disease progression in NP-C patients following 24 months of treatment. We report fi- nal, long-term data from this trial. Methods: Patients aged e12 years who completed a 12-month, open-label, ran- domised trial (miglustat 200 mg t.i.d. vs. standard care) and 12-month, open-label miglustat extension were offered miglustat treatment up to 66 months. Results: Sixteen out of 19 patients (84.2%) continued with treatment (mean SD age 22.6 9.4 years; 44% female). The numbers of patients completing 36, 42, 48 and 66 Months were 15 (93.7%), 11 (68.7%), 9 (56.2%) and 2 (12.5%), respectively. Median (range) treatment duration was 1465 (825–2056) days. At last assessment, swallowing capacity (in 14 evaluable patients) was improved or stable in 11 (78.6%) patients (with water), 12 (85.7%) patients (with puree), and 13 (92.8%) pa- tients (with both soft lumps and cookies). Ambulation Index (in 12 evaluable pa- tients) remained stable in 8 (66.7%) patients (mean change [95% CI], +0.6 [ 0.2, +1.4]). Diarrhoea and weight decrease were each recorded in 50.0% of patients overall, compared with 87.5% and 75.0%, respectively, during the first 24 months. Mean SD (range) weight change from baseline to last value was +0.56 1 8.10 kg (9.3 to +21.0 kg). Three patients discontinued; none because of adverse events. Conclusions: The data indicate that the effect of miglustat on disease stability ob- served in the initial phase of the study could be sustained over the long term. doi:10.1016/j.ymgme.2008.11.100 100. A multicentre retrospective survey of miglustat in patients with Niemann- Pick type C disease Marc Patterson a , Merci Pineda b , Fridiric Sedel c , Eugen Mengel d , Wuh-Liang Hwu e , Marianne Rohrbach f , Brubo Bembi g , Christoph Korenke h , Cicile Luzy i , Peter Schieber i , Ruben Giorgino i , Ed Wraith j , a Mayo Clinic, Rochester, MN, USA, Rochester, MN, USA, b Hospital Sant Joan de Deu, Barcelona, Spain, c Hopital Pitii Salpjtrihre, Paris, France, d University of Mainz, Mainz, Germany, e National Taiwan University Hospital, Taipei, Taiwan, f Kinderspital, Zurich, Switzerland, g Regional Coordinator Centre for Rare Diseases, University Hospital, Udine, Italy, h Elisabeth Kinderkrankenhaus, Oldenburg, Germany, i Actelion Pharmaceuticals Ltd, Allschwil, Switzerland, j Royal Manchester Children’s Hospital, Manchester, UK Introduction: Niemann-Pick disease type C (NP-C) is a progressive neurological disorder. The clinical trial, OGT-918-007, indicated that miglustat is able to slow dis- ease progression in patients with NP-C. Here we present the final results from a mul- tinational, retrospective survey assessing neurological disease progression in NP-C patients treated with miglustat. Methods: NP-C patients prescribed miglustat in 25 selected expert centres were included. Treating physicians were asked to complete a questionnaire on patient demographics, treatment history, disease progression and general health. A disease- specific disability scale was used to evaluate dysphagia, dystonia, ataxia and dysar- thria severity at diagnosis, treatment initiation and last visit. Results: In total, 66 patients were included (mean SD age: 9.7 7.6 years at diag- nosis, 12.8 9.5 years at miglustat initiation). Mean SD time interval between diagno- sis and treatment initiation was 3.1 3.4 years. Median (range) miglustat exposure was 533 (18 1646) days. Most patients remained stable or were improved after miglustat treatment as regards to dysphagia (51/63; 80.9%), dystonia (48/63; 76.2%), ataxia (49/64; 76.5%) and dysarthria (47/61; 77.0%). Of 65 evaluable patients, 49 (75.4%) were classified as good responders (if at least 3 out of 4 disability scale parameters were stable/improved). In physician global assessments, 22/60 (36.7%) evaluable patients improved in general health, and 43/58 (74.1%) evaluable patients experienced excellent, good or fair benefit. Conclusions: Miglustat appears to have a clinically relevant beneficial effect on neurological disease progression in patients with NP-C. doi:10.1016/j.ymgme.2008.11.101 101. Longitudinal study of cognition in subjects with Niemann-Pick disease, type C Marc Patterson a , Forbes Porter b , Rebecca Vaurio c , Tanya Brown a , a Mayo Clinic, Rochester, MN, USA, b National Institutes of Health, c The Hugo W. Moser Research Institute at Kennedy Krieger, Inc. Introduction: Niemann-Pick disease, type C (NPC) is a pan-ethnic, autosomal recessive lysosomal storage disease with an incidence of 1/150,000. Because of the devastating effects of this illness on patients and families, the public health burden of this disease is disproportionate to its prevalence. Most patients experience a pro- gressive dementia accompanied by vertical supranuclear gaze palsy ataxia, dysar- thria, dysphagia, dystonia and in some cases, epilepsy and cataplexy. Several potential human therapeutic agents have been studied invitro and in animal models of NPC. Before human therapeutic trials can be pursued, it is essential to define