Hemimegalencephaly: foetal tauopathy with mTOR hyperactivation and neuronal lipidosis.

[proteus syndrome]

Hemimegalencephaly (HME ) is a hamartomatous malformation of one cerebral hemisphere . As this is a disorder of cellular growth and lineage , we sought evidence of an early ontogenetic disturbance of microtubular assembly or function .Three male infants with HME had brain resections for refractory epilepsy . One died postoperatively at 2 .5 months and an autopsy was performed . Two were isolated cases and one has Proteus syndrome . The phosphorylated form of the microtubule-associated protein tau was studied , transmission electron microscopy (EM ) was performed , and activation of the mTOR pathway was defined .The hippocampus and neocortex of HME exhibited cytoarchitectural abnormalities and intense tau immunoreactivity . The post-mortem non-HME hemisphere exhibited sparse dysmorphic tau-reactive cortical neurones , intense only in the cingulate gyrus , a few isolated dysmorphic white matter neurons and none in subcortical structures . Numerous enlarged and dysmorphic cells exhibited P-4 E -BP 1 and phosphoribosomal P-S 6 immunoreactivity , indicating mTOR activation . Control brains were negative for tau expression and mTOR activation . EM in each case showed abundant lipid in neurones and astrocytic end-feet on capillaries , and well-preserved mitochondria ; oil red O in frozen sections and semi-thin sections also showed lipid storage by light microscopy .Because HME tissue exhibited enhanced levels of phosphorylated tau protein and evidence of mTOR hyperactivation , we propose that the pathogenesis of HME may involve an early defect in microtubules , likely related to the AKT 3 gene . Lipidosis of neurones and glia suggests metabolic impairment of yet undetermined type and relation to tauopathy in HME . Perinatal treatment of HME with everolimus theoretically is plausible .