Malformations of Cortical Development

Disorders of Cellular Proliferation

Malformations in this group include disorders that result in either increased or decreased growth or in increased or decreased apoptosis. These disorders often manifest as abnormal brain size or localized areas of enlargement. Abnormalities in brain size can manifest as microcephaly with a normal to thin cortex, microlissencephaly, microcephaly with polymicrogyria, or macrocephaly. ^{, , ,}

Microcephaly is defined as a head circumference that is greater than 2 standard deviations smaller than normal. Micrencephaly refers to a small brain. Patients with this condition have a brain that may be up to 70% smaller than normal, but the brain has essentially normal cortical laminar architecture. In some cases of micrencephaly, there is a simplified gyral folding pattern observed on MR images. Because any process that interferes with brain growth can lead to reduced head and brain size, microcephalies are a highly heterogeneous group of disorders. Microcephaly can result from a number of prenatal insults including hypoxia-ischemia and fetal alcohol exposure. In addition, a number of genes ( ASPM, MCPH1, CENPJ, and CDK5RAP2 ) have been shown to result in autosomal recessive forms of microcephaly. ^{, , ,} Rare syndromic forms include Amish lethal microcephaly and Seckel syndrome. ^, The ASPM (abnormal spindle-like microcephaly-associated) gene is of particular interest because it is the single most common genetic mutation associated with microcephaly, and it has provided new insights into evolutionary mechanisms governing brain size across species. ASPM is an ortholog of a Drosophila gene that has been shown to be essential for normal mitotic spindle function in embryonic neuroblasts. When the gene is absent, the neuroblasts are arrested in the cell cycle and fail to proliferate, resulting in reduction in the number of cells in the brain and consequently a smaller brain size. When the human ASPM gene sequence was compared with that in primates, there was a correlation between sequence and brain size. Thus ASPM appears to have played a central role in the genetic component in the evolutionary expansion in brain size from primates to Homo sapiens.

Macrocephaly, defined as measurable (>2 standard deviations) enlargement of the head, can occur in association with a large number of syndromes and conditions, some of which, such as hydrocephalus, autism, leukodystrophies, and organic acidurias, are not associated with MCD. Megalencephaly (ME) is the condition in which both brain and head size are increased. In recent years a number of new gene mutations in AKT, PI3KCA, PTEN, and TBC1D7 have been identified to account for ME. Hemimegalencephaly (HME) is a malformation characterized by the abnormal enlargement of one entire hemisphere ( Fig. 79.1 ); a variant of HME is lobar dysplasia in which an entire brain lobe is enlarged. HME may be seen in isolation or in the setting of known syndromes, such as linear sebaceous nevus, hypomelanosis of Ito, tuberous sclerosis complex (TSC), or Proteus syndrome. HME is highly associated with intractable seizures and, often, infantile spasms. Pathologic analyses of HME brains demonstrate loss of cortical lamination dysmorphic neurons and cytomegalic cells similar to those seen in FCD and TSC (discussed later). Over the past several years, somatic or germline mutations in a number of genes including AKT, PI3KCA, PTEN, and DEPDC5 have been linked to HME.

In addition to changes across broad cortical areas, disorders of cellular proliferation can result in focal malformations or dysplasias. These lesions include FCDs, which have been divided into types Ia, Ib, Ic, IIa, IIb, and III (see Crino ). In some schemas, low-grade neoplastic lesions such as dysembryoplastic neuroepithelial tumor, ganglioglioma ( Fig. 79.2 ), and gangliocytoma are linked to MCD. This is not irrational, because they share some genetic mutations and other features such as upregulation of abnormal tau, one of several microtubular proteins important in cellular growth and differentiation. ^,

TSC results from mutations in TSC1 , encoding TSC1 or hamartin, or TSC2 , encoding TSC2 or tuberin. ^, TSC1 and TSC2 are known modulators of the mammalian target of rapamycin (mTOR) pathway, which governs cell size and proliferation. Neurological manifestations of TSC include epilepsy, infantile spasms, cognitive disabilities, and autism. Cortical tubers are focal areas of disorganized cortical lamination characterized by the presence of cytomegalic cells known as giant cells, which are morphologically similar to balloon cells in FCD type IIb (see later). The number of tubers across patients is variable and does not seem to vary with mutation type, patient age, or, necessarily, neurological phenotype.

FCD is an often sporadic condition for which specific gene mutations have been recently identified, especially among regulatory components of the mTOR pathway. ^, The existing classification scheme for FCD delineates three broad categories that reflect a spectrum of pathologic severities. FCD types Ia and Ib are characterized by often subtle alterations in, respectively, columnar and laminar architecture of restricted areas of cortex; type Ic is a combination of Ia and Ib. Gene mutations have not been clearly associated with these subtypes. Types IIa and IIb exhibit more dramatic histopathologic changes, including large dysmorphic neurons in type IIa and the presence of balloon cells in type IIb that are similar to giant cells found in TSC ( Fig. 79.3 ). Both germline and somatic mutations in a number of genes associated with the mTOR pathway including PI3K, AKT3, DEPDC5, and MTOR itself have been associated with types IIa and IIb FCD.