Malformations of Cortical Development and Epilepsype ?· Malformations of Cortical Development and Epilepsy…

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Malformations of Cortical Developmentand Epilepsy

A. James Barkovich1, William B. Dobyns2, and Renzo Guerrini3

1Department of Radiology and Biomedical Imaging, Neurology, Pediatrics, and Neurosurgery,University of California, San Francisco, San Francisco, California 94143-0628

2Center for Integrative Brain Research, Seattle Childrens Research Institute, Seattle, Washington98101

3Pediatric Neurology Unit and Laboratories, Childrens Hospital A. Meyer, University of Florence,Florence 50139, Italy

Correspondence: james.barkovich@ucsf.edu

Malformations of cortical development (MCDs) are an important cause of epilepsy and anextremely interesting group of disorders from the perspective of brain development and itsperturbations. Many new MCDs have been described in recent years as a result of improve-ments in imaging, genetic testing, and understanding of the effects of mutations on the abilityof their protein products to correctly function within the molecular pathways by which thebrain functions. In this review, most of the major MCDs are reviewed from a clinical, em-bryological, and genetic perspective. The most recent literature regarding clinical diagnosis,mechanisms of development, and future paths of research are discussed.

Malformations of cortical development(MCDs) are common causes of medicallyrefractory epilepsy, particularly in children(Barkovich et al. 2012). Although most child-hood epilepsies respond to treatment, 15%are resistant to pharmacologic treatments(drug-resistant childhood epilepsies) (Guerrini2006); 40% of these are caused by MCDs(Kuzniecky et al. 1993b; Frater et al. 2000; Pas-quier et al. 2002). One type of MCD, called focalcortical dysplasia (FCD), has an incidence of50/100,000/yr in children ,16 yr of age, add-ing up to ~0.8% of children (Nelligan andSander 2011; Ngugi et al. 2011). Approximately25% (range 10%30%) of patients with FCD

progress to intractable epilepsy, enriched inthose with focal epilepsies (Braathen and Theo-rell 1995; Wirrell et al. 2013). FCDs of all typesare seen in 25%100% of brain tissue from ep-ilepsy surgery (Mischel et al. 1995; Tassi et al.2002). Not all people with MCDs have epilepsy,however; presentations typically include vari-able levels of motor or cognitive impairment,but some are discovered incidentally after mag-netic resonance (MR) scans for other medicalconditions or unrelated events (e.g., injuries)(de Wit et al. 2008), whereas an unknown num-ber are probably never detected.

Although MCDs have been known for manyyears and classified for 20 years, the basic ge-

Editors: Gregory L. Holmes and Jeffrey L. Noebels

Additional Perspectives on Epilepsy: The Biology of a Spectrum Disorder available at www.perspectivesinmedicine.org

Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a022392Cite this article as Cold Spring Harb Perspect Med 2015;5:a022392

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netic and molecular processes that underlie thedevelopment of these disorders has becomemuch clearer in the past few years. The purposeof this review is to discuss the current classifi-cation and molecular underpinnings of thesedisorders. In doing so, we will concentrate onnew concepts that have developed as a result ofrecent discoveries in the field.

FRAMEWORK OF THE CLASSIFICATION

In the initial classification in which the termmalformation of cortical development wasderived (Barkovich et al. 1996), the investigatorsseparated the disorders into three main groups,based on the earliest stage development that isaffected (recognizing that alteration of early de-velopmental events often affects later events, aswell): disorders caused by abnormal cell prolif-eration, abnormal neuronal migration, and ab-normal postmigrational cortical development.The discoveryof many genes, proteins, and path-ways involved in these steps, however, has madethe classification more complex in some areasand more simplified in others. In this review,we will first discuss the fundamental conceptsunderlying each major component of the clas-sification, followed (when appropriate) by adiscussion of new discoveries regarding genemutations, the effects of these mutations onthe function of their protein products, the con-sequent effects on molecular pathways, andhow alterations of pathways affect brain devel-opment. In areas in which new discoveries havebeen few, and which, consequently, remainpoorly understood, we will discuss potential rea-sons for the poor understanding.

