; 20 years: data on late treatment initiation from the Hunter Outcome Survey (HOS)

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participants’ knowledge, working practice and attitude were assessed by another survey. Emergency standard operating procedures and equipment, as well as training policies have been adopted as result of the training. Thus our training impacted the participants’ skills and working practice at the individual, team, environmental and organisational level.

doi:10.1016/j.ymgme.2016.11.191

183 Sudden, pronounced height increase for adolescent and young adult males with Fabry disease Dawn A. Laney, Emory University, Decatur, GA, United States Fabry disease (FD) is an X-linked progressive, multisystemic inborn error of glycosphingolipid catabolism resulting from mutations in the α-galactosidase A (GLA) gene. Slow growth (mean height/weight b50th percentile) in pediatric males affected with FD is a documented feature of the condition. We hypothesized that during adolescence/young adulthood these shorter stature males with FD may experience a sudden increase in growth and may move into higher percentiles. In this study, we analyzed height values from 198 males affected with FD enrolled in the Fabry Registry (NCT00196742, sponsor: Sanofi Genzyme) regardless of enzyme replacement therapy status. These males were aged 12-21 years old, had initial height values in the b50th percentile and at least one follow up height value two or more years later while b 30 years of age. All subjects were then categorized into 2 groups: Stable (b50% for height) and Growth (moved into the N50% for height). An additional subset of the growth group of males moving into the N75% was also created. Mean age at the baseline height values was similar for both groups: age 15.5 years for Stable males and age 14.6 years for the Growth group. Of the 198 males, 128 (65%) stayed in the Stable group. Seventy males (35%) moved into the Growth group. Twenty of the 70 males in the Growth group reached the 75th percentile. Our analysis found that over 35% of males with FD had a clinically substantial increase in height over their projected growth curve during adolescence/young adulthood. Further research should be undertaken in the males Growth group to determine if this growth spurt could be correlated with a change in expected course of FD natural history. Possible factors to explore could be positive health changes such as gastrointestinal improvements, improved nutrition, or years of FD specific therapy.

doi:10.1016/j.ymgme.2016.11.192

184 Reported outcomes of 453 pregnancies in patients with Gaucher disease: an analysis from the Gaucher Outcome Survey Heather Laua, Nadia Belmatougb, Patrick Deeganc, Ozlem Goker-Alpand, Ida Vanessa D. Schwartze,f, Suma P. Shankarg, Zoya Panahlooh, Ari Zimrani, aDivision of Neurogenetics, New York University School of Medicine, New York, NY, United States, bReferral Centre for Lysosomal Diseases, University Hospital Paris Nord Val de Seine, Clichy, France, c Addenbrooke's Hospital, Cambridge, United Kingdom, dLysosomal Disorders Unit and Center for Clinical Trials, O&O Alpan, LLC, Fairfax, VA, United States, eHospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, f Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, gEmory University School of Medicine, Atlanta, GA, United States, hShire, Zug,

Switzerland, iShaare Zedek Medical Center and the Hebrew UniversityHadassah Medical School, Jerusalem, Israel The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD)-specific registry established in 2010 for patients with a confirmed GD diagnosis, regardless of their GD type or treatment status. We examined the fetal outcomes of pregnancies reported in GOS to obtain evidence that may assist pregnant women with Gaucher disease (GD) and their physicians in their consideration of treatment during pregnancy. Data on pregnancy events, treatment status during pregnancy, and fetal outcome were collected. A normal outcome is defined as delivery at term resulting in a live birth with no congenital abnormalities. Pregnancies with delivery or end dates from January 1959 to July 2015 (n= 453) were reported in 189 women. Most pregnancies (336/453) were in women who did not receive GD treatment during pregnancy. Of these pregnancies, 312 (92.9%) had normal outcomes, 12 (3.6%) ended in spontaneous abortion, 11 (3.3%) in elective abortion, and 1 (0.3%) in neonatal death. Enzyme replacement therapy (ERT) was received in 117/453 pregnancies. In women who received velaglucerase alfa b1 month before conception and/or at some time during pregnancy, 34/36 (94.4%) pregnancies had normal outcomes and 2 (5.6%) ended in spontaneous abortion. Of the 36 pregnancies exposed to velaglucerase alfa, there were 20 in which velaglucerase alfa was received before conception and in all trimesters; all 20 had normal outcomes. There were 81 pregnancies in women on other ERTs (alglucerase, imiglucerase, or taliglucerase). Outcome was unspecified in 1 of these pregnancies; of the remainder, 72 (90.0%) had normal outcomes, 6 (7.5%) ended in spontaneous abortion and 2 (2.5%) in elective abortion. In conclusion, most pregnancies in GD patients had normal outcomes. The normal outcomes of all 20 pregnancies exposed to velaglucerase alfa throughout adds to information in the literature suggesting that continuation of ERT during pregnancy may be appropriate for some GD patients.

