A Developmental and Genetic Classification for Malformations of Cortical Development

Update 2012

A. James Barkovich; Renzo Guerrini; Ruben I. Kuzniecky; Graeme D. Jackson; William B. Dobyns


Brain. 2012;135(5):1348-1369. 

In This Article

Group I: Malformations Secondary to Abnormal Neuronal and Glial Proliferation or Apoptosis

This group continues to be separated into three categories: reduced proliferation or accelerated apoptosis (congenital microcephalies); increased proliferation or decreased apoptosis (megalencephalies); and abnormal proliferation (focal and diffuse dysgenesis and dysplasia).

Groups I.A and III.D: Microcephaly

Most genes known to cause primary microcephaly (Appendix 1) affect pathways involving neurogenesis: transcription regulation (MCPH1, CENPJ, CDK5RAP2; Thornton and Woods, 2009), cell cycle progression and checkpoint regulation (MCPH1, CENPJ, CDK5RAP2; Thornton and Woods, 2009), centrosome maturation (CDK5RAP2 and CENPJ; Thornton and Woods, 2009), dynein binding and centrosome duplication (NDE1; Alkuraya et al., 2011; Bakircioglu et al., 2011), DNA repair (MCPH1; Thornton and Woods, 2009), progenitor proliferative capacity (ASPM and STIL; Desir et al., 2008; Kumar et al., 2009; Passemard et al., 2009), interference with mitotic spindle formation [WDR62 (Bilgüvar et al., 2010; Yu et al., 2010) and NDE1 (Feng and Walsh, 2004)] and DNA repair deficit [PNKP (Shen et al., 2010) and PCNT (Griffith et al., 2008)]. These pathways affect processes—alterations of cell cycle length, spindle positioning or DNA repair efficiency—that affect neurogenesis and, in particular, the cell cycle phases of mitosis (Supplementary Table 1). WDR62, ASPM and STIL are spindle pole proteins, suggesting that focused spindle poles are of great significance in neural progenitor cell division. Spindle poles attach to mature centrosomes; they control the position of the central spindle and, hence, the direction of the last stage of the cytokinesis cleavage furrow (Nicholas et al., 2010). If cell division is perfectly symmetric, it produces two daughter cell neural precursors. If not, the daughter cell may fail to inherit a part of the cadherin hole; as a result, it differentiates into a neuron, becomes postmitotic, and migrates out of the neuroepithelium (Nicholas et al., 2010). Microcephaly secondary to mutations of WDR62 has associated cortical malformations (Yu et al., 2010). Mutations of ARFGEF2 have associated periventricular nodular heterotopia (de Wit et al., 2009) and some individuals with microcephalic osteodysplastic primordial dwarfism have cortical dysgenesis (Juric-Sekhar et al., 2011). Mutations of other primary microcephaly genes described so far do not have obvious brain anomalies other than simplification of the gyral pattern and hypoplasia of the corpus callosum (Passemard et al., 2009; Rimol et al., 2010; Shen et al., 2010), although few have had pathological analyses. No definable clinico-radiological characteristics have been identified that separate microcephalies caused by mutations affecting different parts of the mitotic cycle. Although no human microcephaly syndromes have yet been described in association with excessive developmental neuron apoptosis, AMSH-deficient mice have been shown to have postmigrational microcephaly due to increased developmental neuronal death (Ishii et al., 2001). Overall, a great deal of progress has been made in the understanding of genetic causes of microcephaly but not enough to justify a purely genetic- or pathway-based classification. Therefore, for the current classification, microcephalies are classified based upon inheritance, associated clinical features, and causative gene.

Patients born with normal to slightly small head size (2 standard deviations or less below mean) and developing severe microcephaly in the first 1–2 years after birth form a separate group designated postmigrational microcephaly (now listed in Group III), because brain growth seems to slow during late gestation or the early postnatal period after normal early development. X-linked postmigrational microcephaly associated with mutations of CASK is placed in this group; this disorder is seen in girls with mental retardation, short stature, and disproportionate cerebellar and brainstem hypoplasia (Najm et al., 2008; Takanashi et al., 2010). Also in this group are pontocerebellar hypoplasias due to mutations in transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34), prenatal onset neurodegenerative disorders in which significant microcephaly develops after birth (Barth et al., 2007; Namavar et al., 2011). Also in this group is microcephaly due to mutations or genomic deletions of FOXG1, sometimes described as a congenital variant of Rett syndrome (Kortüm et al., 2011). The processes that interfere with normal brain development in late gestation or the early postnatal period are not understood. With the disruption of normal brain development occurring late, these disorders may be good candidates for intervention once the molecular cause of the disorder is understood.

