American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 166C:227–239 (2014)

A R T I C L E

Polymicrogyria: A Common and Heterogeneous Malformation of Cortical Development CHLOE A. STUTTERD

AND

RICHARD J. LEVENTER

Polymicrogyria (PMG) is one of the most common malformations of cortical development. It is characterized by overfolding of the cerebral cortex and abnormal cortical layering. It is a highly heterogeneous malformation with variable clinical and imaging features, pathological findings, and etiologies. It may occur as an isolated cortical malformation, or in association with other malformations within the brain or body as part of a multiple congenital anomaly syndrome. Polymicrogyria shows variable topographic patterns with the bilateral perisylvian pattern being most common. Schizencephaly is a subtype of PMG in which the overfolded cortex lines full‐thickness clefts connecting the subarachnoid space with the cerebral ventricles. Both genetic and non‐genetic causes of PMG have been identified. Non‐genetic causes include congenital cytomegalovirus infection and in utero ischemia. Genetic causes include metabolic conditions such as peroxisomal disorders and the 22q11.2 and 1p36 continguous gene deletion syndromes. Mutations in over 30 genes have been found in association with PMG, especially mutations in the tubulin family of genes. Mutations in the (PI3K)‐AKT pathway have been found in association PMG and megalencephaly. Despite recent genetic advances, the mechanisms by which polymicrogyric cortex forms and causes of the majority of cases remain unknown, making diagnostic and prenatal testing and genetic counseling challenging. This review summarizes the clinical, imaging, pathologic, and etiologic features of PMG, highlighting recent genetic advances. © 2014 Wiley Periodicals, Inc. KEY WORDS: polymicrogyria; schizencephaly; malformation of cortical development

How to cite this article: Stutterd CA, Leventer RJ. 2014. Polymicrogyria: A common and heterogeneous malformation of cortical development. Am J Med Genet Part C Semin Med Genet 166C:227–239.

INTRODUCTION Malformations of cortical development (MCD) are a significant cause of neurological and developmental disability. They have been diagnosed with increased frequency since the routine use of brain magnetic resonance imaging (MRI) in the workup of children with epilepsy, cerebral palsy, developmental delay, and multiple congenital anomaly syndromes. Polymicrogyria (PMG) is one of the most common brain malformations accounting for 20% of all MCD [Leventer et al., 1999]. There is a

PMG can be caused by both genetic and non‐genetic causes, with multiple chromosomal loci and causative genes described in recent years. It can be seen as an accompanying feature in numerous genetic syndromes. Despite recent advances, our understanding of this highly

heterogeneous brain malformation remains incomplete wide spectrum of both the type and severity of the clinical sequelae. PMG can be caused by both genetic and non‐ genetic causes, with multiple chromosomal loci and causative genes described in recent years. It can be seen as an accompanying feature in numerous genetic syndromes. Despite recent

Grant sponsor: Royal Children's Hospital/Murdoch Childrens Research Institute Flora Suttie Neurogenetics Fellowship made possible Thyne‐Reid Foundation and the Macquarie Foundation. Grant sponsor: Victorian State Government Operational Infrastructure Support Program. The authors have no conflict of interest to declare. Chloe A. Stutterd is a Fellow in Neurogenetics in the Murdoch Childrens Research Institute and the Department of Neurology, Royal Children's Hospital. She is a Ph.D. student in the University of Melbourne Department of Pediatrics. Richard J. Leventer is a Consultant Pediatric Neurologist and directs the Brain Malformation Clinical and Research Program in the Department of Neurology, Royal Children's Hospital and the Murdoch Childrens Research Institute. He is a Senior Lecturer in the University of Melbourne Department of Pediatrics. *Correspondence to: Richard J. Leventer, Department of Neurology, Royal Children's Hospital, Flemington Road, Parkville, Victoria, Australia 3052. Email: [email protected] DOI 10.1002/ajmg.c.31399 Article first published online in Wiley Online Library (wileyonlinelibrary.com): 28 May 2014

ß 2014 Wiley Periodicals, Inc.

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advances, our understanding of this highly heterogeneous brain malformation remains incomplete making the task of the geneticist and neurologist difficult when attempting to give accurate genetic and prognostic counseling, and to provide the most appropriate management.

TERMINOLOGY AND CLASSIFICATION Bielschowsky [1916] first used the term “polymicrogyria (PMG)” in 1916 to describe a cerebral or cerebellar cortex with multiple excessive small convolutions. Synonymous terms include micropolygyria [Haberland and Brunngraber, 1972] and microgyria [Crome and France, 1959]. PMG is not a single entity but a spectrum of cortical malformations with the common features being excessive gyration and a microscopic abnormality of cortical structure and lamination. Schizencephaly (SCZ) is one specific pattern of PMG defined by Yakovlev and Wadsworth in 1946 to describe full thickness clefts in the brain [Yakovlev and Wadsworth, 1946a,b]. These clefts must be lined by PMG to be called SCZ as opposed to porencephalic cysts, which are lined by white matter or gliosis. There is no uniform system of classification for PMG. It has been classified according to imaging patterns [Barkovich, 2010b; Leventer et al., 2010], histopathological appearance [Friede, 1989], and the presumed timing of the etiology in cortical development [Barkovich et al., 2012]. As pathological data are rarely available, the spectrum of MCD now labelled as PMG includes many disorders grouped together primarily due to a similar “overfolded” appearance of regions of the cerebral cortex on MRI, the main means by which PMG is now diagnosed. There is some overlap between true PMG and other disorders with a similar imaging appearance such as some of the cobblestone malformations, in which the term PMG has often been used to describe the malformation of the cerebral or cerebellar cortex. This “lumping together” of various malformations under the label

