ase/alglucerase; average doses were 40–47 U/kg/2 wk after 5 yr compared to Europe/Middle East/Africa (27 U/kg/2 wk).

Conclusion: Regional differences in GD are indicated by the N370S mutation in US,Europe/Middle East/Africa and Latin America and the L444P mutation in Asia-Pacific.

doi:10.1016/j.ymgme.2009.10.164

148. A randomized controlled trial of enzyme replacement therapy in Fabrydisease: The Canadian Fabry disease initiative at year three

Michael Westa, Kaye LeMoineb, Daniel Bichetc, Joe Clarked, Robin Caseye, Sandra Sirrsf,Christiane Auray-Blaisg, David Sinasace, Gordon Flowerdewh, aDepartment of Medicine,Dalhousie University, Halifax, NS, Canada, bQE II Health Sciences Centre, Halifax, NS,Canada, cDepartment of Medicine, University of Montreal, Montreal, QC, Canada,dBiochemical Genetics, Hospital for Sick Children, Toronto, ON, Canada, eDepartment ofGenetics, University of Calgary, Calgary, AB, Canada, fDepartment of Medicine, Universityof British Columbia, Vancouver, BC, Canada, gDepartment of Pediatrics, University ofSherbrooke, Sherbrooke, QC, Canada, hDepartment of Community Health andEpidemiology, Dalhousie University, Halifax, NS, Canada

The Canadian Fabry Disease Initiative (CFDI) is a multicentre study of Fabry dis-ease (FD). Patients ages 5–85 are divided into Cohort 1a-prior enzyme replacementtherapy (ERT) to continue; cohort 1b enzyme nave randomized to agalsidase-beta1.0 mg/kg q2wks or agalsidase-alfa 0.2 mg/kg q2wks; and cohort 1c enzyme navewho do not meet Canadian ERT criteria or who refuse ERT. 259 patients (95 males,149 females) have been enrolled with data reported on 244 to date: 82 (33.6%) incohort 1a, 37 (15.1%) in cohort 1b and 125 (51.3%) in cohort 1c. Males had moresevere disease than females with a higher MSSI, earlier age at diagnosis, lower age,lower eGFR and greater urine protein/creatinine. In cohort 1b, females predominated(23) over males (14) but were equally distributed between treatment groups. Clinicalfeatures at baseline did not differ except for older age at diagnosis and at baseline inthe agalsidase-beta group compared with the agalsidase-alfa group. There were 52different mutations, 35 missense, 6 stop, 8 deletion, 2 insertion and 1 duplication.Nine mutations were novel. Urine GB3 levels were lower with ERT and with femalegender. Outcomes data in cohorts 1a and 1b for 24 months showed no differencesbetween patients on agalsidase-alfa and agalsidase-beta. We conclude that in theshort term no significant differences in clinical outcomes can be determined betweenthe two forms of agalsidase treatment for Fabry disease.

doi:10.1016/j.ymgme.2009.10.165

149. Children with MPS III (Sanfillipo syndrome) do demonstrate significantmusculoskeletal findings

Klane Whitea, Lori Karolb, Dustin Whitea, aSeattle Childrens Hospital, USA, bTexasScottish Rite Hospital for Children, USA

The most pronounced symptom in mucopolysaccharidosis type 3 (MPS III, Sanfi-lippo Syndrome) is the severe deterioration of the central nervous system. The effectsof MPS III on the musculoskeletal system are less severe than those caused by otherforms of MPS, however, it is our experience that many families seek orthopedic atten-tion for perceived musculoskeletal discomfort, particularly about the hip and spine.The purpose of this study is to report musculoskeletal findings in a case series ofpatients with MPS III. Our hypotheses are: (1) Musculoskeletal abnormalities are pre-valent in children with MPS III. (2) Musculoskeletal deformities in children with MPSIII may require surgical intervention. This study represents a retrospective case seriesof all records available from two institutions on patients with MPS III. Eighteenpatients were identified (10 female and 8 male) at an average age of 10.3 years. Threehad significant scoliosis (21–99), and two others had L1 hypoplasia. Four patients hadosteonecrosis of the femoral heads. One patient required a carpal tunnel release, andanother a trigger thumb release. There were no cases of cervical instability. In ourwork with these patients, we have observed several unreported musculoskeletalmanifestations of MPS III, and believe that this information will prove extremely use-ful to those who treat these children.

