Methods: Four international experts weighted the SST domains usingnominal group technique to reach consensus. First, all domains were rankedaccording to the amount of morbidity each contributes to NGD severity.Based upon these rankings the experts assigned the range of scores, repre-senting the relative weights, for the clinical measurements within eachdomain. A Likert-like scale was used allowing for a maximum range of 0–10.

Results: Experts ranked the epilepsy domain as contributing the mostto severity, followed by pyramidal, cognitive ability, extrapyramidal, cer-ebellar signs, swallowing, ataxia/gait, speech, kyphosis, ophthalmology,horizontal gaze palsy (HGT) (least). The attributed severity scores werelater supported in the individual domain scoring, identifying a maximumaverage score of 2.25 for the HGT domain and average scores of 9.25 forepilepsy and pyramidal domains. Overall consistency in scoring wasobserved in all domains except cerebellar signs and swallowing.

Conclusion: Assigned SST domain weights reflect the amount of mor-bidity each domain contributes to NGD severity. The SST will now bedeveloped to reflect this, and utilised for international cohort comparison,for the management of medical interventions, and as an endpoint in clin-ical studies.

doi:10.1016/j.ymgme.2007.10.032

21. Recent developments on lysosomal storage disorder activities at the

Centers for Disease Control and Prevention

Victor De Jesus, Robert Vogt, W. Harry Hannon, Centers for Disease

Control and Prevention, Atlanta, GA, USA

Lysosomal storage disorders (LSDs) are a group of over 40 genetic dis-orders caused by inborn errors of metabolism. Individuals with LSDs arecharacterized by low activities of particular enzymes found in the lysosome,resulting in the accumulation of molecules that are meant to be processed bythese enzymes. While lysosomal storage disorders are each rare diseases, as agroup they are estimated to affect 1 in 7700 to 1 in 10,000 live births world-wide. Most LSDs are progressive and life threatening; if left untreated, theycan cause physical debilitation, mental retardation and early death.

Newborn screening for LSDs using dried blood spots and tandem massspectrometry is an emerging field in clinical chemistry, and currently thereis fervent debate over the launch of LSD screening on a population-basedbasis. At present, New York is the only state performing newborn screen-ing for one disorder, Krabbe disease. Other states (Illinois, Washington)will conduct population-based pilot studies using tandem mass spectrom-etry. With this in mind, the Newborn Screening Translational ResearchInitiative (NSTRI), in collaboration with the Centers for Disease Controland Prevention (CDC) and the CDC Foundation, has established state,industry and international partnerships to address newborn screeningfor lysosomal storage disorders. Recent developments include the distribu-tion of reagents to newborn screening laboratories performing tandemmass spectrometry-based LSD screening, and the creation of qualityassurance materials for laboratories performing newborn dried blood spotscreening for LSDs.

doi:10.1016/j.ymgme.2007.10.033

22. Initial experience with intrathecal recombinant human a-L-iduronidase

for spinal cord compression in two mucopolysaccharidosis I patients

Patricia Dickson a, David Naylor b, Anton Mlikotic c, Alla Victoroff a,

Agnes Chen b, Merry Passage a, Steven Le a, a Division of Medical

Genetics, LA Biomed at Harbor-UCLA, Torrance, CA, Torrance, CA,

USA, b Department of Neurology, Harbor-UCLA Medical Center,

Torrance, CA, USA, c Division of Neuroradiology, Harbor-UCLA

Medical Center, Torrance, CA, USA

Intrathecal recombinant human a-L-iduronidase (IT rhIDU) led toimprovements in signs and symptoms of spinal cord compression in one

adult MPS I patient (Muqoz-Rojas et al., in press). We treated threepatients 13–31 year with MPS I and spinal cord compression with 3–7doses of 1.74 mg IT rhIDU at 1–3 month intervals. Two received ITrhIDU as part of an ongoing clinical trial. Subjective improvement wasnoted in 3/3 patients in at least three major CNS symptoms. Theseincluded ability to move legs, pain in the legs, back and/or neck, blad-der/bowel incontinence, restless legs, numbness/tingling of the feet, fati-gue, and reduced hand use. Improvement in neurologic examinationoccurred in 3/3 patients: in pain/temperature asymmetries, strength, deeptendon reflexes, and range of motion. One patient gained independence insome aspects of self-care, resulting in a 9-point improvement in FunctionalIndependence Measure (FIM) score (11%, from 82 to the maximum scoreof 91). Adverse events with >1 occurrence included headache, pain in but-tocks, back, and neck, pneumonia, low platelets, anemia, and sore throat.One subject developed CSF pleocytosis which responded to a short courseof oral steroids. Two subjects with hydrocephalus and implanted shunts atstudy entry developed apparently transient elevated CSF opening pres-sure. One serious adverse event occurred (pneumonia). MPS I patients tol-erate IT rhIDU well and have experienced improvement in signs andsymptoms of spinal cord compression. Further study is ongoing.

doi:10.1016/j.ymgme.2007.10.034

23. Pharmacological chaperone treatment for Pompe disease

Hung Do, John Flanagan, Xiaoyang Wu, Allan Powe, Richie Khana,

Rebecca Soska, Wei Liang, Elfrida Benjamin, David Palling, Sheela

Sitaraman, Brandon Wustman, Ken Valenzano, David Lockhart, Amicus

Therapeutics, Inc., Cranbury, NJ, USA

Pompe disease is caused by mutations in the enzyme acid alpha-gluco-sidase (GAA) that alter lysosomal glycogen metabolism. The disease ischaracterized by progressive skeletal muscle weakness, reduced cardiacfunction, respiratory insufficiency, and CNS impairment. We are develop-ing small molecule pharmacological chaperones that can increase cellularactivity by selectively binding and stabilizing the target protein. Here, weshow that the pharmacological chaperone AT2220 (1-deoxynojirimycinHCl) significantly increased enzyme activity for several GAA missensemutants in patient-derived fibroblasts and improved the proteolytic pro-cessing of mutant forms of GAA. The effects of AT2220 on GAA with dif-ferent missense mutations were further characterized using transientexpression in COS-7 cells, and multiple responsive mutations wereidentified.

We subsequently evaluated AT2220 in wild type mice and found thatthe compound significantly increased GAA activity in multiple tissuesaffected in Pompe disease, including heart, gastronemius, soleus, tongue,diaphragm and brain. Similar results were also observed in normal ratsand cynomologus monkeys. These results suggest that AT2220 mayincrease enzyme activity for the common IVS1 splice variant which pro-duces low levels of wild type GAA.

AT2220 was evaluated in normal subjects (up to 1000 mg/day for14 days) in a Phase 1 clinical trial. The drug was well-tolerated and nodrug-related serious adverse events were observed. Collectively, these dataindicate that AT2220 merits further evaluation as a treatment for patientswith Pompe disease.

doi:10.1016/j.ymgme.2007.10.035

24. Data collection tools for compiling accurate health histories

Colleen Doyen, University of Minnesota, Minneapolis, MN, United States

Background: The University of Minnesota began submitting patientinformation to the Genzyme MPS I Registry in June 2005. This Registryis an observational database that tracks natural history and outcomes ofpatients with MPS I. One of the primary objectives of the Registry is tocharacterize and describe the MPS I patient population as a whole.

Abstracts / Molecular Genetics and Metabolism 93 (2008) S14–S46 S19