“PMG” is one reason why PMG is seemingly such a heterogeneous disorder with varied etiologies, imaging appearances and manifestations. For the purposes of this review, we will discuss those disorders most typically diagnosed as PMG based on their MRI appearance, as this is the means by which patients will be referred to a geneticist or neurologist for counseling and investigation of etiology. We therefore include disorders secondary to mutations in the tubulin, GPR56 and LAMC3 genes in which there is emerging evidence of overlap with the cobblestone malformations.

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PATHOLOGY Macroscopically, typical PMG appears as an irregular cortical surface with multiple small gyri and an abnormal sulcal and gyral pattern (Fig. 1A). The distribution varies significantly and includes unilateral forms and bilateral forms, with the perisylvian cortex being the most frequently affected area. Midline cortex and the hippocampus are usually spared. The clefts of SCZ can be unilateral or bilateral and “open‐lipped” (walls of the clefts do not appose) or “closed‐lipped” (walls of the cleft appose and are often fused).

Figure 1. Pathology of polymicrogyria. Macroscopic image (A) and low power (hematoxylin and eosin stain) microscopic image (B) of the brain of an infant who died from intractable epilepsy secondary to extensive right hemisphere PMG. The brain is oriented according to imaging convention with the right hemisphere on the left side of the image. The macroscopic image shows a small right hemisphere with an abnormal gyral pattern characterized by multiple small, shallow and abnormally oriented gyri and an impression of cortical thickening. The microscopic image shows an undulating surface of microgyri with fusion of the molecular layer (arrows) and deep underlying complex sulcal branching. In some areas the cortex appeared four‐layered, while in others it was poorly laminated.

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Although the cortex may appear thickened, when viewed microscopically it is actually overfolded and not truly thick (Fig. 1B). There may be associated brain malformations including gray matter heterotopia, ventriculomegaly and abnormalities of the corpus callosum, brainstem and cerebellum, although PMG is usually the isolated brain malformation. Agenesis of the septum pellucidum is present in approximately 70% of cases of SCZ [Barkovich and Norman, 1989], raising the suggestion that SCZ and septo‐optic dysplasia may be related malformations in the spectrum of “septo‐optic dysplasia plus” [Miller et al., 2000]. PMG may show a variety of histological patterns, but all show abnormal cortical lamination, excessive folding, and fusion of adjacent gyri through fusion of the molecular layer [Judkins et al., 2011]. Both unlayered (also known as two‐layered) and layered forms of PMG are described. Occasionally, both forms are found in the same patient, suggesting that they may be variations of the same malformation [Judkins et al., 2011]. The layered form may show either four or six layers [Judkins et al., 2011]. At the boundaries of layered PMG there is an abrupt transition to normal cortex [Kuzniecky et al., 1993]. Layered PMG has been described in association with the congenital bilateral perisylvian syndrome [Kuzniecky et al., 1993] and in congenital cytomegalovirus infection [Crome and France, 1959]. The boundaries of unlayered PMG and normal cortex are not abrupt [Ferrer, 1984]. The unlayered form of PMG is associated with porencephalic cysts, Aicardi syndrome [Ohtsuki et al., 1981], and Zellweger syndrome [Liu et al., 1976]. The PMG seen lining the clefts of SCZ is usually of the unlayered type [Yakovlev and Wadsworth, 1946a,b]. In both layered and unlayered PMG ultrastructural examination reveals different neuronal types positioned at appropriate cortical depths. The relative preservation of laminar organization and the positioning of most neurons in appropriate layers have led some to assert that PMG is not a primary neuronal migration disorder [Judkins et al., 2011].

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IMAGING FEATURES PMG is difficult to discern using computerized tomography (CT), and may appear as thickened cortex and therefore misdiagnosed as pachygyria or lissencephaly. CT may be used in the evaluation of PMG to assess for calcification as seen in congenital cytomegalovirus infection. CT or MRI is usually

Using MRI it is possible to reliably differentiate PMG from other MCD provided that the individual interpreting the MRI has appropriate experience. The Sylvian fissures are best seen on sagittal imaging and should be scrutinized as PMG often affects these areas preferentially sufficient to diagnose SCZ and determine whether the SCZ is open or closed‐lipped, although MRI is the

