma Aldrich, St Louis, MO) and then cycle sequenced on

both strands using BigDye Terminator versus 1.1 chemistry (Applied

Biosystems, Foster City) and an ABI310 automated sequencer.

ResultsWe identified three major subtypes of malformation by brain

imaging (always MRI) or autopsy (two patients). Combined

PNH–PMG most severe in the frontal and perisylvian regions

was found in 10 children, with adequate records for review in

eight. PNH and PMG most severe in the temporal, parietal

and occipital regions was found in 21 patients including two

adults, but adequate records were not available for one of

them so we present data on 20 patients. Finally, a

PNH–PMG subtype associated with severe congenital MIC

and a diffuse cortical abnormality was seen in two unrelated

children. The 15 remaining patients with combined PNH and

PMG had suboptimal brain imaging studies or very variable

patterns of malformation that did not fit into well-defined

groups and were excluded from further analysis.

The clinical and brain imaging features in these 30 patients

are summarized in Table 1, and presented in detail in

Table 1 Clinical features of PNH–PMG subtypes

Phenotypes Frontal-PS Posterior MIC

SexMale 7/8 15/20 0/2Female 1/8 5/20 2/2

Motor delayTotal 7/7 16/19 2/2Mild 2 8 0Moderate 1 5 0Severe 4 3 2

Language delayAll 7/7 16/16 2/2Mild 2 9 0Moderate 1 4 0Severe 4 3 2

Abnormal toneTotal 5/5 11/17 2/2Spasticity 1 2 2Hypotonia 4 9 0Seizures and onsetTotal 6/6 10/17 1/20–1 month 1 2 11–12 months 4 5 01–10 years 1 1 011–16 years 0 2 0

Seizure typesAny type 6/7 10/17 1/2Infantile spasms 3 0 0Generalized 1 3 1Complex partial 1 9 0

Abnormal head sizeTotal 2/8 7/14 2/2Microcephaly 1 2 2Macrocephaly 6 0 0

Other brain malformationTotal 7/8 19/20 2/2ACC 2 7 1CVH or CBLH 3 13 1HIP 5/5 10/10 2

Brain asymmetryTotal 0/8 16/20 0/2L > R 0 11 0R > L 0 5 0

Other anomaliesTotal 4/6 11/16 2/2Face anomalies 4 10 2GI anomalies 2 0 0

ACC, agenesis of the corpus callosum; CBLH, cerebellarhemisphere hypoplasia; CVH, cerebellar vermis hypoplasia; GI,gastrointestinal; HIP, hippocampus; L > R, left more severe thanright; MIC, microcephaly; PS, perisylvian; R > L, right more severethan left.

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Supplementary Table 1. Representative MRI images are

shown in Figs 1–4 and Supplementary Fig. 1, pathological

images (for the posterior subtype) in Fig. 5 and representative

photographs in Supplementary Fig. 2.

The frontal-perisylvian PNH–PMGsubtypeImaging characteristicsThis subtype had a pattern of malformation (Fig. 1) that was

clearly distinguishable from the posterior subtype. We iden-

tified five characteristic imaging findings that define this

group, as follows.

Bilateral PNH along the bodies of the lateral ventricles.

All eight children had PNH present along the bodies of the

lateral ventricles, ranging from the anterior portions only to

the entirety of the lateral walls. Four children also had PNH

along the lateral portions of the frontal horns. None had

heterotopia in the posterior or temporal horns. The PNH

nodules ranged from small (1–3 mm) to moderate (4–6 mm)

in size. The number of heterotopia ranged from a few scat-

tered or non-contiguous nodules, to contiguous nodules lin-

ing most of the lateral walls. The PNH was seen bilaterally in

all patients and was typically symmetrical.

Perisylvian PMG. The PMG was always most severe over the

perisylvian regions and extended into the posterior frontal

lobes in six of eight patients and into the anterior frontal lobes

in only one boy (Patient 22). None had convincing extension

into the posterior parietal, temporal or occipital regions. The

appearance was typical of PMG by brain imaging, consisting

of a pebbled brain surface, irregular gyral pattern with or

without obvious microgyri, large infolded gyri and moder-

ately thick (5–10 mm) cortex.

