GAG excretion, clinical symptoms or intercurrence with 0.58 mg/kgweekly or 1.2 mg/kg every 2 weeks were observed. The double-doseevery other week infusions did not change the disease progressionor the urinary GAG excretion. All families were satisfied with suchalternative for ERT, especially due to less school/work days missedand fewer venepunctures. We believe this may be an acceptabletreatment for MPS I. Longer dosing studies involving more patientsmust be encouraged, as this is a long term therapy and longerinterval between infusions could be a meaningful change in patients’quality of life.

doi:10.1016/j.ymgme.2013.12.248

236Fabry disease in Northern Ireland

Fiona Stewarta, Alison Muirb, Joanne McOskerc, Tracy Jardineb, AlisonWilsona, PascalMcKeownd, aBelfast CityHospital, Belfast, UK, bBelfast HeartCentre, Royal Victoria Hospital Belfast, UK, cBelfast Heart Centre, RoyalVictoria Hospital Belfast, UK, dBelfast Heart Centre, Belfast, UK

Fabry disease is a multi-system lysosomal disease due to adeficiency of alpha galactosidase. It is caused by mutations in theGLA gene which is on the X chromosome. However it differs frommany X-linked disorders in that females frequently show clinicalfeatures. Affected individuals may show the classical form or a moreattenuated form. Treatment for this condition is available in the formof enzyme replacement therapy with agalsidase beta and agalsidasealpha. The incidence has been estimated at approximately 1:50 000males (Desnick 2001). However a newborn screening study sug-gested an incidence of 1:3000 with an 11:1 ratio of individuals withthe more attenuated phenotype (Spada 2006). Northern Ireland hasa population of 1.7 million. To date we have found 11 families whohave Fabry disease within which are 46 individuals with a GLAmutation. All individuals with a mutation are followed up on anannual basis at our multidisciplinary Fabry clinic. Three families havethe p.A13P mutation. All other mutations are seen in only one familyand they are Exon 1 deletion, p.R392SfsX2, p.R220X, c.144delG,p.W209X, p.A13T, p.D313G and c.802_804delCA. 10 patients are agedunder 18. The eldest female is aged 79. The eldest male is 75. Thetypical skin angiokeratoma are seen in 6 individuals – all male. 16show signs of cardiac involvement. Two patients have had smallstrokes but most over the age of 30 show some bright changes onMRI. No patients have renal failure though some show evidence ofmild proteinuria. 11 patients are on treatment with agalsidase alphaand 7 with agalsidase beta. The remaining patients are monitored onan annual basis with cardiac and renal investigations. They haveeither declined ERT treatment or have no clinical features to warranttreatment at this stage. The majority of our patients have come fromfamily follow up of the index cases and the offer of genetic testing toat risk relatives. This may explain why we have a significant numberof individuals not currently on treatment. These figures suggest anincidence of at least 1:37000 in our population. We feel that we donot have 100% ascertainment of cases and therefore we believe thismay be an underestimate of the true incidence. We feel that familyfollow up of newly diagnosed cases and genetic testing of at riskrelatives is essential as clinically asymptomatic individuals may missout on the opportunity for monitoring and possible treatment.

doi:10.1016/j.ymgme.2013.12.249

237Newborn Screening - impact of new methods and criteria

Dean Suhr, University of Southern California, West Linn, OR, USA

Metachromatic leukodystrophy is not detectable using a tradition-al newborn bloodspotwithmass spectrometry due to low reliability ofdetecting ARSA activity in blood and an estimated 12 percentfrequency of pseudo-deficiency of ARSA-A that can't be reliablysegregated from those affected by actual low ARSA-A levels that causedisease. Research indicates a novel approach using a screen forsulfatides in newborn urine may be effective in detecting MLD. Ifproven through a proposed pilot study, the use of a urine screen todetect sulfatide levels leads to two challenges ⋯ a change to thetraditional newborn blood spot capture process to add a urine samplecapture to paper disc, and the potential that this screen may bescientifically proven in advance of a “viable therapy” for MLD. Thispaper addresses some of the concerns of these two potential changesand calls for a summit to discuss the impact of the proposed changesto the NBS and RUSP processes for MLD and other rare diseases.

doi:10.1016/j.ymgme.2013.12.250

238Clinical, biochemical and histopathological effects of 11 yearsof enzyme therapy in Gaucher disease type III: UnexpectedCNS vascular and cellular manifestations

Ying Suna, Andrew T. Burrowa, Wujuan Zhanga, David P. Wittea,Kenneth D.R. Setchella, Laurie Baileya, Carlos E. Pradaa,b, Gregory A.Grabowskia, aCincinnati Children's Hospital Medical Center, Cincinnati,OH, USA, bFundación Cardiovascular de Colombia, Floridablanca, Colombia

Gaucher disease results from GBA1 mutations that lead to defectiveacid β-glucosidase (GCase) mediated cleavage of glucosylceramide(GluCer) and glucosylsphingosine (GluS) as well as heterogeneousviscera and CNS manifestations. Enzyme therapy (ET) with recombi-nant GCase hasmajor visceral outcomes in Gaucher disease, but limitedeffect in correcting brain and lung diseases. The effects of 11 years of ETon brain and visceral tissues were examined from autopsy of a type 3,chronic neuronopathic Gaucher disease patient. Hepatic, splenic, andbone marrow lipid storage was nearly completely corrected by ET. Incontrast, the large clusters of Gaucher cells, positive for macrophagemarker CD68, were in the interstitia/alveolae of lungs, periadventitialspaces of brain blood vessels, and within the cerebellar, basal ganglialand hippocampus parenchyma. Expression of the macrophage man-nose receptor (MMR) was nearly absent in CNS perivascular macro-phage and storage cells. GCase substrates, GluCer and GluS, were atnormal level in the liver and spleen, but accumulated in massivemesenteric lymph nodes, lung, and brain including cortical graymatter,basal ganglia, and hippocampus. GluCer species in those brain regionscontained the long fatty acid acyl chains (C24:0 and C24:1), indicativeof their visceral origin. In addition to large losses of neurons andabsence of Purkinje cells, the brain regions had evidence of pro-inflammation, e.g., GFAP staining (astrogliosis), and neurodegenerationby enhanced phosphorylated Tau, ubiquitin, LC3, and α-synuclein.These unique data show that long-term ET with mannose-terminatedGCase was corrective for liver, spleen, and bone marrow. In com-parison, ET had limited access to lung, lymph nodes, and brain.Absence of MMR in brain parenchyma and the perivascular macro-phages implies blunted MMR-targeted ET, if delivered to the brain,would impact therapies on either side of the blood brain barrier.

AbstractsS102