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modality of choice. Using MRI it is possible to reliably differentiate PMG from other MCD provided that the individual interpreting the MRI has appropriate experience. The Sylvian fissures are best seen on sagittal imaging and should be scrutinized as PMG often affects these areas preferentially (Fig. 2). It is important that optimal imaging protocols are used including the use of thin sections and age‐specific protocols that provide the best contrast between gray and white matter with good spatial resolution and adequate signal to noise ratio [Barkovich, 2010a]. With such high quality imaging microgyri and microsulci may be appreciated and a “stippled” gray‐white junction may be seen [Leventer et al., 2010]. Stippling of the gray‐white junction is a specific feature of PMG not seen in other MCD. In younger children the polymicrogyric cortex may appear thinner than at later ages. This is thought due to the immature state of myelination in subcortical and intracortical fibres [Takanashi and Barkovich, 2003]. Follow‐up imaging once myelination is complete may be required to appreciate the full extent of PMG. T2 signal within the cortex is usually normal, although there may be delayed myelination. High T2 signal in the underlying white matter

Figure 2. Magnetic resonance imaging of perisylvian polymicrogyria. Parasagittal image of a T1‐weighted MRI showing over‐folding and apparent thickening of the cortex surrounding an abnormally‐extended and superiorly‐oriented Sylvian fissure. Note the stippled gray‐white boundary of the polymicrogyric cortex compared to the smooth gray‐white boundary in normal cortical areas.

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should raise the question of an in utero infection (such as cytomegalovirus) or a peroxisomal disorder [van der Knaap and Valk, 1991]. Other developmental anomalies may also be appreciated including gray matter heterotopia, ventricular enlargement or dysmorphism, and abnormalities of the corpus callosum and cerebellum [Wieck et al., 2005; Leventer et al., 2010]. PMG has been described in a number of recurrent topographic patterns using MRI as shown in Figure 3. The most common patterns are bilateral perisylvian and unilateral perisylvian (52% and 9% of all forms, respectively in the largest series) [Leventer et al., 2010]. The remaining common patterns are all bilateral including generalized [Chang et al., 2004], bilateral frontal [Guerrini et al., 2000], bilateral fronto-

parietal [Chang et al., 2003], and bilateral parasagittal parieto‐occipital [Guerrini et al., 1997].

CLINICAL FEATURES PMG is associated with a wide variety of clinical associations and clinical sequelae. The clinical features will depend on a number of factors including the cause of the PMG, associated syndromic features, the presence of other brain malformations, the extent and location of the PMG, and the influence of complications such as epilepsy. Named syndromes associated with PMG are listed in Table I. The extent and topography of the PMG will have a significant influence on the clinical manifestations, with generalized forms resulting in more severe sequelae than bilateral focal or

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unilateral forms [Leventer et al., 2010; Shain et al., 2013]. PMG is variably reported in multiple conditions including metabolic disorders, chromosome deletion syndromes and multiple congenital anomaly syndromes. These patients may have a variety of clinical problems other than those attributable to the PMG. The most common clinical sequelae of PMG are epilepsy (78%), global developmental delay (70%), and spasticity (51%), either spastic quadriplegia in bilateral forms or hemiplegia in unilateral forms [Leventer et al., 2010]. As expected, patients with generalized or bilateral patterns of PMG show more severe clinical sequelae and an earlier age of presentation [Leventer et al., 2010; Shain et al., 2013]. Five percent of patients will present in utero due to an abnormal ultrasound, usually due to the

Figure 3. Magnetic resonance imaging of common subtypes of polymicrogyria. All images are either axial T1 or T2‐weighted. Image A shows bilateral perisylvian PMG with microgyri visible around both Sylvian fissures (arrows) and insulae. The white matter appears bright as the patient is a neonate. Image B shows unilateral perisylvian PMG with PMG maximal in the left perisylvian region extending anteriorly and posteriorly beyond the immediate perisylvian region (arrows). Image C shows bilateral generalized PMG, bright white matter and dilated lateral ventricles with periventricular low signal suggestive of calcification in a child with congenital cytomegalovirus infection. Image D shows bilateral frontal PMG with subtle irregular PMG throughout both frontal lobes (arrows). Image E shows bilateral perisylvian PMG (white arrows) with periventricular nodular gray matter heterotopia (black arrows). Image F shows a small right hemisphere containing a full‐thickness cleft lined by PMG (arrow) consistent with schizencephaly.

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TABLE I. Named Syndromes in which Polymicrogyria has been Reported Multiple Times Syndrome

PMG pattern

Aicardi

Variable—multifocal

Chudley‐McCullough syndrome

Frontal

DiGeorge/velocardiofacial

Perisylvian—unilateral or bilateral

Ehlers–Danlos

Perisylvian and frontal Perisylvian

Kabuki make‐up (Niikawa–Kuroki) Knobloch syndrome Leigh and other mitochondrial disorders including PDH deficiency Meckel–Gruber

Megalencephaly‐capillary malformation‐polymicrogyria syndrome (MCAP) Megalencephaly‐polymicrogyria‐ polydactyly‐hydrocephalus syndrome (MPPH) Micro–Warburg