Hippocampal malformation. We were only able to obtain

adequate coronal images of the hippocampus in three patients

and suboptimal images in two others. However, the hippo-

campi in these patients appeared mildly globular with poor

organization of the surrounding cortex that suggests a mild

Fig. 1 Magnetic resonance images of the frontal-perisylvian PNH–PMG subtype from Patients 27/LR01-369 (A–D), 24/LR01-165 (E–H) and21/LP99-023 (I–L). Midline sagittal images demonstrate partial agenesis of the corpus callosum due to absent rostrum and splenium(downward pointing arrowheads in A and E) and mild cerebellar vermis hypoplasia (upward pointing arrowheads in A and E) in twopatients, while both of these structures were normal in the third patient shown (I). In the remaining parasagittal (B, F and J), axial (C, G andK) and coronal (D, H and L) images, all black arrows point to nodular heterotopia lining the walls of the lateral ventricles, while all whitearrows point to areas of PMG including the extended sylvian fissures characteristic of perisylvian involvement (F and J).

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developmental anomaly (Supplementary Fig. 1) that is less

severe than seen in the posterior form.

Hemispheric symmetry. In this subtype the malformation

was always bilateral and showed a generally symmetrical dis-

tribution between hemispheres. The lateral ventricles were

often mildly enlarged but were regularly shaped and symmet-

rical, in contrast to the posterior form.

Frequent callosal and occasional cerebellar abnormalities.

Malformations of the corpus callosum and cerebellum

occurred in this subtype, but were less frequent than in

the posterior subtype of PNH–PMG. This included partial

ACC in two patients, none with complete ACC, and CVH

in three patients, only one of whom had symmetrical cere-

bellar hemisphere hypoplasia. Another four had thin corpus

callosum, but all were very young so this is probably not

significant.

Clinical characteristicsAt last follow-up, the eight children in this group were

between 7 months and 6 years of age, and there was one

death at 2 days of life (further clinical details for this child

were not available). The sex ratio was skewed towards

males with seven males and one female, which just reaches

statistical significance (x2 = 4.50 with one degree of freedom,

P = 0.034).

Development. In comparison to the patients with posterior

PNH–PMG, patients with the frontal-perisylvian subtype ten-

ded to have more severe delay in both cognitive and motor

development. Of the seven children younger than 3 years,

three were 2–6 months behind in reaching typical motor

and speech milestones. The other four patients had severe

motor and speech delay, with no head control or postural

development and no speech development at ages 7 months

Fig. 2 Magnetic resonance images of the posterior PNH–PMG subtype from Patients 16/LR03-157 (A–D), 5/LR00-086 (E–H) and6/LR00-120 (I–L). Midline sagittal images demonstrate severe partial agenesis of the corpus callosum in one patient (downwardpointing arrowhead in E), and severe cerebellar vermis hypoplasia in two patients (upward pointing arrowheads in E and I), while bothstructures were normal in the third patient shown (A). Coronal images show mild hypoplasia of the right (H) or left (L) cerebellarhemispheres in the same patients with vermis hypoplasia. In the remaining parasagittal (B, F and J), axial (C, G and K) and coronal (D, H andL) images, all black arrows point to nodular heterotopia lining the walls of the lateral ventricles, while all white arrows point to areasof PMG including an extended sylvian fissure (F). Also, the lateral ventricles were mildly asymmetric, with the left side moderately largerthan the right in all three patients (C–D, H, K–L).



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(Patient 22), 10 months (Patient 28) and 2 years (Patients 24

and 27).

Epilepsy. All of the children for whom we have adequate

history had epilepsy, which typically had an earlier onset and

greater severity compared with the posterior subtype. All five

children had onset of their seizures before 6 months of age,

and three had infantile spasms beginning between 4 and

5 months. The infantile spasms stopped following treatment

with oral prednisone in one boy, who went on to have only

mild developmental delay (Patient 21). The other two chil-

dren with infantile spasms had moderate or poor response to

treatment, and subsequently had severe delay and mental

retardation (Patients 24 and 27). Another child had early

onset, intractable myoclonic and complex partial

seizures, and also had severe delay and mental retardation

(Patient 22).