MALFORMATIONS SECONDARY TOABNORMAL CELL PROLIFERATION ORAPOPTOSIS

A good deal of new information has becomeavailable over the past few years with regard tomalformations in this category, in particular,pertaining to reduced cell proliferation (micro-cephalies) (Thornton and Woods 2009; Alku-raya et al. 2011; Bakircioglu et al. 2011; Bicknell

et al. 2011) and malformations associatedwith abnormal cell proliferation (type II FCDs)(Blumcke et al. 2011), gangliogliomas (Boeret al. 2010; Koelsche et al. 2013), tuberous scle-rosis complex (TSC) (Crino 2013), and mega-lencephalies associated with cerebral dysgeneses(Kurek et al. 2012; Lee et al. 2012; Riviere et al.2012).

Microcephalies

Our understanding of microcephalies has in-creased greatly in the past few years with thediscovery of the responsible genes and the func-tions of their protein products. Most of theresponsible genes function in cell replication.For example, patients with microcephaly associ-ated with osteodysplastic primordial dwarfism(MOPD), such as MeierGorlin syndrome,have mutations affecting subunits of the originrecognition complex, which is loaded ontochromatin at DNA origins before the S phaseof mitosis to license replication; in conjunctionwith additional components CDC6, CDT1, andMCM27, it forms the prereplication complex,which initiates DNA replication (Bicknell et al.2011). Other genes that, when mutated, result inmicrocephaly include those involved in micro-tubule formation (TUBA1A, TUBB2B, TUBB3,TUBG1) (Poirier et al. 2010, 2012, 2013; Cu-shion et al. 2013), those coding for microtu-bule-associated proteins (DYNC1H, KIF5C,NDE1) (McKenney et al. 2010; Alkuraya et al.2011; Bakircioglu et al. 2011; Poirier et al.2013), those involved in spindle organization andpositioning (ASPM) (Desir et al. 2008; Passe-mard et al. 2009), those regulating centriolelength (CENPJ) (Tang et al. 2009; Al-Dosariet al. 2010) or centrosome integrity (STIL) (Cas-tiel et al. 2011), those that repair genomic defectsand regulate genomic integrity (CEP152) (Kalayet al. 2011), and manyothers involved in the verycomplex process of cell replication. By a combi-nation of clinical characteristics (Mahmoodet al. 2011), imaging characteristics (Fig. 1) (Bar-kovich et al. 2012), and family histories, many ofthe causes of microcephalies can now be identi-fied in families.

A.J. Barkovich et al.

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Malformations that May Be Associatedwith Mutations Affecting theMammalian Target of Rapamycin(mTOR) Pathway

For many years, several malformations caused byabnormal cell proliferation were thought to berelated because of their similar histological ap-pearances and MR imaging patterns (Barkovichet al. 2012). These included the brain lesionsassociated with TSC, a localized enlargementof dysmorphic and dysplastic brain called hemi-megalencephaly (HME; also referred to as dys-plastic megalencephaly), tumors with dysplasticfeatures (ganglioglioma), and focal cortical dys-plasia type IIb (FCD IIb) all are characterized bylocalized dysplastic, enlarged neurons, impaired

myelination, and large, ovoid dysmorphic cellswith laterally displaced nucleus and limited ax-ons and dendrites called balloon cells (HMEs),giant cells (TSCs), or atypical ganglion cells(ATGCs) (gangliogliomas). In the past 2 years,it has become clear that all of these disorders, aswell as others classified as malformations, as aresult of abnormal cell proliferation, result frommutations affecting mTOR signaling pathways(Fig. 2). The mTOR signaling cascade functionsas a central controller of organism growth andhomeostasis; it integrates the input from up-stream pathways, including insulin, growth fac-tors (such as insulin-like growth factor [IGF]-1and IGF-2), and amino acids and senses cellularnutrient, oxygen, and energy levels. MessengerRNA (mRNA) translation is suppressed in un-

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Figure 1. Sorting of microcephalies by morphologic characteristics. (A) Microcephaly with extremely smallcerebellum and small pons. (B) Microcephaly with cerebellum and pons that are proportional and slightlydisproportionately small compared with cerebrum. (C) Profound microcephaly with proportional cerebellumand brainstem that are disproportionately large compared with cerebrum. (D) Severe microcephaly withbrainstem that is disproportionately large compared with cerebrum and cerebellum that is disproportionatelylarge compared with brain stem. (E) Microce