Surgical reconstruction for severe tracheal obstruction in Morquio syndrome type A

S114

Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124

brachiocephalic artery, increases with age in Morquio syndrome type A patients. Greater attention to the trachea is needed when evaluating cervical MRI and other imaging, with the goal of establishing a timely treatment to reduce the mortality rate. doi:10.1016/j.ymgme.2015.12.463

tracheal obstruction was relieved by timely surgical trachea vascular reconstruction with dramatic resolution of his respiratory symptoms. This is the first surgical intervention of tracheal correction to avoid tracheostomy which is difficult to manage in this population. We expect that this new surgical procedure rescues many lives of patients with Morquio syndrome type A. doi:10.1016/j.ymgme.2015.12.465

306 Hematopoietic stem cell transplantation for Morquio syndrome type A Shunji Tomatsua, Hiromasa Yabeb, Akemi Tanakac, Yasutsugu Chinend, Shunichi Katob, Yasuyuki Suzukie, Tadao Oriie, aNemours/Alfred I. duPont Hospital for Children, Wilmington, DE, United States, bTokai University, Isehara, Japan, cOsaka City University, Abeno-ku, Japan, dUniversity of the Ryukyus, Nishihara, Japan, eGifu University, Gifu, Japan Morquio syndrome type A features systemic skeletal dysplasia. To date, there has been no curative therapy for this skeletal dysplasia. No systemic report on a long-term effect of hematopoietic stem cell transplantation (HSCT) for Morquio syndrome type A has been described. We conducted HSCT for 4 cases with Morquio syndrome type A (age at HSCT: 4-15 years, mean 10.5 years) and followed them at least 10 years (range 11-28 years; mean 19 years). Current age ranged between 25 and 36 years of age (mean 29.5 years). All cases had a successful full engraftment of allogeneic bone marrow transplantation without serious graft-versus-host (GVHD). Transplanted bone marrow derived from HLA-identical siblings (three cases) or HLA-identical unrelated donor. The levels of the enzyme activity in the recipient’s lymphocytes reached the levels of donors’ enzyme activities within two years after HSCT. For the successive over 10 years post-BMT, GALNS activity in lymphocytes was maintained at the same level as the donors. Except one case who had osteotomy in both legs one year later post BMT, other three cases had no orthopedic surgical intervention. All cases remained ambulatory, and three of them could walk over 400 m. Activity of daily living (ADL) in patients with HSCT was better than untreated patients. The patient who underwent HSCT at four years of age showed the best ADL score. In conclusion, the long-term study of HSCT has demonstrated therapeutic effect in amelioration of progression of the disease in respiratory function, ADL, and biochemical findings, suggesting that HSCT is a therapeutic option for patients with Morquio syndrome type A. doi:10.1016/j.ymgme.2015.12.464

307 Surgical reconstruction for severe tracheal obstruction in Morquio syndrome type A Shunji Tomatsu, Christian Pizarro, Ryan R. Davies, Ellen A. Spurrier, Mary Theroux, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, United States Progressive tracheal obstruction is commonly seen in Morquio syndrome type A, and can lead to life threatening complications including sleep apnea, airway obstruction, pulmonary hypertension and death. Two-thirds of this population die of respiratory failure. Although tracheostomy can address severe upper airway obstruction, additional features including a narrow thoracic inlet, the variable level of obstruction as well associated vascular compression can make tracheostomy a non-suitable intervention. We describe the case of a 16-year-old patient affected by Morquio syndrome type A during 2.5 years of enzyme replacement therapy whose near fatal

308 Biomarker analysis of Fabry disease patient cell fractions using tandem mass spectrometry Amanda Toupina, Pamela Lavoieb, Michel Boutinb, Mona Abaouib, Anne-Marie Côtéa, Bruno Marandaa, Pedro Miguel Geraldesa, Christiane Auray-Blaisa, aUniversité de Sherbrooke, Sherbrooke, QC, Canada, bCRCHUS Hôpital Fleurimont/Université de Sherbrooke, Sherbrooke, QC, Canada Fabry disease is an X-linked lysosomal disorder presenting a marked phenotypic and genotypic heterogeneity. Glycosphingolipids such as globotriaosylceramide (Gb3 and related isoforms/analogs), globotriaosylsphingosine (lyso-Gb3 and related analogs) and galabiosylceramide (Ga2) accumulate in tissues and biological fluids of affected patients. The main objective of this study was to understand the biochemical and pathological mechanisms of Fabry disease by analyzing the aforementioned biomarkers in different cell fractions (lysosome, nuclei, membranes, endoplasmic reticulum, Golgi apparatus, mitochondria, etc.). Secondary objectives were: 1) to develop a protocol in order to sequentially separate organelles of interest from monocytes and lymphocyte B cells of Fabry patients; 2) to develop and validate a relative quantification method using tandem mass spectrometry for glycosphingolipids in different cell fractions; and 3) to establish correlations between the levels of biomarkers from each cell fraction and clinical manifestations of the disease. Urine and blood samples were collected from Fabry patients to isolate different cell types. Cell organelles were separated and a liquid-liquid extraction was performed to quantify Gb3 and related isoforms/analogs and eventually Ga2. An Oasis MCX cartridge was used for the purification of lyso-Gb3 and its related analogs. All biomarkers were analyzed by a validated tandem mass spectrometry method using a UPLC-Xevo TQ-S system. Preliminary results from control human monocyte samples revealed the presence of methylated Gb3 isoforms/analogs, as well as saturated/unsaturated fatty acids. Our results also show that Gb3(C22:0)Me is the most abundant among the methylated Gb3 isoforms which is consistent with prior results obtained in urine and plasma of Fabry patients. Only lyso-Gb3 was detectable in cultured cells. Levels of Fabry disease biomarkers in different organelles might help to establish correlations with clinical manifestations of the disease, as well as its severity and progression. doi:10.1016/j.ymgme.2015.12.466

309 Prospective natural history study of mucopolysaccharidosis types IIIA and IIIB (Sanfilippo syndrome) Kristen Truxala,b, Kim L. McBridea,b, Kelly McNallya,b, Krista Kunklerb, Jill Twerskyb, Rebecca Grimesb, Tamar Sherrod-Canaanb, Shawn Aylwarda, Lindsay Alfanob, Katherine Berryb, Linda Lowesb, Nicholas Zumbergea, Lisa Martina, Marco Corridorea, Christopher McKeea, Douglas McCartyb, Haiyan Fub, Kevin M. Flanigana,b, aNationwide Children's Hospital, Columbus, OH, United States, bThe Research Institute at Nationwide Children's Hospital, Columbus, OH, United States