Exam. Dysmorphic features were present in four of seven

patients with this data available, and some patients had other

malformations. These included children with mild hyper-

telorism, cleft palate and bilateral hand and foot syndactyly

(Patient 21), small jaw (Patient 24), bilateral metatarsus

adductus (clubfeet), post-axial polydactyly (digiti minimi)

and small bowel rotation (Patient 25), and hypertelorism,

microphthalmia and micropenis with cryptorchidism

(Patient 27). Two patients had congenital MIC with head

circumference �3 SD below the mean at birth, and one

Fig. 3 Magnetic resonance images of the posterior PNH–PMG subtype in Patients 2/LP98-080 (A), 3/LP98-130 (B), 12/LR02-422 (C) and18/LR03-379 (D). Coronal images show striking malformations of the hippocampi and surrounding gyri. The hippocampi (arrows in A–D)all appear round or globular, and vertically oriented when this can be seen (B–D). The border is often indistinct and the surroundinggyri and collateral sulci difficult to identify.

Fig. 4 Magnetic resonance images of the microcephalic PNH–PMG subtype from Patients 29/LR01-173 (A–D) and 30/LR03-131 (E–H).Midline sagittal images show severe partial agenesis of the corpus callosum (downward pointing arrowhead in A) in one, and mildly enlargedcisterna magna (upward pointing arrowhead in E) in the other. In the remaining parasagittal (B and F) and axial (C, D, G, H) images, allblack arrows point to nodular heterotopia lining the walls of the lateral ventricles, while all white arrows point to areas of PMG, presentdiffusely in both patients. The frontal lobes are very small in both patients (B and F).



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6-year-old boy had post-natal macrocephaly. Most of these

children had axial hypotonia, or mixed central hypotonia with

limb spasticity. Typical facial features are seen in Supplement-

ary Fig. 2B.

Family history and genetic testing. Four children had

second-generation and third-generation relatives with over-

lapping features, such as macrocephaly, dysmorphic features

and mental retardation, but none was known to have PNH or

PMG. One boy (Patient 24) had a balanced translocation

between Chromosomes 1 and 6, but this is probably unrelated

to his phenotype as his normal father carries the same trans-

location (Leeflang et al., 2003). Chromosome analysis and

fluorescence in situ hybridization (FISH) with a subtelomeric

probe set were normal in three and one patient, respectively.

Mutation screening of FLNA in four patients was normal,

although two of them had polymorphisms detected (Supple-

mentary Table 1).

The posterior PNH–PMG subtypeImaging characteristicsThe posterior subtype was characterized by a posterior more

severe than anterior as well as an inferior more severe than

superior gradient of malformation (Fig. 2). The one patient

with pathological (post-mortem) but not imaging data had a

similar gradient of malformation. The five defining imaging

characteristics of this subtype are detailed below.

Bilateral posterior predominant PNH. All 20 patients in this

group had PNH that was most prominent along the posterior

bodies, trigones, temporal horns and posterior horns of the

lateral ventricles. In six patients, the PNH was also present in

the lateral body of the lateral ventricles, most noticeable pos-

teriorly, and two patients had isolated nodules in one frontal

horn. The nodules ranged in size from small (1–3 mm) to

large (>7 mm), were always multiple and bilateral, and could

be either contiguous or non-contiguous (‘pearls on a string’)

along the ventricular wall.

Posterior predominant PMG overlying the heterotopia. All 20

patients in this group had extensive PMG that was clearly

most severe over the temporal, parietal and occipital lobes

with frequent extension to the perisylvian region (14 out of

20) and sometimes to the posterior frontal lobes (5 out of 20).

None had PMG visible in the anterior frontal lobes. The PMG

was always found overlying areas of PNH, and appeared as

areas of thickened and irregular cortex, typically 5–10 mm

(Fig. 2). Most had obvious microgyri and microsulci, typically

with large infolded gyri, or a simplified and poorly organized

gyral pattern without obvious microgyri, usually with scans of

Fig. 5 Gross (A and B insert) and microscopic (B and C) photosfrom the brain of Patient 1/LP98-023, who had the posterior formof PNH-PMG. A coronal slice through the fixed brain (A) shows adiffusely undersulcated cerebral surface, and moderately enlargedlateral ventricles with nodular heterotopia in the walls (whitearrows). H&E stain (black arrow in B insert) demonstrates aninfolded sulcus with polymicrogyria. Photomicrograph ofpolymicrogyric cortex shows multiple shallow sulci and fusedgyri (asterisks in B). Photomicrograph of the ventricular walldemonstrates several heterotopic nodules bulging into the lateralventricles (black arrows in C).



