administration of a single dose of the antioxidant N-acetylcysteine (NAC), which is a glutathione (GSH) precursor, will increase red blood cell (RBC) and brain GSH concentrations in GD and PD. 7 Tesla magnetic resonance spectroscopy (MRS) will be employed to measure baseline and brain GSH levels after infusion. We intend to quantitate plasma, red blood cell, and brain GSH concentrations and compare NAC and GSH pharmacokinetics at baseline and after i.v. NAC infusion. These data will also be used to evaluate the relationship between peripheral (plasma and RBC) and central (brain) GSH measurements. Methods: Participants (3 controls, 3 PD, and 3 GD) will receive NAC (150 mg/kg) intravenously. Blood samples will be collected prior to and at specified time points over an hour period after infusion. NAC and GSH concentrations in plasma and RBCs will be measured using a validated HPLC-MS method. Brain GSH concentrations will be measured via 7 Tesla MRS prior to and for 1 hour following NAC infusion. Results: NAC and GSH pharmacokinetics in plasma and RBCs will be presented for all completed subjects, as well as comparison of baseline and post-infusion brain GSH concentrations between study groups. doi:10.1016/j.ymgme.2011.11.078 Fabry Registry Data Indicate that Early Initiation of Agalsidase Beta Treatment is Associated with Fewer Clinical Events Robert Hopkin a , Michael Mauer b , Roberta Lemay c , Jörg Strotmann d , Katherine Sims e, f , a Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, b University of Minnesota, Division of Pediatric Nephrology, Minneapolis, MN, USA, c Genzyme, Biomedical Data Sciences and Informatics, Cambridge, MA, USA, d I. Medizinische Klinik, Städtisches Krankenhaus, Kiel, Germany, e Massachusetts General Hospital, Center for Human Genetic Research, Boston, MA, USA, f Harvard Medical School, Neurology Department, Boston, MA, USA Longitudinal data from the Fabry Registry were analyzed to quantify the occurrence of clinical events after initiation of agalsidase beta as enzyme replacement therapy (ERT) for Fabry disease. Men age 18 years who received agalsidase beta as their first source of ERT at an average dose of 1 mg/kg/2 weeks were included in these analyses (N=1,013), based on data collected through June 2009. Most men (783/1,013, 77%) did not experience renal, cerebrovascular, or cardiovascular events during treatment (follow-up time 4 2.5 years, mean SD). Men who had events during treatment (230/ 1,013, 23%, follow-up time 5 2.4years, mean SD) were more likely to have experienced events before initiating treatment than were men who remained event-free during treatment: 48% (111/230) versus 18% (145/783). Multivariate Poisson regression analyses were used to identify prognostic factors associated with clinical events. Four hundred sixty of the 1,013 men in the cohort had data available for averaged urinary protein, estimated glomerular filtration rate, and age at initiation of treatment. Men who initiated agalsidase beta treatment at age 40 years were more likely to experience clinical events, compared with men who initiated treatment at age <30 years (rate ratio 3.5, 95% CI 1.46—7.42, p=0.001). Elevated averaged urinary protein ( 1 g/g) and having advanced chronic kidney disease (stages 3–5) at baseline were also associated with the occurrence of clinical events during treatment. These findings indicate that early initiation of agalsidase beta treatment is associated with fewer clinical events. doi:10.1016/j.ymgme.2011.11.079 The E3 Ligase Itch Regulates Degradation of Mutant Glucocerebrosidase Mia Horowitz, Gali Fiterman, Tel Aviv University, Ramat Aviv, Israel Inability to properly degrade unfolded or misfolded proteins in the ER leads to ER stress and unfolded protein response. This is particularly important in cases of diseases in which the mutant proteins undergo ER associated degradation (ERAD), like Gaucher disease. Gaucher disease (GD) is a genetic, autosomal recessive disease that results from mutations in the gene encoding the lysosomal enzyme acid-β-glucocerebrosidase (GCase). We have shown that all mutant GCase variants undergo ERAD, the degree of which is a major determinant of disease severity. We have also shown that there is unfolded protein response in GD derived fibroblasts, manifested by increase in BiP (Grp78) or CHOP and splicing of XBP1. However, there was no direct correlation between the level of UPR and GD severity. Most ERAD substrates undergo ubiquitination and proteasomal degradation. Since GCase is not a natural substrate for ubiquitination and proteasomal degradation, one would expect that mutant GCase variants will interact with a wide variety of E3 ligases, in different cells. We tested the possibility that Itch, a known E3 ligase, with a pivotal role in differentiation of the skin, recognizes mutant GCase variants and mediates their ubiquitination and degradation. Our results show that Itch mediates K48 ubiquitination and degradation of mutant GCase variants. Itch controls the capacity of p63, a transcription factor, to direct expansion of the basal epithelial layer of the skin. Our results demonstrate that elevation in expression of mutant GCase, correlates with elevation in p63 levels in cells, which may interfere with the homeostasis of differentiation and proliferation of the skin. doi:10.1016/j.ymgme.2011.11.080 Evaluation of Brain Volumetrics in an MPS VI Patient With Cervical Cord Compression – A Case Study Lisa Hostetler a , Igor Nestrasil b , Elsa Shapiro b , Chester Whitley b , a University of Minnesota Clinical and Translational Science Institute, Minneapolis, MN, USA, b University of Minnesota Department of Pediatrics, Minneapolis, MN, USA In September 2010 the University of Minnesota treated a 16-year old MPS VI subject with spinal cord compression with four doses of intrathecal (IT) Galsulfase under a single patient emergency use IND application. The IT doses were completed by the end of December 2010. The subject experienced no complications or toxicities from the IT administrations. An MRI scan 12 months after the initial IT dose showed no change in spinal cord compression although the subject reported slight improvements in his symptoms. The subject was concurrently involved a longitudinal study of MPS VI disease where MRI brain volumetrics utilizing FreeSurfer were being conducted. The subject had a total of four MRI scans during his time in the IT galsulfase project. Analysis of the scans shows a 14.95% decrease in cortical volume and a 18.45% increase in the size of the ventricles during the same time period. Very little is known about the rate of cortical and ventrical volume change in MPS VI patients over time. With no baseline data it is difficult to determine whether the IT galsulfase treatments may have helped to slow the rate of these changes or whether the treatments resulted in a marked decrease in storage material which might be accompanied by increased ventricular size. It is hoped that additional information regarding the brain volumetric changes in MPS VI patients that is gained through the Lysosomal Disease Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69 S36