Oculocerebrocutaneous (Delleman) Pena–Shokeir

Sturge–Weber Thanatophotoric dysplasia Zellweger and other peroxisomal disorders

Frontal Variable

Variable

Variable

Variable

Frontal

Frontal Variable

Underlying cortical angiomatosis Temporal Generalized

finding of microcephaly or associated malformations. PMG is difficult to detect by ultrasound until late in the pregnancy [Leventer et al., 2010]. Dysmorphic features may be seen in 45% of patients, the most common of which are abnormal facies or hand, feet or digital anomalies, although no uni-

Other features

Genetic basis

Agenesis of corpus callosum, retinal lacunes Sensorineural hearing loss, hydrocephalus, agenesis of corpus callosum Cardiac defects, parathyroid hypoplasia, facial dysmorphism, thymus hypoplasia Skin fragility, cutaneous extensibility, joint laxity, bruising Facial dysmorphism, digital anomalies, skeletal anomalies, microcephaly Eye abnormalities, occipital skull defects Multiple CNS abnormalities, lactic acidosis, neurodegeneration, ocular abnormalities Occipital meningo‐ encephalocoele, arhinencephaly, polycystic kidneys, polydactyly, bile duct abnormalities Macrocephaly, vascular malformations, syndactyly, occasional hyperelasticity or thick skin Macrocephaly, polydactyly

X‐linked: gene unknown

Microcephaly, cataracts, microcornea, optic atrophy, hypogenitalism, hypoplasia of corpus callosum Orbital anomalies, skin defects and multiple brain anomalies IUGR, camptodactyly, multiple ankyloses, facial dysmorphism, pulmonary hypoplasia Facial hemangioma, glaucoma

RAB3GAP mutations

Skeletal anomalies, hypoplastic lungs, megalencephaly White matter dysmyelination, facial dysmorphism, intrahepatic biliary dysgenesis, stippled epiphyses, renal cysts

form pattern of anomalies is reported [Leventer et al., 2010]. Arthogryposis or talipes equinovarus may accompany bilateral perisylvian PMG [Poduri et al., 2010]. Microcephaly is reported in up to 50% of patients, and is usually congenital [Leventer et al., 2010]. Macrocephaly is seen in 5% of cases,

GPSM2 mutations

22q11.2 deletion

Multiple genes MLL2 and KDM6A mutations COL18A1 mutations Mitochondrial including respiratory chain disorders Autosomal recessive, multiple genes PIK3CA mutations

PIK3R2 and AKT3 mutations

Possibly autosomal dominant, gene unknown Autosomal recessive: multiple genes Somatic mutations in GNAQ Autosomal dominant, multiple genes Peroxisomal (PEX, PXMP and PXR gene family mutations)

and may be associated with hydrocephalus, vascular or digital anomalies as part of the megalencephaly‐capillary malformation (MCAP) and megalencephaly‐polydactyly‐polymicrogyria‐ hydrocephalus (MPPH) syndromes [Mirzaa et al., 2012]. The presence of cardiac lesions in association with PMG

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should raise suspicion of a 22q11.2 microdeletion syndrome [Robin et al., 2006]. The presence of PMG in association with sensorineural hearing loss should raise the suspicion of congenital cytomegalovirus infection. The combination of bilateral perisylvian PMG (BPP) associated with oro‐ motor dysfunction and a seizure disorder has been called the “congenital bilateral perisylvian syndrome.” Patients with

The combination of bilateral perisylvian PMG (BPP) associated with oro‐motor dysfunction and a seizure disorder has been called the “congenital bilateral perisylvian syndrome.” BPP typically have difficulties with tongue movement, expressive speech, sucking and swallowing, excessive drooling and facial diplegia as seen in the Worster‐Drought syndrome [Worster‐Drought, 1974]. There may be mild to moderate intellectual disability in up to 75% [Kuzniecky et al., 1993]. Motor dysfunction may include limb spasticity, although this is rarely severe if present. As mentioned in the imaging section, multiple other subtypes of PMG have been delineated based primarily on imaging criteria. A comprehensive description of the sequelae of each of these subtypes is beyond the scope of this review, and is summarized in a study of 328 patients by Leventer et al. [2010]. Review of the epileptic manifestations of the various patterns of PMG is presented in the article by Shain et al. [2013]. Some patients with PMG or SCZ have far fewer clinical problems than would be expected based on their imaging appearance showing involvement of eloquent cortical areas representing language or primary motor functions. This is especially true of unilateral perisylvian PMG or unilateral

SCZ, suggesting retained cortical function within the malformed cortex as confirmed by functional MRI studies [Araujo et al., 2006].