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lower resolution. In either case, an irregular or blurred

grey–white junction was seen.

Hippocampal malformation. In all patients with good cor-

onal images, the hippocampi appeared rounded or globular

with thick lamina (Ammon’s horn and dentate gyrus) and

more vertically oriented than usual. The margins were often

indistinct, surrounding landmarks such as the collateral sulci

difficult to find, and the temporal horns moderately enlarged

(Fig. 3).

Hemispheric asymmetry. The malformation was bilateral in

all patients, although it appeared asymmetric in 16 of

20 patients. The left side was more severely affected than

the right in 11 of 16 patients, which is interesting but this

does not reach statistical significance (x2 = 2.25 with one

degree of freedom, P = 0.134). The lateral ventricles were

often dysmorphic, especially posteriorly, and were also asym-

metrical in most patients.

Callosal and cerebellar abnormalities. Malformations of the

corpus callosum or cerebellum were common, with total or

partial agenesis of the corpus callosum (ACC) alone found in

2 out of 20, cerebellar vermis hypoplasia (CVH) alone in 8 out

of 20, and both ACC and CVH in 5 out of 20. Of the

13 patients with CVH, 6 also had hypoplasia of the cerebellar

hemispheres, which was asymmetric in four patients, usually

contralateral to the more severely affected cerebral hemi-

sphere. The two patients with symmetrical cerebellar hemi-

sphere hypoplasia also had brainstem hypoplasia.

Brain pathologyBrain pathology was available for Patient 1, who died at 5 days

of life (Fig. 5). Histological examination confirmed extensive

PMG that was most prominent posteriorly and largely spared

the anterior frontal lobes. In polymicrogyric regions of cortex,

adjacent molecular layers were fused, neurons were sparse and

their arrangement was abnormal with scattered large pyram-

idal cells in the deepest layers. The subcortical white matter

was sparse with multiple, almost confluent, ectopic neuronal

nodules in the subependymal zones. There were many single

neurons scattered in the white matter. No corpus callosum

was seen. The cerebellum was well formed with normal-

appearing cortex, and no ectopic cells were seen in the cere-

bellar white matter.

Clinical characteristicsThe 20 patients in this subtype ranged in age from 5 days to

40 years of age at the time of last follow-up. There were two

deaths in the group: one at 5 days and another at 7 months.

The sex ratio was skewed towards males with 15 males and

5 females, which is potentially important as it reaches stat-

istical significance (x2 = 5.00 with one degree of freedom,

P = 0.025).

Development. Motor delay was observed in 16 of the 19 chil-

dren with available data and was mild or moderate in all but

one child. This child (Patient 12) had poor head control,

no sitting with support and no purposeful hand use, and

died at 7 months from pneumonia. The 13 patients with

mild or moderate delay invariably had delayed sitting and

standing in the first year, although all children older than

2 years were cruising or walking. Motor function in children

older than 2 years ranged from walking with mild ataxia and

poor self-feeding at 3 years (Patient 6), to normal motor

function (Patients 10 and 11). All children under 2 years of

age had mild to moderate speech delay, while all but one

(Patient 15) of the children who were older than 2 years of

age at last follow-up had developed some speech. Language

expression tended to be more affected than comprehension.

An older child (Patient 3) had language at a 4 year level at

8 years of age, while the two adults had mild mental retarda-

tion (Patient 10) or borderline to normal intelligence and

dysarthria (Patient 11).

Exam. Dysmorphic features were present in 11 of 17 chil-

dren for whom we had data. Two had cleft lip or palate, two

had hypertelorism, two had flat mid-face, and one each had

hypothalamic dysfunction, partial bowel malrotation, talipes

equino-varus, hydronephrosis at birth, micropenis or small

feet. Six children had significant macrocephaly (>3 SD above

the mean). Of the 17 patients for whom data were available,

five had normal neurological exams at the time of last follow-

up, although several older children were reported to have been

hypotonic as infants. Nine had axial hypotonia and two had

spasticity, including one 8-month-old boy with left hemi-

paresis. Typical facial features are shown in Supplementary

Fig. 2A.