the clinical course of NPC, and to identify clinical, neuropsychological and laboratory markers of disease burden and progression. Hypothesis: Patients with NPC will demonstrate a specific pattern of neurocogni- tive deficits that will be present prior to development of significant neurological def- icits and that will correlate with disease progression. Methods: Subjects will be recruited from participants in studies at two network sites the NIH Clinical Center and Mayo Clinic. NPC patients enrolled in the current NIH NPC observational study will be recruited into the neurocognitive study that will be performed at the Kennedy Krieger Institute (KKI) in Baltimore. Patients are evalu- ated every 6–12 months in the NIH study, neurocognitive testing will be done every 12 months. NPC patients participating in the miglustat study will be seen every 12 months at Mayo Clinic, where neurocognitive evaluation will be performed using the same instruments as are employed at KKI. The neurocognitive phenotype of Niemann Pick disease type C will be defined using age and functionally appropriate instruments to assess the following domains: intelligence, visuospatial abilities, memory (verbal visual, working, non-verbal work- ing), visual-spatial construction, language, motor, attention/executive function, adap- tive and behavioral/emotional. Data will be analyzed using descriptive statistics. doi:10.1016/j.ymgme.2008.11.102 102. Genz-112638, an investigational oral treatment for Gaucher disease type 1: Preliminary Phase 2 clinical trial results Judith Peterschmitt a , Elena Lukina b , Nora Watman c , Elsa Arreguin d , Maryam Banikazemi e , Gregory Pastores e , Marcelo Iastrebner f , Marta Dragosky f , Hanna Rosenbaum g , Ari Zimran h , Fanny O’Brien a , Sharon Smith a , Ana Cristina Puga a , a Genzyme Corporation, Cambridge, MA, USA, b Russian Academy of Medical Sciences, c Hospital Ramos Mejia, d Instituto Mexicano del Seguro Social Hospital de Especialidades, e New York University, f Instituto Argentino de Diagnostico y Tratamiento, g Rambam Medical Center, h Sha’are Zedek Medical Center Introduction: Genz-112638 is a novel oral small molecule inhibitor of glucosylcer- amide synthase under development for the treatment of Gaucher disease type 1 (GD1). An open-label Phase 2 clinical study of the efficacy, safety, and pharmacokinet- ics of Genz-112638 in patients with GD1 has recently completed 52-week follow-up. Methods: This clinical trial of Genz-112638, given 50 or 100 mg bid orally, treated 26 adults with GD1 (16F:10M; mean age 34 years, range 18–60; all Caucasian) at 7 sites in 5 countries. Patients were to have splenomegaly (volumee10 normal) and either thrombocytopenia (platelets 45,000–100,000/mm 3 ) or anemia (hemoglobin 8–10 g/dL, female; 8–11 g/dL, male). None received enzyme replacement or substrate reduction therapy in the prior 12 months. The composite primary efficacy endpoint is based on improvements in e2 of the 3 main parameters: spleen volume (15%), hemo- globin level (+0.5 g/dL) or platelet count (+15%) after 52 weeks of treatment. Liver vol- ume, chitotriosidase, glucosylceramide are also assessed. Patients continue to be treated and monitored long-term. Results: To date, Week 52 data are available for up to 20 patients; 4 others with- drew prematurely and 2 are ongoing. The composite primary endpoint was met by 19 of the 20 patients. Mean (1SD) changes from baseline to Week 52 were: hemoglobin +1.6 (11.35) g/dL; platelet count +43.6% (137.59%); spleen and liver volume (multiples of normal) 40.2% (110.44%) and 15.8% (110.39%), respectively; and chitotriosidase 49.9% (120.75%). Plasma glucosylceramide levels normalized after 4 weeks in all pa- tients. Genz-112638 was well tolerated with an acceptable safety profile. As of June 2008, 7 adverse events in 6 patients have been reported as related; all were mild and transient. Conclusions: Preliminary data from this Phase 2 study indicate that Genz-112638 may be a safe, effective, and convenient oral therapy for patients with GD1. Clinical development of Genz-112638 is proceeding, and Phase 3 studies are planned. doi:10.1016/j.ymgme.2008.11.103 103. Bilateral coordination in children with Hurler and Hunter syndrome Dawn Phillips a , Dawn Phillips a , Maria Escolar b , a Division of Physical Therapy, School of Medicine, UNC at Chapel Hill, Chapel Hill, NC, USA, b Center for Development and Learning, UNC at Chapel Hill Children with MPS I (Hurler Syndrome) and MPS II (Hunter Syndrome) are living longer lives due to medical treatment advances,such as hematopoietic stem cell transplantation and enzyme replacement therapy. The Peabody Developmental Motor Scales II has been used to document gross motor delay in children with MPS through 6 years of age but little has been documented on the motor ability of the older child with MPS. The purpose of this report is to describe the bilateral coordination of 10 S34 Abstracts / Molecular Genetics and Metabolism 96 (2009) S12–S47