doi:10.1016/j.ymgme.2016.11.193

185 Profile of patients with mucopolysaccharidosis type II without cognitive impairment who started idursulfase treatment aged N20 years: data on late treatment initiation from the Hunter Outcome Survey (HOS) Heather A. Laua, Julia Hennermannb, Nathalie Guffonc, Shuan-Pei Lind, Virginie Jegoe, David Whitemanf, aNew York University, New York, NY, United States, bUniversity Medical Center, Mainz, Germany, c Hôpital Femme Mère Enfants, Bron, France, dMackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan, eCytel, Inc., Geneva, Switzerland, fShire, Lexington, MA, United States Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a progressive X-linked disease caused by deficient activity of iduronate-2-sulfatase (I2S). The so-called attenuated (slowly progressive) form has minimal CNS involvement; however, extraneurologic manifestations can be as significant as in the severe (early progressive) form. Enzyme replacement therapy with recombinant I2S (idursulfase; Shire) was available in 2006 in the USA, 2007 in the EU and subsequently in other countries globally. Herein, we describe patients with MPS II without cognitive impairment from the Hunter Outcome Survey (HOS; a global observational registry) who were aged N20 years at treatment initiation. Cognitive impairment was based on the answer to the yes/no question from the database: ‘Cognitive impairment?’. As of March 2016, 59/947 patients followed

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prospectively in the registry met these criteria. Patients were stratified by age at treatment start: N20 to b25 years (n =21), ≥25 to b30 years (n =18), ≥30 to b35 years (n=7) and ≥35 years (n = 13). Retrospective analyses of median ages at symptom onset in years (P10;P90) were: 3.3 (0.8;8.0), 3.5 (0.2;7.5), 4.8 (4.1;18.2) and 4.0 (1.0;44.3), respectively. Overall, the systems most commonly affected (between birth and last visit) were musculoskeletal (59/59), abdominal/gastrointestinal (57/59) and ear (56/58). Median ages at diagnosis were: 7.2 (0.3;19.0), 4.6 (2.9;26.0), 18.8 (4.5;32.6) and 7.5 (4.0;19.0). Median ages at treatment initiation were: 22.5 (20.6;24.8), 27.7 (25.2;29.2), 31.9 (30.4;34.2) and 39.3 (36.7;47.8). Reasons for delaying treatment initiation after diagnosis are unknown. Apart from drug availability, factors may include very mild clinical symptoms, physician/patient decision or perception of inefficacy after a certain age, balancing infusion regimens with daily life, or symptom onset/worsening. Further analysis is required to delineate these barriers and raise awareness of the importance of early diagnosis and timely treatment initiation. (Funding information: Shire sponsors HOS and funds medical writing support.) doi:10.1016/j.ymgme.2016.11.194

186 Heterogeneity in Fabry disease Lucia Lavalle, Alison Thomas, Brendan Beaton, Hatim Ebrahim, Matthew Reed, Uma Ramaswami, Atul Mehta, Derralynn Hughes, University College London, London, United Kingdom Fabry disease (FD) is clinically heterogeneous. Neither disease severity nor progression can be predicted completely by genotype. “Classical” versus “non-classical” phenotypes cannot be predicted exclusively by GLA variant. Our aim is to understand factors influencing phenotypic variability in FD. We analysed a single-centre cohort of 170 Fabry patients: 58 N215S mutation (25 males) and 112 non-N215S mutations (40 males). We classified both groups according to clinical severity, based on MSSI scores, into “mild” (MSSI b 20) and “moderate” (MSSI 20 – 40) phenotypes. N215S males have higher leukocyte α-Gal A activity compared to nonN215S (6.73, SD: 3.33 vs. 2.07, SD: 1.36 nmol/ml/hr, pb0.005). Globotriaosylsphingosine (lyso-Gb3) levels are higher in the nonN215S group (45.15, SD: 31.46 vs. 6.50, SD: 2.68 nmol/L, pb0.0001). When segregating both groups by severity a similar disposition is maintained among the subgroups (lyso-Gb3: mild N215S = 4.60, SD: 1.34 vs. mild non-N215S = 33.46, SD: 30.85 nmol/L, not significant, and moderate N215S = 7.77, SD: 2.72 vs. moderate non-N215S = 47.14, SD: 32.39 nmol/L, p b0.0001). Lyso-Gb3 in moderate severity N215S patients, however, is lower than in mild non-N215S patients. N215S males have a lower age adjusted severity score (total means: -4.80, SD: 5.80 vs. 7.57, SD: 8.55, pb0.0001), mild (-7.38, SD: 6.37 vs. -6.94, SD: 15.02, not significant) and moderate (-3.35, SD: 5.14 vs. 9.10, SD: 5.05, pb0.0001). In females, there were no differences in leukocyte α-Gal A activity between the mutations, however, N215S have lower levels of lyso-Gb3 (1.50, SD: 1.06 vs. 6.68, SD: 4.05, pb0.0001) and lower age adjusted severity score (-1.74, SD: 6.21 vs. 5.25, SD: 7.32, pb0.0001). In conclusion, the N215S population reach a severity comparable with the non-N215S population without equivalent elevation of lyso-Gb3. Further work is required to understand the pathogenesis in this mutation and possible presence of modifying factors.

