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 II: Malformations Due to Abnormal Neuronal Migration

Several studies have shown that abnormalities of the neuroependyma (ventricular epithelium) are associated with periventricular nodular heterotopia (Ferland et al., 2009). Group II has, therefore, been divided into four subcategories: malformations resulting from abnormalities of the neuroependymal (initiation of migration), mainly including periventricular heterotopia; generalized abnormalities of transmantle migration, mainly including lissencephalies; localized abnormalities of transmantle migration, mainly subcortical heterotopia; and abnormalities due to abnormal terminal migration/defects in pial limiting membrane. The latter group now consists mostly of cobblestone malformations, although less severe forms of these have been defined in foetal alcohol syndrome and in mice with mutations of some transcription factors such as Foxc1 (Zarbalis et al., 2007).

Group II.A: Heterotopia

Macroscopic collections of heterotopic neurons come in many forms and sizes, ranging from periventricular nodular heterotopia, the most common form, to periventricular linear heterotopia, consisting of a smooth layer of grey matter lining the ventricular wall, to columnar heterotopia, a linearly arranged collection of neurons that span the cerebral mantle from the pia to the ependyma, to large subcortical heterotopia that consist of curvilinear swirls of grey matter originating from deep sulci, which wind their way through the cerebral mantle to the ependyma. Little is known about the genetic and embryological causes of the more complex heterotopia. As the neurons are deposited everywhere between the ventricle and the pia in these disorders, they remain classified as malformations due to abnormal neuron migration. However, as periventricular nodular heterotopia appears to have a different embryogenesis than other heterotopia, and many have known genetic causes, they have been separated from the others and placed in the subcategory of malformations with neuroependymal abnormalities (Group II.A).

Ferland et al. (2009) showed that injury to, or denudation of, the neuroependyma (ventricular zone epithelium) is likely an important factor in the formation of periventricular nodular heterotopia (rather than a cell-intrinsic motility defect. This observation clarifies why periventricular nodular heterotopia is caused by ARFGEF1 mutations even though its protein product (BIG2) is not involved in neuronal migration (Ferland et al., 2009). Similar to subpial heterotopia in cobblestone malformations, which result from a loss of structural integrity of the pial limiting membrane (Yamamoto et al., 2004; Luo et al., 2011), the denuded ventricular epithelium in periventricular nodular heterotopia may cause disengagement of radial glia, resulting in an inability of young neurons to migrate away (Ferland et al., 2009). Neurons in periventricular nodular heterotopia seem to be arranged in a layered pattern (Garbelli et al., 2009); analysis of layer-specific genes suggests that the outer layer of neurons in the nodule is composed of layer 6 neurons (expressing Rorβ), with the next layer being composed of layer 5 (expressing Er81) and the next for layer 4 (expressing Nurr1) (Garbelli et al., 2009). Compared with controls, fewer cells in the overlying cortex expressed these three genes in the appropriate layers, suggesting that late migrating neurons are less affected (Garbelli et al., 2009).

Group II.B: Lissencephaly

Malformations due to widespread abnormal transmantle migration including agyria, pachygyria and subcortical band heterotopia, are all part of the lissencephaly spectrum. A major change in this group has come from the discovery that mutations of TUBA1A are responsible for 1–4% of classic (four-layered, with a cell-sparse zone) lissencephalies (Morris-Rosendahl et al., 2008; Kumar et al., 2010) and 30% of lissencephalies with cerebellar hypoplasia (Kumar et al., 2010). The TUBA1A-associated classic lissencephalies can have a wide range of dysgenesis involving the cortex, corpus callosum, basal ganglia/white matter and mid/hindbrain (Kumar et al., 2010). Patients with TUBA1A-associated classic lissencephaly have either p.R402C mutations, resulting in frontal pachygyria and posterior agyria with a cell-sparse zone, or p.R402H mutations, resulting in nearly complete agyria; both of these phenotypes are essentially identical to those associated with LIS1 mutations (Kumar et al., 2010), suggesting involvement of the same molecular pathways. Other groups with TUBA1A-associated lissencephaly had variant lissencephaly with heterogeneous missense mutations throughout the gene resulting in cortical dysgenesis varying from diffuse, often asymmetric, pachygyria with moderately thick cortex to a smooth, relatively thin cortex associated with diminution of cerebral white matter (Kumar et al., 2010). These phenotypes had absent or nearly absent corpus callosum, thin brainstem and severe cerebellar hypoplasia; callosal and mid-hindbrain malformations were most severe in the patients with thinner cerebral cortex (Kumar et al., 2010). Some patients have upward rotation of the cerebellar vermis with a dilated fourth ventricle and enlarged posterior fossa, fulfilling the criteria for Dandy–Walker malformation (Kumar et al., 2010). In our prior classification, these phenotypes were listed as variant lissencephaly with extreme microcephaly, absent (or nearly absent) corpus callosum, moderate to severe cerebellar hypoplasia and brainstem hypoplasia; they are likely the malformation that Forman et al. (2005) called 'two layer lissencephaly'. The clinical phenotypes caused by mutations of TUBA1A also vary considerably; however, most affected patients have congenital microcephaly, mental retardation and severe neurodevelopmental delay with di/tetraplegia (Bahi-Buisson et al., 2008).

