Activation of microglia/macrophages expressing phosphorylated S6 ribosomal protein in a case of hemimegalencephaly with progressive calcification and atrophy

Abstract

A 3-year-old boy with right hemimegalencephaly (HME) showed massive calcification in the subcortical white matter and progressive atrophy of the affected hemisphere. Hemispherotomy was successful in amelioration of the patient's intractable epilepsy, and a surgical specimen from the epileptic focus was examined pathologically. Disarrangement of cortical layers along with dysmorphic appearance of neurons, balloon cells in the cortex and white matter, bi-layered calcifications in the superficial cortical layer and subcortical white matter, heterotopic neurons in the white matter, and diffuse astrogliosis were noted. Perivascular clustering of alpha-B-crystallin positive balloon cells was occasionally observed in the area of calcification. A diffuse increase was observed in the number of CD68-positive microglia/macrophages, particularly in perivascular and peri-calcification areas. These cells were often located within the calcification foci, which implicates their participation in the calcification process. Phosphorylated S6 ribosomal protein (P-S6) was expressed in large-sized neurons and numerous balloon cells, as well as in CD68-positive cells. In contrast, phosphorylated mammalian target of rapamycin (mTOR) was expressed in a small percentage of astrocytes, and phosphorylated p70S6 kinase was rarely identified in perivascular cells. These findings suggest that inflammatory processes have contributed to the pathogenesis of progressive calcification and atrophy in the megalencephalic hemisphere in this patient. Dissociation of expression of mTOR cascade components is common to other reported cases of HME, but P-S6 expression in microglia/macrophages has not been recognized. The cellular mechanism and significance of P-S6-specific activation of the mTOR cascade in HME, particularly in the inflammatory cell lineage, should be explored further.