Group I.B: Megalencephalies

As reasons for megalencephaly are not established in many disorders in this group, many are clinically defined, even if the mutated gene is known. Megalencephaly is seen in 6% of patients with polymicrogyria (Leventer et al., 2010). These megalencephalic polymicrogyria syndromes have been named macrocephaly, polymicrogyria, polydactyly, hydrocephalus (MPPH) (Mirzaa et al., 2004), Macrocephaly–Cutis Marmorata Telangiectata Congenita (M-CMTC) and the Macrocephaly Capillary Malformation (MCAP) syndromes (Conway et al., 2007; Tore et al., 2009). Nearly all of these patients have some sort of cortical malformation; most have perisylvian polymicrogyria, but the polymicrogyria may be more widely scattered and is sometimes more severe over the convexities. Progressive tonsillar ectopia (herniation) is characteristic. Until the different entities are sorted out, we have chosen to list all patients with polymicrogyria and macrocephaly within a single group, called MCAP (megalencephaly capillary malformation-polymicrogyria). Further subcategories will likely be established based upon genetic findings and associated anomalies.

Hemimegalencephaly is not included in this group because of the presence of abnormal (dysmorphic) cells in that disorder (Flores-Sarnat et al., 2003).

Group I.C: Cortical Dysgeneses With Abnormal Cell Proliferation

An important advance in understanding cell proliferation has been the elucidation of specific molecular pathways that control proliferation, in particular the mammalian target of rapamycin (mTOR) pathway, which is important in abnormal cerebral cortical development (as well as renal, cardiac and pulmonary development) of the tuberous sclerosis complex (Crino et al., 2006). The tuberous sclerosis complex1–tuberous sclerosis complex2 protein complex integrates cues from growth factors, the cell cycle and nutrients to regulate the activity of mTOR, p70S6 kinase (S6K), 4E-BP1 and ribosomal S6 proteins. A number of groups have contributed to work showing that mutations leading to loss of function of the tuberous sclerosis complex1 or tuberous sclerosis complex2 genes result in enhanced Rheb-GTP signalling and consequent mTOR activation, causing increased cell growth, ribosome biogenesis and messenger RNA translation; ultimately, the result is overgrowth of normal cells and production of abnormal cells in many organs (Crino et al., 2006). This discovery has had significant therapeutic implications in managing cerebral, visceral and cognitive disorders associated with tuberous sclerosis (de Vries, 2010).

A major change in this group has been the proposal of a new classification of FCDs, a heterogeneous group of disorders that commonly cause medically refractory epilepsy in children (Taylor et al., 1971; Blümcke et al., 2011). FCDs are very likely to have many aetiologies (Krsek et al., 2010; Orlova et al., 2010; Blümcke et al., 2011). The new classification and several other works support the classification of FCD type II (FCDII) as a malformation due to abnormal proliferation. Histological characteristics of FCDII are fairly consistent across affected patients and it is likely to be a much more homogeneous disorder than FCDI or the new FCDIII (both discussed in the 'Group III: Malformations secondary to abnormal postmigrational development' section). Several groups have demonstrated that FCDI and FCDII cells (neurons and balloon cells) express different proteins at different cortical layers (Hadjivassiliou et al., 2010; Orlova et al., 2010). The protein phenotype of cells found in FCDII is similar to that seen in tubers of the tuberous sclerosis complex, justifying their classification together; both have progenitor proteins that appear early in development, are present in deep cell layers, and are similar to those found in multipotent or pluripotent stem cells. In contrast, cells from FCDI express few early proteins (Hadjivassiliou et al., 2010; Orlova et al., 2010) and those expressed are found in more superficial layers (junction of layers I and II) (Hadjivassiliou et al., 2010). Other studies (Yasin et al., 2010; Han et al., 2011) suggest that balloon cells in patients with FCDII originate from glioneuronal progenitor cells, strongly suggesting that defects of neuronal and glial specifications are important in the histogenesis of FCDII. These findings support the concept that cells of FCDII derive from radial glial progenitors (Lamparello et al., 2007) and may support the 'dysmature cerebral developmental hypothesis' that seizures in some forms of FCD may be the result of interactions of dysmature cells with normal postnatal ones (Cepeda et al., 2006). Focal transmantle dysplasia (Barkovich et al., 1997) and bottom of sulcus dysplasia (Hofman et al., 2011), described as specific types of cortical dysplasia based on imaging features, have histological features of FCDIIb and are likely different names for the same entity (Krsek et al., 2010). They have excellent outcomes after surgical resection, probably because their presence and location are easily identified by imaging (Krsek et al., 2010).

Several authors have made the observation that hemimegalencephaly has increased cell densities in the outer cortical layers and white matter of the affected hemisphere, but decreased cell densities in the inner cortical layers (Salamon et al., 2006; Mathern et al., 2007). MRI studies showed that the non-affected hemisphere was smaller than hemispheres of age-matched normal subjects, resulting in the suggestion that somatic mutations affect each developing cerebral hemisphere differently (Salamon et al., 2006), possibly due to incomplete apoptosis (Mathern et al., 2007). The abnormal contralateral hemisphere may explain the poorer than expected post-surgery seizure control and cognitive outcomes (Salamon et al., 2006; Mathern et al., 2007). Hemimegalencephaly is divided into three categories because the appearance of hemimegalencephaly associated with tuberous sclerosis is one of multiple tubers in a single hemisphere (Griffiths et al., 1998; Galluzzi et al., 2002; Parmar et al., 2003), rather than the more diffuse process involving a variable portion of a hemisphere, seen in other neurocutaneous disorders and in isolated hemimegalencephaly. This classification will need to be re-evaluated as more cases are carefully analysed.