doi:10.1016/j.ymgme.2016.11.195

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187 Corpus callosum white matter myelination by neuroimaging and myelin composition analysis in murine mucopolysaccharidosis type I Steven Lea, Shih-hsin Kana, Nathan Granta, Igor Nestrasilb, Ivan Tkacb, Jakub Tolarb, Jennifer Yeea, Patricia I. Dicksona, aHarbor-UCLA/ LABioMed, Torrance, CA, United States, bUniversity of Minnesota, Minneapolis, MN, United States Previously, we reported abnormal myelination on diffusion tensor neuroimaging in corpus callosum in canine mucopolysaccharidosis (MPS) I (Provenzale et al, 2015), results that appear similar to human MPS I. Dogs also showed abnormal myelin composition. Here, we studied myelination in murine MPS I, to determine the presence of similar findings. For the first experiment, male MPS I mice (B6.129-Iduatm1Clk/J) and heterozygous male littermate controls (n= 10/group) were fed a cuprizone-rich diet for 6 weeks beginning at age 4 weeks to induce demyelination. Mice were then switched to normal chow for 6 more weeks. Animals were sacrificed at 16 weeks and corpus callosum was dissected for analyses. RT-PCR of myelinrelated genes showed a consistent reduction in gene expression in MPS I mice compared to controls (n =5/group). However, there were no intergroup differences in myelin basic protein (MBP) levels by ELISA, total cholesterol by Amplex Red assay, or total protein levels. Luxol fast blue staining for myelination appeared similar in both groups. To determine whether abnormal myelination would manifest in older mice, we performed a cross-sectional study in 11 male MPS I mice and 12 male carrier controls age 52 weeks. MRI and 1H MRS was performed using a 9.4T MR scanner. In vivo 1H MRS of white matter utilized FASTMAP shimming, ultra-short echo-time STEAM (TE = 2 ms, TR = 5 s) with VAPOR water suppression. Volumetric MRI was also performed. The expression of myelinrelated genes, MBP levels and total cholesterol in these older animals showed no intergroup differences in corpus callosum. Lipids were extracted from these samples and are undergoing analysis by LCMSMS for polar lipids, ceramides, and hexosylceramides. Myelination and myelin composition abnormalities may differ between murine and canine MPS I models. The differences may have implications for the use of these models in basic and translational studies.

doi:10.1016/j.ymgme.2016.11.196

188 Immunosuppressive effect on ERT inhibition in transplanted patients with Fabry disease Malte Lendersa, Daniel Oderb, Albina Nowakc, Sima Canaan-Kühld, Christiane Drechslerb, Boris Schmitza, Peter Nordbeckb, Stefan-Martin Branda, Christoph Wannerb, Eva Branda, aUniversity Hospital Muenster, Muenster, Germany, bUniversity of Wuerzburg, Wuerzburg, Germany, c University Hospital of Zurich and University of Zurich, Zurich, Switzerland, d University Hospital Charité, Campus Virchow-Klinikum, Berlin, Germany Inhibitory antibodies towards enzyme replacement therapy (ERT) are suspected a leading cause of therapy failure in male patients with Fabry disease (FD). Inhibition-positive patients suffer from disease progression and poor outcome despite ERT. So far, little is known about the effect of immunosuppressive therapy on ERT inhibition in affected FD patients. Thus we investigated the effect of long-term immunosuppression on ERT inhibition in FD patients who underwent organ transplantation. We retrospectively analyzed