Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology

Abstract

Megalencephaly (MEG) is a developmental disorder characterized by brain overgrowth that occurs due to either increased number or size of neurons and glial cells. The former may be due to either increased neuronal proliferation or decreased apoptosis. The degree of brain overgrowth may be extensive, ranging from generalized MEG affecting the entire cortex-as with mutations in PTEN (phosphatase and tensin homolog on chromosome ten)-to unilateral hemispheric malformations-as in classic hemimegalencephaly (HME). On the other hand, some lesions are more focal or segmental. These developmental brain abnormalities may occur in isolation in some individuals, whereas others occur in the context of a syndrome involving dysmorphic features, skin findings, or other organ system involvement. Brain overgrowth disorders are often associated with malformations of cortical development, resulting in increased risk of epilepsy, intellectual disability, and autistic features, and some are associated with hydrocephalus. The past few years have witnessed a dramatic leap in our understanding of the molecular basis of brain overgrowth, particularly the identification of mosaic (or post-zygotic) mutations in core components of key cellular pathways such as the phosphatidylinositol 3-kinase (PI3K)-vakt murine thymoma viral oncogene homolog (AKT)-mTOR pathway. These molecular insights have broadened our view of brain overgrowth disorders that now appear to span a wide spectrum of overlapping phenotypic, neuroimaging, and neuropathologic features and molecular pathogenesis. These molecular advances also bring to light the possibility of pathway-based therapies for these often medically devastating developmental disorders.

Keywords: PI3K-AKT-mTOR pathway; Ras/MAPK pathway; hemimegalencephaly; megalencephaly; overgrowth; polymicrogyria; somatic mosaicism.