Huntington's disease (HD) is a hereditary and devastating neurodegenerative disorder caused by a mutation in the huntingtin protein. Understanding the functions of normal and mutant huntingtin protein is the key to reveal the pathogenesis of HD and develop therapeutic targets. Huntingtin plays an important role in vesicular and organelle trafficking. Lysosomes are dynamic organelles that integrate several degradative pathways and regulate the activity of mammalian target of rapamycin complex 1 (mTORC1). In the present study, we show that the perinuclear accumulation of lysosomes is increased in a cellular model of HD derived from HD knock-in mice and primary fibroblasts from a HD patient. This perinuclear lysosomal accumulation can be reversed when normal huntingtin is overexpressed in HD cells. To further investigate the functional significance of the increased perinuclear lysosomal accumulation in HD cells, we demonstrate subsequently that basal mTORC1 activity is increased in HD cells. In addition, autophagic influx is also increased in HD cells in response to serum deprivation, which leads to a premature fusion of lysosomes with autophagosomes. Taken together, our data suggest that the increased perinuclear accumulation of lysosomes may play an important role in HD pathogenesis by altering lysosomal-dependent functions.

BACKGROUND Stereoelectroencephalography (SEEG) is an alternative addition to subdural grids (SDG) in invasive extra-operative monitoring for medically refractory epilepsy. Few studies exist on the clinical efficacy and safety of these techniques in pediatric populations. OBJECTIVE To provide a comparative quantitative summary of surgical complications and postoperative seizure freedom associated with invasive extra-operative presurgical techniques in pediatric patients. METHODS The systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A literature search was conducted utilizing Ovid Medline, Embase, Pubmed, and the Cochrane database. RESULTS Fourteen papers with a total of 697 pediatric patients undergoing invasive SDG monitoring and 9 papers with a total of 277 pediatric patients undergoing SEEG monitoring were utilized in the systemic review. Cerebral spinal fluid (CSF) leaks were the most common adverse event in the SDG studies (pooled prevalence 11.9% 95% confidence interval [CI] 5.7-23.3). There was one case of CSF leak in the SEEG studies. Intracranial hemorrhages (SDG: 10.7%, 95% CI 5.3-20.3; SEEG: 2.9%, 95% CI –0.7 to 10.8) and infection (SDG: 10.8%, 95% CI 6.7-17) were more common in the SDG studies reviewed. At the time of the last postoperative visit, a greater percentage of pediatric patients achieved seizure freedom in the SEEG studies (SEEG: 66.5%, 95% CI 58.8-73.4; SDG: 52.1%, 95% CI 43.0-61.1). CONCLUSION SEEG is a safe alternative to SDG and should be considered on an individual basis for selected pediatric patients.

Introduction: MR-guided laser interstitial thermal therapy (MRgLITT) has emerged as a safe and effective treatment option for the ablation of epileptic foci. Its minimally invasive nature makes it attractive due to decreased morbidity and hospital stay. Objective: To report the efficacy and safety of MRgLITT as a minimally invasive procedure for the ablation of epileptic foci in the pediatric population of medically refractory lesional epilepsy. Methods: A retrospective review of patients who underwent MRgLITT via Visualase laser ablation at a single pediatric center was performed. Demographic and outcome data were compiled and analyzed. Results: Twelve pediatric patients with a total 18 lesions underwent MRgLITT procedures between December 2013 and September 2017. Mean age at surgery was 11.1 years. Surgical substrates included 4 hypothalamic hamartomas, 3 periventricular heterotopias, 2 deep focal cortical dysplasias, 2 tuberous sclerosis, and 1 mesial temporal sclerosis. Methods of stereotaxis used included Leksell frame, BrainLab VarioGuide, ROSA robot guidance, and ClearPoint navigation. Mean procedure length was 250 min, and mean length of stay was 1.3 days. After treatment, 8 patients were seizure free (Engel I, 66.7%), 2 patients demonstrated significant improvement (Engel II, 16.7%), and 2 patients showed worthwhile improvement (Engel III, 16.7%). One patient developed a left superior quadrantanopsia postoperatively. Mean follow-up duration was 10 months. Conclusion: This study contributes to the sparse literature in this field by demonstrating the high efficacy and low morbidity of MRgLITT as a minimally invasive method of ablation of epileptic foci in the pediatric population of medically refractory lesional epilepsy.