ETIOLOGY, GENETIC, AND MOLECULAR BASIS The etiology and pathogenesis of PMG have remained issues of active discussion in the literature for over a century. The main points of discussion are the timing of the etiology (before or after neuronal migration has completed) and the nature of the etiology (developmental or destructive). The concept of PMG being secondary to a vascular defect has remained a prevalent theme in the literature since initial suggestions that it was the result of a vascular defect such as arterial ischemia [Kundratt, 1882] or impaired venous drainage [Marburg and Casamajor, 1944]. PMG often occurs in the middle cerebral artery territory, or at the peripheries of ischemic porencephalic defects [Dekaban, 1965; Levine et al., 1974]. Current consensus of opinion reflected in classification systems and supported by pathological data is that most forms of PMG are a “postmigrational” disorder, occurring after the majority of neurons destined to form the cerebral cortex have completed their migration from the periventricular region [Judkins et al., 2011; Barkovich et al., 2012]. It is likely that PMG has a heterogeneous etiology with both environmental and genetic causes resulting in a

It is likely that PMG has a heterogeneous etiology with both environmental and genetic causes resulting in a similar phenotypic endpoint; a cortex with excessive folding and abnormal lamination similar phenotypic endpoint; a cortex with excessive folding and abnormal lamination. Non‐genetic causes other

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than hypoxia or hypoperfusion include congenital infections such as cytomegalovirus [Crome and France, 1959], toxoplasmosis [de Leon, 1972], syphilis [Evrard et al., 1989], and varicella zoster [Harding and Baumer, 1988]. Inflammation or obliteration of the microvasculature has been proposed as the mechanism by which infection affects cortical development [Toti et al., 1998]. There have been no convincing reports of PMG occurring secondary to toxin exposure, radiation or medications, other than one case of maternal ergotamine use in which the PMG was thought secondary to placental vasoconstriction [Barkovich et al., 1995]. There is an association of PMG with metabolic diseases including Zellweger syndrome [van der Knaap and Valk, 1991], neonatal adrenoleukodystrophy [van der Knaap and Valk, 1991], fumaric aciduria [Kerrigan et al., 2000], mitochondrial diseases [Keng et al., 2003], Pelizaeus‐Merzbacher disease [Pamphlett and Silberstein, 1986], glutaric aciduria type II [Bohm et al., 1982], maple syrup urine disease [Martin and Norman, 1967], and histidinemia [Corner et al., 1968]. Based on a mouse model, it is proposed that PMG in Zellweger syndrome is secondary to glutamate receptor dysfunction and defective NMDA glutamate receptor‐ mediated calcium mobilisation during neuronal migration [Gressens et al., 2000]. The etiology of SCZ remains highly controversial, and there are likely both genetic and non‐genetic causes. There is definite evidence for non‐genetic causes such as congenital cytomegalovirus infection [Iannetti et al., 1998] and in utero ischemic insults [Landrieu and Lacroix, 1994]. Curry et al. identified a number of associations of SCZ, many of which implicate a vascular cause. These include an association with monozygotic twins as well as non‐CNS abnormalities with a vascular etiology such as gastroschisis, bowel atresia, and amniotic band sequence [Curry et al., 2005]. Other associations that implicate a non‐ genetic, intrauterine cause for SCZ include young parental age, lack of prenatal care and alcohol use [Curry

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et al., 2005; Dies et al., 2013]. A number of patients with both familial and non‐ familial SCZ were found to have mutations in the homeobox gene EMX2 [Brunelli et al., 1996]; however others have failed to replicate these findings in over 100 patients with SCZ. More recently, mutations in the COL4A1 gene have been found in a number of patients with either prosencephaly or SCZ, suggesting a possible vascular/destructive etiology [Yoneda et al., 2013]. Other genetic causes include chromosome aneuploidy and some rare syndromes [Curry et al., 2005]. There are now a multitude of reports of PMG in association with genetic factors, either as part of a known genetic disease or a multiple congenital anomaly syndrome, in association with a structural chromosomal abnormality, or in families with multiple affected members and/or consanguinity. Numerous loci and more than 30 genes have been identified, the latter of which are listed in Table II. We will review in detail those loci and genes for which there is the best evidence suggesting a causative role in PMG. Discussion of the role of genes in the PIK3‐AKT3 pathway in PMG‐ megalencephaly syndromes is reviewed elsewhere in this issue. Autosomal Dominant Genes The cytoskeleton is critically important for neuronal migration and mutations disrupting the function of microtubules, in particular, have been identified as causing a spectrum of MCD including lissencephaly and PMG. PMG has been identified in association with the a‐tubulin genes TUBA1A and TUBA8 [Abdollahi et al., 2009; Poirier et al., 2013b], and the b‐tubulin genes TUBB2B and TUBB3 [Jaglin et al., 2009; Poirier et al., 2010], all mutations of which have been heterozygous except for those of TUBA8 that were homozygous. The phenotypic spectrum of TUBA1A mutations has been expanded from lissencephaly to include bilateral, asymmetrical perisylvian PMG with dysmorphic basal ganglia, cerebellar vermis dysplasia, and pontine hypopla-

