Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate, and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5 Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. MRI and postmortem brain analysis supports important roles for WDR62 in proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat-containing protein expressed in neuronal precursors as well as postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The diverse phenotypes of WDR62 suggest central roles in many aspects of cerebral cortical development.

Hemimegalencephaly is a rare hamartomatous malformation of the brain, remarkable for its extreme asymmetry. It can be isolated or associated with several neurocutaneous syndromes; less frequently, it also involves the brain stem and cerebellum. Traditionally, hemimegalencephaly has been considered a primary neuroblast migratory disturbance. At present, genetic theories of pathogenesis and modern histopathology provide a basis for this complex malformation as a primary disturbance in cellular lineage, differentiation, and proliferation, interacting with a disturbance in gene expression of body symmetry, with earlier onset than radial neuroblast migration. From my personal experience with 10 patients with hemimegalencephaly and review of the literature, I have found the same clinical neurologic, neuroimaging, and neuropathologic features in isolated and syndromic hemimegalencephaly. Magnetic resonance imaging (MRI) reveals abnormal gyration, ventriculomegaly, colpocephaly, an "occipital sign" (displacement of the occipital lobe across the midline), and increased volume and T2 signal of white matter, in addition to the overall increased size of the involved hemisphere. Mild, moderate, and severe grades of severity can be recognized, providing a functional neurologic prognosis and therapeutic plan. Early diagnosis is crucial because despite neuroimaging and pathologic evidence, hemimegalencephaly sometimes still is unrecognized. Also, misdiagnosis of obstructive hydrocephalus or cerebral neoplasm can lead to unnecessary surgical procedures. Although hemispherectomy has a high morbidity, it is recommended early for patients with severe, intractable epilepsy. The mildest forms of hemimegalencephaly are infrequent and the least recognized.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either the TSC1 or TSC2 genes and characterized by developmental brain abnormalities. We defined the spectrum of brain abnormalities in fetal TSC brain ranging from 23 to 38 gestational weeks. We hypothesized (1) prenatal activation of the target-of-rapamycin complex 1 (TORC1) signaling pathway and (2) activation of inflammatory pathways in fetal brain lesions. Immunocytochemical analysis of cortical tubers, as well as subependymal lesions in all cases confirmed the cell-associated activation of the TORC1 signaling pathway in both the cortical tubers and subependymal lesions (including a congenital subependymal giant cell astrocytoma) with expression of pS6, p4EBP1 and c-myc proteins, as well as of p70 S6 kinase 1. The lesions contained macrophages and T-lymphocytes; giant cells within the lesions expressed inflammatory response markers including major histocompatibility complex (MHC) class I and II, Toll like receptor (TLR) 2 and 4 and advanced glycation end products (RAGE). These observations indicate that brain malformations in TSC are likely a consequence of increased mTOR activation during embryonic brain development. We also provide evidence supporting the possible immunogenicity of giant cells and the early activation of inflammatory pathways in TSC brain.

Cerebral tissue from hemispherectomy in three children (two 4-month-old girls and one 4-year-old boy) with hemimegalencephaly was studied using histochemical and immunocytochemical markers of neuronal and glial maturation and identity. Histologic abnormalities of cellular growth and cytomorphology, including "balloon cells," were present in both gray and white matter, in addition to disorganized tissue architecture. Cells in the mitotic cycle were absent. Many hypertrophic, atypical cells with enlarged processes exhibited mixed or ambiguous lineage, with immunoreactivity for both glial (glial fibrillary acidic protein [GFAP]; S-100beta) and neuronal proteins (microtubule-associated protein 2 [MAP2], neuronal nuclear antigen, chromogranin A, and neurofilament protein [NFP]). Strong vimentin reactivity was present in neurons, as well as glial cells and cells of mixed lineage, suggesting incomplete maturation. Synaptophysin-reactive axons terminated on a minority of balloon cells and on most heterotopic single neurons in white matter, confirmed by electron microscopy, demonstrating that single heterotopic neurons are not synaptically "isolated," as they may appear; thus, they are capable of contributing to epilepsy. Oligodendrocytes are the least affected cells, at least in some cases. The findings are reminiscent of the hamartomas of tuberous sclerosis. We conclude that hemimegalencephaly is a primary disorder of neuroepithelial lineage and cellular growth. A migratory disturbance contributes to disorderly tissue architecture but is secondary. No pathologic difference is detected between isolated and syndromic forms of hemimegalencephaly.