Epilepsy. Ten patients had epilepsy. All but one had com-

plex partial seizures, and three also had generalized seizures

including one with disabling atonic seizures. In contrast to the

frontal-perisylvian subtype, none had infantile spasms or

myoclonic seizures. Most had onset of seizures in the first

year, while the two adults had onset in adolescence. Seven

children had no seizures reported at the time of last follow-up,

but all were 3 years of age or younger. Seizure control with

anticonvulsant medications was variable (Supplementary

Table 1).

Family history and genetic testing. None of these patients

had a relative with PNH or PMG recognized, and only the two

adults were known to have first-degree or second-degree relat-

ives with epilepsy. All of the genetic tests reported for these

patients were normal, including normal chromosomes in

three of the children, and normal telomeric FISH testing

in one child. Testing for FLNA mutations was negative in

four patients, although two polymorphisms were identified

(Supplementary Table 1).

The MIC-PNH–PMG subtypeImaging characteristicsTwo girls (Patients 29 and 30) had another novel subtype of

PNH–PMG characterized by severe congenital MIC. The key

features of this new subtype consist of (i) severe congenital

MIC, (ii) PNH in the posterior trigones and temporal horns,



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(iii) diffuse PMG that is most severe in the temporal and

parietal lobes, (iv) symmetrical appearance of the malfor-

mation and (v) mild and variable hypoplasia of the corpus

callosum and cerebellar vermis (Fig. 3). We did not have good

images of the hippocampi, although the entire anterior tem-

poral lobes appeared malformed. The PMG was characterized

by an irregular and simplified gyral pattern and dysplastic but

only minimally thickened cortex. One girl had partial ACC

(Patient 29), while the other had a mildly enlarged cisterna

magna (Patient 30).

Clinical characteristicsThese two girls had birth head circumferences of 28.5 and

29.5 cm, which are 4–6 SD below the mean for age. At the

time of their last follow-up at 7 months and 2 years of age,

respectively, their neurological exams were significant for

truncal hypotonia, limb spasticity, no postural development

and no speech. Both had subtle dysmorphic facial features

(Supplementary Fig. 1C). One had generalized seizures from

birth, while the other had had no seizures in the first 2 years

of life. Genetic testing included normal chromosomal analysis

in both girls. FLNA mutation analysis was negative for

Patient 29.

DiscussionWe have reviewed a large series of patients with both PNH and

PMG on brain imaging (or pathologic examination), and

identified three distinct subtypes with different patterns of

brain involvement and outcome. When first ascertained,

these subjects were variably classified as having heterotopia,

PMG, ACC or cerebellar hypoplasia, so that our recognition

of these patterns did not occur until after numerous improve-

ments in our database search parameters over the past several

years. As we have gained experience, we have come to believe

that the core phenotype for each of these subtypes is specific

and recognizable, supporting a common pathogenesis.

The skewing of the sex ratio that we observed in both the

frontal-perisylvian and posterior forms further supports this

viewpoint.

Alternative explanationsGiven the variability within the first two subtypes and the

overlap between all three subtypes, we should formally con-

sider alternative explanations. First, the co-occurrence of

PNH and PMG could occur by chance alone. Second, these

malformations, especially the frontal-perisylvian and poster-

ior subtypes, could represent a single spectrum with marked

variability in regional involvement. Finally, the PNH–PMG

syndromes could be simple variants of known isolated PNH

or isolated PMG syndromes. We believe that these alternative

explanations are all highly unlikely.