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sia. Dysmorphic basal ganglia has been a recurring association of PMG associated with tubulin mutations [Amrom et al., 2013]. The PMG‐related TUBA1A mutations interfere with the a‐tubulin tertiary structure suggesting that the mechanism of disease may relate to the stability of the microtubules and their interactions with related proteins [Poirier et al., 2013b]. Jaglin et al. [2009] identified five unrelated cases, including one fetus, with de novo, loss‐of‐function mutations in TUBB2B and bilateral, asymmetrical, anteriorly‐predominant PMG with internal capsule hypoplasia, agenesis or dysgenesis of the corpus callosum, and cerebellar and pontine atrophy. Though the cortical malformation in these cases were most consistent with PMG on MRI, histopathological fetal brain analysis in one case demonstrated that the microgyri were in fact extrapial rather than cortical making this, by definition, a cobblestone malformation as a result of overmigration of neurons beyond the pial limiting membrane. In utero RNAi‐based inactivation in the rat demonstrated that the TUBB2B gene was dominantly expressed in post‐mitotic neurons during neuronal migration and differentiation and these mutations were shown to impair tubulin heterodimer formation [Jaglin et al., 2009]. Heterozygous missense mutations in TUBB3, encoding the b‐tubulin isotype III, can cause a spectrum of neurological disorders including the ocular motility disorder CFEOM3 (congenital fibrosis of extraocular muscle type 3) with variable manifestation of intellectual impairment, facial paralysis, and axonal sensorimotor polyneuropathy [Tischfield and Engle, 2010]. MCD had not previously been reported in association with these TUBB3 syndromes. Due to similarities in expression of TUBB3 to TUBA1A and TUBB2B, a cohort of patients with MCD were investigated for TUBB3 mutations and six novel missense mutations (one homozygous) were identified in nine cases of PMG with axonal abnormalities and pontocerebellar hypoplasia [Poirier et al., 2010]. It was found that the PMG‐ associated mutations caused different

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amino acid substitutions and, in most cases, altered different residues to those that cause CFEOM3. Functional studies demonstrated that these mutations disturbed microtubule resistance to depolymerization in contrast to the increased microtubule stability that resulted from CFEOM3‐related mutations [Poirier et al., 2010; Tischfield and Engle, 2010]. Mutations in PAX6, a gene that encodes a highly conserved, transcriptional regulator important in the control of neuronal migration and axonal guidance in the brain, have long been recognized as a single‐gene cause for syndromic PMG. Heterozygous PAX6 mutations cause aniridia with a spectrum of brain malformations including unilateral PMG, absence of the anterior commissure and pineal gland and cerebellar hypoplasia [Mitchell et al., 2002], and homozygous mutations cause anophthalmia, brain malformation and neonatal death [Glaser et al., 1994]. Several chromosome abnormalities are associated with PMG though the causal genes located in these chromosomal regions have not been identified

Several chromosome abnormalities are associated with PMG though the causal genes located in these chromosomal regions have not been identified. The most common are the 1p36.3 microdeletion and the 22q11.2 microdeletion, both of which are associated with unilateral or bilateral perisylvian PMG. [Dobyns et al., 2008]. The most common are the 1p36.3 microdeletion and the 22q11.2 microdeletion, both of which are associated with unilateral or bilateral perisylvian PMG [Robin et al., 2006; Dobyns et al., 2008]. For a reason that remains unexplained, PMG associated with 22q11.2 deletions is more

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TABLE II. Genes Associated with Polymicrogyria Gene

Locus

Autosomal dominant AKT3 1q43–q44

COL4A1

13q34

DYNC1H1

14q32.31

EMX2 FOXP2 KIF5C

10q26.11 7q31.1 2q23.1

NHEJ1

2q35

PAX6

11p13

Protein

Specific features

Reference

Member of AKT protein family

Megalencephaly‐polymicrogyria‐ polydactyly‐hydrocephalus syndrome (MPPH) Schizencephaly

Riviere et al. [2012]

Microcephaly, axonal neuropathy and frontal PMG Schizencephaly Unilateral perisylvian PMG Perisylvian PMG

Poirier et al. [2013a] Brunelli et al. [1996] Roll et al. [2010] Poirier et al. [2013a]

PMG and neuronal heterotopia

Cantagrel et al. [2007]

Aniridia, variable temporal PMG, absent anterior commissure and pineal gland Megalencephaly‐capillary malformation‐polymicrogyria syndrome (MCAP) Megalencephaly‐polymicrogyria‐ polydactyly‐hydrocephalus syndrome (MPPH) Schizencephaly Schizencephaly Bilateral, asymmetrical, perisylvian PMG Bilateral, asymmetrical, anterior predominant PMG Fronto‐parietal PMG Microcephaly and PMG

Mitchell et al. [2003]

Alpha subunit of collagen type IV Heavy–chain of cytoplasmic dynein complex Homeobox protein EMX2 Forkhead box P2 Kinesin family member (neuron‐specific heavy chain) Non‐homologous end‐ joining factor 1 Transcription factor

PIK3CA

3q26.32

Phosphatidylinositol 3‐kinase, catalytic, alpha

PIK3R2

19p13.11

Phosphatidylinositol 3‐kinase, regulatory subunit 2

SHH SIX3 TUBA1A

7q36.3 2p21 12q13.12

Sonic hedgehog Nuclear homeoprotein a1‐tubulin

TUBB2B

6p25.2

b2‐tubulin

16q24.3 19p13.3

b3‐ tubulin b5‐tubulin

6q23.3

Abelson helper integration site 1 Endostatin (Collagen type XVIII, alpha‐1) Member of the TBR1 subfamily of T‐box genes