Group II.C: Subcortical Heterotopia and Sublobar Dysplasia

Subcortical heterotopia are poorly understood malformations in which large collections of neurons are found regionally in the deep cerebral white matter (Barkovich, 2000). Some are transmantle, composed of linear (columnar heterotopia) or curvilinear, swirling nodules of neurons continuous from the ependyma to the cortex. Others are composed of multiple nodules of neurons localized to the deep cerebral white matter. In all, the involved portion of the affected hemisphere is abnormally small and the overlying cortex appears thin, and sometimes, microgyric. The histology and embryogenesis of these disorders is unknown, but they are presumably due to localized abnormal late migration.

Also included in this category is sublobar dysplasia, a very rare malformation characterized by a region of dysmorphic brain within an otherwise normal-appearing hemisphere (Barkovich and Peacock, 1998). Histopathology, recently reported in a single patient, showed leptomeningeal and subcortical heterotopia, disturbance of cortical lamination, and marked cortical and subcortical astrocytosis, but no dysmorphic cells (Tuxhorn et al., 2009). As the early of these features correspond to abnormal cell migration, this disorder was moved to Group II.C.

Group II.D: Cobblestone Malformations

It has become clear that mutations of any genes involved in O-glycosylation of α-dystroglycan can cause a wide range of disorders ranging from Walker–Warburg syndrome to muscle–eye–brain disease to Fukuyama congenital muscular dystrophy to congenital muscular dystrophy types 1C and 1D to limb-girdle (LGMD2I, LGMD2K, LGMD2M) muscular dystrophies (Barresi and Campbell, 2006; Godfrey et al., 2007; Clement et al., 2008; Hewitt, 2009; van Reeuwijk et al., 2010). The precise molecular mechanisms underlying these phenotypic variations are slowly being elucidated (Hewitt, 2009; Ackroyd et al., 2011; Luo et al., 2011). The cause of the muscular, ocular or brain disorders in these patients is defective formation of basement membranes (of skeletal muscle, retina and cerebrum/cerebellum, respectively), which is related to impaired linkage of radial glia to the pial basement membrane, which is, in turn, dependent upon O-mannosylation of α-dystroglycan (Barresi and Campbell, 2006; Hewitt, 2009), laminin α1 deposition (Ackroyd et al., 2011) and GPR56-collagen III interactions (Luo et al., 2011). Resulting deficiencies in the cerebral basement membranes result in impaired anchorage of radial glial cells to the basement membranes, causing abnormal cortical lamination and overmigration of neurons through the incomplete basement membrane into the pial layer (Li et al., 2008; Luo et al., 2011). Less severe mutations may partially allow development of basement membranes and result in a less severe phenotype (Barresi and Campbell, 2006; van Reeuwijk et al., 2010; Luo et al., 2011; Yis et al., 2011). No direct correlation has been found between the severity of clinical disease and the particular gene mutation; however, null mutations of nearly all causative glycosylation genes result in severe (Walker–Warburg syndrome) phenotypes (except for POMGnT1) (van Reeuwijk et al., 2010). Much recent work has focused on cobblestone malformations due to Gpr56 and Col4a1 mutations (Li et al., 2008; Luo et al., 2011) and malformations associated with several genes affecting glycosylation within the endoplasmic reticulum or Golgi apparatus (classified as congenital disorders of glycosylation). Concerning the latter, the two best documented disorders to date are SRD5A3 (Al-Gazali et al., 2008; Cantagrel et al., 2010) and ATP6V0A2 (Kornak et al., 2008; Van Maldergem et al., 2008). GPR56 mutations appear to cause a 'cobblestone cortex' and not true polymicrogyria (Piao et al., 2005; Bahi-Buisson et al., 2010); therefore, the term 'frontoparietal polymicrogyria', which was the original name given to the cortical malformations seen in patients with GPR56 mutations, would be better replaced with a more appropriate one, such as 'frontal-predominant cobblestone malformation'. The cortical malformation associated with TUBB2B mutations also has cobblestone-like features including overmigration of neurons through gaps in the leptomeninges (Jaglin et al., 2009). Its proper classification awaits further study, but it is currently classified in Group III.A.3, syndromes with polymicrogyria, the neuropathology of which may differ from classic polymicrogyria.