We first consider whether co-occurrence of PNH and

PMG could result from chance alone. While no reliable

data regarding the incidence of PNH is available, the rate

of PMG is at least 1 · 10�5 based on data from the

Metropolitan Atlanta Congenital Defects Program (National

Center on Birth Defects and Developmental Disabilities,

Centers for Disease Control and Prevention, Atlanta, GA,

2002, personal communication). Using this rate, we would

expect to find no patients with PMG among the 166 subjects

with PNH in our database (166 · 10�5 = 0.002). Yet we found

51 patients, a number far greater than could be accounted for

by chance alone. Further, the co-occurrence of PNH and

PMG was not evenly distributed across known subtypes of

PMG. We found PNH in 10 out of 326 patients with peri-

sylvian PMG, in 23 out of 41 patients with various posterior

predominant forms of PMG, in 0 of 25 with PMG and diffuse

abnormal white matter (a novel form of PMG) and 0 out of 98

with schizencephaly and PMG. Similarly, we found no

patients with PNH among the �1000 patients with lissen-

cephaly subtypes in our large database.

The shared malformations, consisting of PNH and PMG

often associated with ACC and CVH, and the excess of males

suggest that the frontal-perisylvian and posterior subtypes

could be the same syndrome. While this is possible, we

found significant difference in the frequency of callosal and

cerebellar anomalies, and much more frequent asymmetry in

the posterior form. We think this is sufficient to support

separate classification. Also, the PNH–PMG syndromes

appear to be distinct from other recognized syndromes

with PNH (with one possibly important exception) or

PMG only, as we will review below.

Comparison of PNH–PMG subtypesThe group of patients with PNH and PMG shared several

broad clinical characteristics. All had motor and cognitive

delay or impairment, and most had seizures. However, the

two major subtypes differed in several aspects, which may

result from involvement of different brain regions such as

the motor and premotor areas in the frontal-perisylvian syn-

drome. The frontal-perisylvian subtype had earlier presenta-

tion of developmental delay and relatively frequent infantile

spasms, while the posterior subtype had more favourable

developmental outcomes, such as a higher likelihood of even-

tually achieving ambulation and speech, and none had infant-

ile spasms. These results suggest that earlier onset of seizures

and seizure types, especially infantile spasms, are related to

poor developmental outcome in these patients. However, the

substantially younger ages at last follow-up for the frontal-

perisylvian subtype hinders comparison of developmental

outcome in these two groups.

Within the frontal-perisylvian subtype, the extent of the

PMG correlated with the clinical severity, as more extensive

malformations were associated with more severe phenotypes.

However, the posterior subtype had a less severe phenotype in

comparison with the perisylvian form, and in this group,

neither involvement of the perisylvian region nor extent of

the malformation as seen on MRI always correlated with a

more severe neurological phenotype. The only possible trends



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within this posterior group were that: (i) the presence of

bilateral and symmetrical cerebellar hemisphere hypoplasia

and/or brainstem involvement were associated with worse

outcomes and (ii) patients with normal cerebellum and cor-

pus callosum were less severely affected. The third subtype,

MIC-PNH–PMG, had less cortex overall, and the entire cor-

tex seemed to be affected. As we would have expected given

the extent of the malformation, these two patients had severe

mental retardation. However, these observations all represent

trends, as our patient numbers were too low to reach statist-

ical significance. Identifying and analysing data from a larger

group of patients will be important in developing guidelines

for counselling the families of these children.

Comparison to known PMG types and syndromesA growing list of PMG types and syndromes have been

observed, most of which have not been completely delineated.

These include frontal PMG (Guerrini et al., 2000), fronto-

parietal atypical PMG with abnormal white matter and

brainstem-cerebellar hypoplasia (Chang et al., 2003), peri-

sylvian PMG (Kuzniecky et al., 1993; Guerreiro et al.,

2000), mesial parieto-occipital PMG (Guerrini et al., 1997),

lateral parieto-occipital PMG and multilobar PMG

(Barkovich et al., 1999; Guerrini et al., 1998; Leventer et al.,

2001). We have also seen new subtypes with perisylvian PMG

associated with diffuse white matter signal abnormalities or

with parasagittal PMG (W. B. Dobyns, unpublished data). Of

these, the PNH–PMG frontal-perisylvian subtype clearly

resembles pure perisylvian PMG (without heterotopia),

which has also been designated the ‘congenital bilateral peri-

sylvian syndrome’ (Kuzniecky et al., 1993). This syndrome

accounts for >60% of all PMG based on our review of

220 patients (Leventer et al., 2001). However, the PMG

appears to be more severe in the anterior perisylvian regions

in the PNH–PMG perisylvian subtype, while it is typically

more severe in the posterior perisylvian regions in pure peri-

sylvian PMG. Also, PNH have not been seen in PMG syn-

dromes with recognized genetic abnormalities such as

X-linked perisylvian PMG or PMG with deletion 22q11.2

(Bingham et al., 1998; Bird and Scambler, 2000; Guerreiro

et al., 2000; Kawame et al., 2000; Worthington et al., 2000;