TUBB3 TUBB5 Autosomal recessive AHI1 COL18A1

21q22.3

EOMES (TBR2)

3p24.1

FIG4

6q21

Phosphoinositide phosphatase

GPR56 KIAA1279

16q13 10q22.1

G‐protein receptor Kinesin‐binding protein (KBP)

LAMC3 NDE1

9q34.12 16p13.11

Laminin, gamma‐3 Nude (homolog of A. Nidulans) 1

Yoneda et al. [2013]

Riviere et al. [2012]

Riviere et al. [2012]

Schell‐Apacik et al. [2009] Hehr et al. [2010] Poirier et al. [2013b] Jaglin et al. [2009] Poirier et al. [2010] Breuss et al. [2012]

Joubert syndrome

Dixon‐Salazar et al. [2004]

Knobloch syndrome with frontal PMG Microcephaly with diffuse, asymmetric PMG and agenesis of corpus callosum Temporo‐occipital PMG, psychiatric manifestations and epilepsy Bilateral frontoparietal PMG PMG with or without additional features of Goldberg‐ Shprintzen syndrome Occipital PMG Microcephaly with diffuse PMG

Keren et al. [2007] Baala et al. [2007]

Baulac et al. [2014]

Piao et al. [2004] Valence et al. [2013]

Barak et al. [2011] Alkuraya et al. [2011]

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Table 2. (Continued) Gene

Locus

Protein

Specific features

Reference

OCLN1

5q13.2

Occludin

O’Driscoll et al. [2010]

RAB18 RAB3GAP1

10p12.1 2q21.3

RAB3GAP2

1q41

Warburg–Micro syndrome

Borck et al. [2011]

RTTN TMEM216

18q22 11q12.2

Ras‐associated protein Rab3 GTPase‐activating protein, catalytic subunit Rab3 GTPase‐activating protein, non‐catalytic subunit Rotatin Transmembrane protein 216

Band‐like calcifications with PMG Warburg–Micro syndrome Warburg–Micro syndrome

Kheradmand Kia et al. [2012] Valente et al. [2010]

TUBA8

22q11.21

a8‐tubulin

WDR62

19q13.12

WD40‐repeat containing protein

Diffuse, asymmetric PMG Meckel–Gruber syndrome with variable PMG Generalized PMG and optic nerve hypoplasia Microcephaly with or without diffuse or asymmetric PMG

Xp22.3

Aristaless‐related homeobox protein

Asymmetric PMG with periventricular nodular heterotopia CK syndrome

Oegema et al. [2012]

McLarren et al. [2010]

Bilateral perisylvian PMG

Roll et al. [2006]

X‐Linked ARX

NSDHL

Xq28

SRPX2

Xq22

NAD(P)H steroid dehydrogenase‐like protein Sushi‐repeat containing protein

frequently right‐sided [Robin et al., 2006]. TUBA8 may contribute to cause PMG in the 22q11 deletion syndrome due to its proximity to the low‐copy repeat that mediates this common microdeletion syndrome and the possibility of a positional effect from the deletion on TUBA8 expression [Abdollahi et al., 2009]. Autosomal Recessive Genes GPR56 mutations cause a distinctive radiological phenotype with a bilateral, symmetrical malformation resembling PMG with a decreasing antero‐posterior gradient, white matter changes and brainstem and cerebellar hypoplasia [Piao et al., 2005]. The GPR56 / knockout mouse model has shown that loss of gene function results in abnormal neuronal positioning with over‐migration, rupture of the pial basement membrane and resultant disorganization of the glial scaffold [Li et al., 2008], features that resemble the cobblestone

brain malformation seen in the congenital muscular dystrophies. Subsequently GPR56‐related MCD have been re‐ classified as cobblestone malformations resulting from abnormal terminal migration and defects in pial limiting membrane [Barkovich et al., 2012]. These neuropathological findings, similarly reported in association with TUBB2B‐related cases of PMG [Jaglin et al., 2009], provide a new perspective on PMG pathophysiology, suggesting that the distinct cortical malformations of PMG and cobblestone lissencephaly may in fact be manifestations of a continuum of cortical dysgenesis. FIG4 mutations have previously been described in association with Charcot‐Marie‐Tooth disease type 4J (CMT4J) [Chow et al., 2007] and Yunis–Varón syndrome [Campeau et al., 2013]. Recently a FIG4 mutation, affecting a different protein domain to those affected in CMT4J and YVS, was identified as the causal gene in a consanguineous family with

Bem et al. [2011] Aligianis et al. [2005]

Abdollahi et al. [2009] Bilguvar et al. [2010]

temporo‐occipital PMG [Baulac et al., 2014]. Histological examination of the FIG4 / mouse brain showed abnormal neurodevelopment affecting the cortex and cerebellum with malformed cerebellar gyration and foliation [Baulac et al., 2014]. The investigation of consanguineous pedigrees with recurrent microcephaly and MCD using whole exome sequencing (WES) led to the identification of homozygous mutations in the gene encoding the WD40‐repeat protein 62 (WDR62) in a spectrum of cortical malformation [Bilguvar et al., 2010]. Subsequently a compound heterozygous WDR62 mutation was identified in a nonconsanguineous family with recurrent PMG [Murdock et al., 2011]. Phenotypes variably included microcephaly, agyria/pachygyria, lissencephaly, PMG and hypoplasia of the corpus callosum and cerebellum. Post‐ mortem brain analyses have identified a thin cortex and interruptions in the pial surface with microscopic extrusions of