doi:10.1016/j.ymgme.2009.10.166

150. Gene therapy for Tay-Sachs disease

Chester Whitley, University of Minnesota, USA

Tay-Sachs disease (TSD) is an autosomal recessive neurodegenerative diseaseresulting from deficiency of lysosomal hexosaminidase A enzyme activity. TSD pre-

sents during the first year of life with loss of vision, deafness, seizures, and loss ofother neurologic functions. Death occurs before age of 4 years. Because other clin-ical phenotypes of hexosaminidase A deficiency (e.g., juvenile, late-onset forms ofhexosaminidase A deficiency) have a more attenuated neuropathology, classicinfantile TSD is chosen as the target for this study so as to achieve a rapid assess-ment of this new treatment. Study population: Patients afflicted with TSD areincreasingly treated with multi-modality therapies. This may be substrate inhibitortherapy (miglustat), anti-inflammatory acetylcysteine, or even hematopoietic stemcell therapy (HSCT), or a combination of these. However, there is no evidence thatany or all of the treatments have and therapeutic impact. This study will use spe-cific biomarkers to characterize the response of such multi-modality therapy, andthen initiate a potentially effective AAV gene therapy ‘‘hexavec’’ delivered to theintrathecal space. Hypothesis: Current multi-modality treatments will prove inef-fective to halt the progressive neuropathology of TSD; introduction of humanrecombinant alpha subunit of hexosaminidase A enzyme by AAV-mediated genetherapy into the cerebrospinal fluid (CSF) will prove to be a safe and efficaciousmeans of correcting the metabolic, pathophysiology, and clinical phenotype of thiscondition. The Specific Aims of this study are: Specific Aim 1: Beginning in the firstyear, the study will initiate a retrospective and prospective assessment of patientsreceiving existing multi-modality therapy for hexosaminidase A deficiency (Limb 1).For analysis, patients will be separated into three groups, those receiving: (a) nosystemic therapy; (b) miglustat and acetylcysteine; or (c) miglustat, acetylcysteine,and HSCT. Specific Aim 2: In the second year of this project, treatment with hexa-vec will be initiated with prospective assessment of additional response to addinghexavec CSF gene therapy (Limb 2). During the course of this clinical trial, subjectsreceiving hexavec will be studied with respect to (a) treatment-related toxicity, (b)the response of biomarkers in comparison to subjects in limb 1 (multimodalitytherapy), and (c) with in comparison to the natural history of TSD, i.e., comparedto longevity and behavioral measure outcomes in the natural history of this disor-der (see Bjoraker, Project 9). Outcome measures will include the biomarkers (a) CSFhexosaminidase A activity, (b) CSF GM2- ganglioside, (c) CSF protein and (d) CSFchitotriosidase. Clinical indicators will be changes in (e) cranial MRI morphology,(f) ophthalmologic examination (cherry red spot), (g) behavioral assessment onthe Bjoraker scales, and (h) longevity. Statistical considerations: Because the num-ber of subjects will be so small, it will be important to employ a number of modal-ities including the ‘‘N of 1 model’’ (RDCRN meeting, 2007) as well as to assess thelong-term outcome in comparison to natural history (i.e., longitudinal study of Pro-ject 9, Bjoraker). Conclusion and Significance: This two-year pilot study will providean initial assessment of the potential outcome measures that are sensitive forinfantile TSD, and provide and initial Phase l/ll assessment of hexavec AAV genetherapy for this disorder providing the basis for an ongoing and expanded clinicaltrial.

doi:10.1016/j.ymgme.2009.10.167

151. Pulmonary disease and exercise tolerance in boys with Fabry disease

William Wilcox, Cedars-Sinai, USA

Fabry disease (FD) is an X-linked inborn error of metabolism characterized bydecreased or absent activity of a-galactosidase A (aGAL). Subsequent deposition ofGL-3 causes acroparesthesias, angiokeratoma, strokes, arrhythmias, hypertrophiccardiomyopathy, gastrointestinal symptoms, hypohidrosis, temperature andexercise intolerance, and kidney failure. Enzyme replacement therapy (ERT) effec-tively reduces GL-3 accumulation, improving many clinical symptoms and stabiliz-ing kidney function. Pulmonary involvement is an under-recognized component ofFD. In our center, the majority of FD patients had abnormal pulmonary functiontests (PFTs) with reduced FEF25-7sand decreased V02max on treadmill testing.Furthermore, the diastolic blood pressure declined with increasing exercise, anabnormality that correlated with fatigue in females. In the few patients we fol-lowed as part of a clinical trial of ERT, exercise testing improved with ERT. Thesymptoms of Fabry disease most often experienced by children include pain, gas-trointestinal dysfunction, hypohidrosis, and abnormal heat and cold tolerance. Inaddition to these symptoms, children often complain of exercise intolerance.

Hypothesis: Exercise intolerance is common in boys with FD and correlates withabnormal treadmill testing and PFTs.

Specific aim: Determine the frequency and severity of pulmonary disease andexercise intolerance in boys with FD. In this pilot study, 20 FD boys between age 8and 18 who have not been treated with ERT will be evaluated with standardFabry Registry assessments as well as urine GL-3, PFTs and treadmill testing.Pulmonary function and treadmill testing could be useful in monitoring childrenwith FD and in making decisions about when to initiate enzyme replacementtherapy.

doi:10.1016/j.ymgme.2009.10.168

Abstracts/Molecular Genetics and Metabolism 99 (2010) S8–S41 S39