Ghariani et al., 2002; Ehara et al., 2003; Koolen et al., 2004;

Sztriha et al., 2004). The posterior PNH–PMG subtype

resembles a very rare posterior form of PMG without

PNH, but the latter has not been associated with callosal

or cerebellar hypoplasia (Ferrie et al., 1995).

Comparison to known PNH syndromes(with macroscopic PNH)PNH have been observed in several malformation syndromes,

but the most common of these appears to be X-linked PNH

that affects females predominately and males rarely, and is

associated with mutations of the FLNA gene (Dobyns et al.,

1996; Fox et al., 1998; Poussaint et al., 2000; Guerrini et al.,

2004). The heterotopia in patients with FLNA mutations typ-

ically line the lateral borders of the bodies and trigones of the

lateral ventricles, occasionally with a few nodules along the

frontal and posterior horns, none along the medial borders of

the bodies and very few in the temporal horns (Poussaint et al.,

2000). This distribution is very similar to the distribution of

heterotopia seen in the frontal-perisylvian PNH–PMG sub-

type, but none of these patients have had the pronounced and

symmetrical PMG seen in the frontal-perisylvian PNH–PMG

subtype. No females with PNH due to FLNA mutations have

had PMG. One possible explanation for the excess of affected

males in the PNH–PMG syndromes would be mutations of

FLNA in males. In a small group of six males with PNH and

known FLNA mutations, all had similar distribution of PNH

but no PMG, except for one boy who died in the first week of

life and had a small area of PMG in the insular cortex on one

side found at autopsy (Sheen et al., 2001; Guerrini et al.,

2004). The other phenotypic feature that may help distinguish

these two syndromes is the presence of the callosal hypoplasia,

which is common in both PNH–PMG syndromes but rare in

patients with FLNA mutations (Poussaint et al., 2000).

Several other PNH syndromes and loci have also been

described. At least three families with autosomal recessive

PNH have been reported; affected individuals from two of

the three families had MIC and severe neurological abnor-

malities but PMG was not described. Mutations of ARFGEF2

were found in both families (Sheen et al., 2003a, 2004). Affec-

ted individuals of both sexes from the remaining family had

contiguous PNH and epilepsy but normal development.

No PMG was described (Sheen et al., 2003a). Two apparently

distinct loci have been associated with small duplications of

Chromosome 5. These include a patient with a few frontal

PNH and severe mental retardation with dup 5p15.1, and

another with more diffuse PNH and a few subcortical nodular

heterotopia with dup 5p15.33 (Sheen et al., 2003b). At least

one syndrome with PNH, mental retardation and limb anom-

alies has been described in four boys (Dobyns et al., 1997; Fink

et al., 1997). One of these boys had a small duplication of

Xq28 that included FLNA [Patient 1 in (Dobyns et al., 1997)],

while another, upon further review, does appear to have PMG

in the perisylvian region [Patient 2 in (Dobyns et al., 1997)].

Another syndrome with PNH, mild mental retardation and

frontonasal dysplasia has also been described in two boys

(Guerrini and Dobyns, 1998). In addition, girls with Aicardi

syndrome, which consists of ACC, chorioretinal lacunae,

mental retardation and infantile spasms in females,

may also have periventricular or subcortical heterotopia

(Aicardi, 2005; Aicardi et al., 1965).

Possible X-linked inheritanceIn compiling our data, we noticed that more males than

females were affected in both the frontal-perisylvian and pos-

terior subtypes of PNH–PMG. These ratios just reached stat-

istical significance (P-values of 0.034 and 0.025) and suggest

that one or both may have X-linked inheritance. Review of



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brain imaging studies from published families with known

X-linked perisylvian PMG demonstrated no visible hetero-

topia (Borgatti et al., 1999; Guerreiro et al., 2000).