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cells forming heterotopia [Yu et al., 2010]. WDR62 is expressed in the neocortex during embryonic neurogenesis and enriched in both neuronal precursors and post‐mitotic neurons. Proteomic studies have generated conflicting results regarding the role of WDR62, indicating a predominantly nuclear role in one study [Bilguvar et al., 2010] and interacting with centrosomal proteins in another [Yu et al., 2010]. Though the role of WDR62 in neuronal migration is not yet fully understood, the diversity of phenotypes associated with WDR62 gene mutations suggests that its role may be central to many aspects of cerebral cortical development. The role of the RAB3 GTPase activating protein complex (RAB3GAP) in the pathogenesis of PMG is not clear though mutations in genes encoding this complex can cause the Warburg–Micro syndrome, of which PMG is a feature. RAB3GAP is a heterodimer composed of catalytic and non‐catalytic sub‐units encoded by RAB3GAP1 and RAB3GAP2, respectively. Via the inactivation of Rab3A in nerve terminals, RAB3GAP plays a key role in the regulation of neurotransmitter release in the brain and in synaptic plasticity [Sakane et al., 2006]. Warburg–Micro syndrome (WARBM1) is characterized by microcephaly, developmental eye abnormalities, cortical malformations, severe intellectual disability, spastic diplegia, and hypogonadism. Mutations in RAB3GAP1 were first identified as a cause for WARBM1 in a cohort of 12 consanguineous Pakistani and Moroccan families [Aligianis et al., 2005]. All affected individuals had homozygous inactivating mutations in RAB3GAP1 and typical features of WARBM1 with no genotype‐phenotype correlation. It was proposed that the abnormalities in eye and CNS development caused by RAB3GAP mutations resulted from a failure of the normal exocytic release of ocular and neurodevelopmental trophic factors [Aligianis et al., 2005]. X‐Linked genes The largest study of PMG has shown a highly significant sex skewing towards

males, particularly for perisylvian PMG [Leventer et al., 2010]. Three loci of interest on the X‐chromosome for BPP have been identified through linkage studies of multiplex pedigrees [Villard et al., 2002; Roll et al., 2006; Santos et al., 2008] and numerous other pedigrees suggestive of X‐linked inheritance have been reported [Guerreiro et al., 2000]. A causative mutation in the SRPX2 gene at Xq22 was initially identified in a family with X‐linked Rolandic epilepsy, speech dyspraxia, and variable intellectual disability. Subsequently this gene was tested, and a mutation found, in an unrelated patient with Rolandic epilepsy and BPP. This proband’s mother and three maternal aunts carried the SRPX2 mutation but only two of the aunts had mild intellectual disability and none of the carrier females had cortical abnormality on brain MRI. In this cohort, SRPX2 mutations were shown to cause a phenotype that may variably include Rolandic epilepsy, oral‐motor incoordination and perisylvian PMG. Identification of a FOXP2 mutation (associated with verbal dyspraxia) in a patient with perisylvian PMG, along with functional studies demonstrating FOXP2’s regulation of SRPX2 promoter activity, provided insight into a regulatory network that is altered in disorders affecting the development of speech‐related brain areas [Roll et al., 2010]. Bilateral perisylvian PMG has been described in a family with CK syndrome [du Souich et al., 2009]. CK syndrome is caused by mutations in the NSDHL gene at Xq28, yet there are no reports of mutations in NSDHL in a wider cohort of PMG patients [McLarren et al., 2010].

CONCLUSION The significant clinical, imaging, and etiological heterogeneity of PMG makes it one of the most challenging brain malformations to define, characterize and understand. The gene mutations, that are known to cause this malformation, impact on a variety of cellular processes and it is not possible to ascribe a single genetic pathway to the pathophysiology of PMG. As it is a relatively

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common condition, it is essential that we continue to progress our understanding of PMG so that clinicians can access genetic testing and provide accurate prognostic and genetic counseling to patients and their families. Understanding the molecular basis of PMG will also help unravel the mechanisms by which the human brain develops its uniquely complex pattern of gyrification.

ACKNOWLEDGMENTS Dr. Stutterd is supported by the Royal Children’s Hospital/Murdoch Childrens Research Institute Flora Suttie Neurogenetics Fellowship made possible through the generous donations of the Suttie family and their supporters, the Thyne‐Reid Foundation and the Macquarie Foundation. We would like to thank Dr. Duncan MacGregor for providing the images for Figure 1. This work was supported by the Victorian State Government Operational Infrastructure Support Program.

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Polymicrogyria: a common and heterogeneous malformation of cortical development.

Polymicrogyria (PMG) is one of the most common malformations of cortical development. It is characterized by overfolding of the cerebral cortex and ab...
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