Researchers at University of Calgary and Alberta Children's Hospital, Canada; and University of Pennsylvania, Philadelphia studied brain resections from 3 male infants with hemimegalencephaly (HME) and refractory epilepsy. One infant died at 2.5 months, and one has Proteus syndrome. The hippocampus and neocortex of HME showed cytoarchitectural abnormalities on electronmicroscopy and intense tau immuno-reactivity. The post-mortem non-HME hemisphere had sparse dysmorphic tau-reactive cortical neurons but none in subcortical regions. Numerous enlarged and dysmorphic cells exhibited immunoreactivity indicative of mTOR activation. Tau expression and mTOR activation were absent in control brains. Electron microscopy in each case showed lipid in neurons and lipid storage by light microscopy. The investigators propose that the pathogenesis of HME may involve an early defect in microtubules, probably related to the AKT3 gene. Lipidosis of neurons and glia suggests a metabolic impairment of undetermined type, related to tauopathy in HME. Perinatal treatment with everolimus (rapamycin), an inhibitor of mTOR pathway, might reduce the morbidity of HME, including epilepsy. [1]

COMMENT. Hemimegalencephaly is a hamartomatous dysgenesis, sometimes associated with other neurocutaneous syndromes, especially epidermal nevus and Proteus syndromes. Infants with Proteus syndrome [alt: Wiedemann syndrome] are normal at birth and develop skin tumors and bone growths with increasing age, especially involving the skull and soles of feet. Neurological involvement in rare reports of Proteus syndrome includes HME, Ohtahara syndrome, syringomyelia, arachnoid cyst, craniocutaneous lipomatosis, vascular malformation, and meningioma [2, 3]. Proteus syndrome is caused by a mutation in AKT1, and is classed as a genetic mosaicism. A knowledge of neurological syndromes helps in the selection of diagnostic tests and our understanding of the cause of refractory epilepsies.