However, we have recently recognized a syndrome consist-

ing of posterior PNH, hippocampal malformation and severe

cerebellar hypoplasia (Ramazzotti A, Guerrini R, unpublished

data). All patients have had PNH lining the lateral walls of the

temporal horns and atria of the lateral ventricles, normal

cognitive development and severe cerebellar hypoplasia.

This differs from the posterior subtype of PNH–PMG

owing to a less severe cortical malformation with no PMG

and more severe cerebellar hypoplasia. The sex ratio in this

syndrome may be skewed towards females with nine females

and three males. While this data does not reach statistical

significance, the trend is in the opposite direction from the

PNH–PMG syndromes. Given the similar malformations and

location seen in this group of patients and the posterior

PNH–PMG syndrome, we wonder whether they might rep-

resent male and female presentations of a single malformation

spectrum. If so, the ‘male’ phenotype of posterior PNH–PMG

should be more severe than the ‘female’ phenotype, and the

cortical malformation clearly is more severe. Yet the cerebellar

hypoplasia appears to be more severe in the ‘female’ pheno-

type, which tends to argue against this. Clearly, future studies

need to consider both syndromes.

The developmental basis of PNH and PMGThe co-occurrence of PNH and PMG may shed light on the

pathogenesis of PMG, which is poorly understood. PNH are

clusters of neurons that fail to migrate away from the embry-

onic ventricular (proliferative) zone to the developing cereb-

ral cortex and so persist as nodules of neurons that line the

ventricular surface. They thus comprise a class of malforma-

tions associated with deficient neuronal migration. PMG is a

cortical malformation characterized by numerous small 2–3

mm gyri (microgyri) separated by shallow sulci, with fusion of

adjacent molecular layers. The classic form of PMG also has

infolding of the cortex, disorganization of layers II–IV and VI

and loss of neurons in layer V, which is continuous with the

cell sparse zone of polymicrogyric cortex (Crome, 1952;

Levine et al., 1974; Ferrer, 1984).

Older reports classify PMG as a ‘neuronal migration dis-

order’, due primarily to the thick cortex, which resembles the

cortex in lissencephaly, a true migration malformation. But

the thick cortex results primarily from infolding. The cortical

ribbon is typically thinner than usual given the loss of layer

V neurons. The latter has been compared with laminar nec-

rosis, and supported by reports of PMG associated with dis-

orders potentially affecting the fetal vascular supply in the

second trimester, such as twinning (Crome, 1952; Norman,

1980; Barth and van der Harten, 1985; Sugama and Kusano,

1994) and intrauterine cytomegalovirus infections (Hayward

et al., 1991; Barkovich and Lindan, 1994; Iannetti et al., 1998;

Sener, 1998).

Our observation of PNH with overlying PMG implies that

an original disruption in neuronal migration can lead to

PMG, a mechanism very different from fetal vascular disrup-

tion. But this could be a secondary rather than a primary effect

of deficient neuronal migration. For example, it is entirely

possible that radial glia are disrupted in some or all types of

PMG. First, heterotopia may physically disrupt formation or

function of radial glia; or the presumed genetic defect may

affect neural progenitor cells, which also function as radial glia

(Noctor et al., 2001, 2002), in addition to their post-mitotic

migrating daughter cells. In this scenario, early migrating cells

arriving by somal translocation and interneurons arriving by

non-radial migration may be less affected. Further, all cells

arriving by radial migration may not be affected equally con-

sidering the different migratory phases and directional

changes known to occur (Kriegstein and Noctor, 2004).

This would differ markedly from the situation in lissen-

cephaly, in which all neuronal types appear to be affected.

Further studies in humans and animal models using gene

expression to recognize neuronal types and origins will be

needed to answer these questions.

AcknowledgementsWe would like to thank the patients and their families, as well

as their referring physicians and genetic counsellors, without

whom this study would not have been possible. This work was

supported in part by grants from the Child Neurology

Foundation to Dr Wieck, from the Fondazione Mariani

Grant R-04-35 to Drs Ramazzotti and Guerrini, and from

the NIH (NS39404) to Dr Dobyns. Dr Leventer is supported

by a Murdoch Children’s Research Institute part time salary

grant.

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