University of Calgary and Alberta Children's Hospital Calgary, Alberta, Canada.
Folia Neuropathol. 2012;50(4):330-45. doi: 10.5114/fn.2012.32363.
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-4E-BP1 and phosphoribosomal P-S6 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 AKT3 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.
偏侧巨脑症（HME）是一侧大脑半球的错构瘤性畸形。由于这是一种细胞生长和谱系的紊乱，我们寻求微管组装或功能早期发育障碍的证据。
3 名患有 HME 的男性婴儿因难治性癫痫进行了脑切除术。其中 1 例在术后 2.5 个月死亡并进行了尸检。2 例为孤立病例，1 例患有 Proteus 综合征。研究了微管相关蛋白 tau 的磷酸化形式，进行了透射电镜（EM）检查，并定义了 mTOR 途径的激活。
HME 的海马体和新皮质表现出细胞结构异常和强烈的 tau 免疫反应。尸检非 HME 半球仅在扣带回中表现出稀疏的形态异常的 tau 反应性皮质神经元，强烈表达，少数孤立的形态异常的白质神经元，皮质下结构中无神经元。大量增大和形态异常的细胞表现出 P-4E-BP1 和核糖体磷 S6 免疫反应性，表明 mTOR 激活。对照脑为 tau 表达和 mTOR 激活阴性。每种情况下的 EM 均显示神经元和星形胶质细胞毛细血管末端大量脂质，以及保存完好的线粒体；油红 O 在冷冻切片和半薄切片中也通过光镜显示脂质储存。
由于 HME 组织表现出磷酸化 tau 蛋白水平升高和 mTOR 过度激活的证据，我们提出 HME 的发病机制可能涉及微管的早期缺陷，可能与 AKT3 基因有关。神经元和神经胶质的脂质沉积表明代谢受损，其类型和与 HME 中的 tau 病的关系尚不确定。理论上，HME 围产期用依维莫司治疗是合理的。
