progression. Hydroxy-propyl-beta-cyclodextrin (HPBCD) was re-cently shown in NPC animals models to reverse cholesterol traffickingdefects. Therefore, we initiated an investigational study (FDA INDexempt) to treat identical twin girls with NPC with intravenous andintrathecal HPBCD. Blood and cerebrospinal fluid (CSF) samples werecollected during these studies to test the response of numerouspotential biomarkers, including oxysterols, -amyloid, tau protein,mineral content, amino acids, and several redox couples. Plasmaoxysterols and CSF -amyloid decreased during HPBCD treatment. CSFtau protein levels were elevated at baseline levels, decreased duringHPBCD treatment, increased during a period of drug discontinuation,and again decreased with re-initiation of HPBCD. The levels ofcalcium, magnesium, potassium, and sodium in the CSF changed onlyslightly or remained constant during HPBCD treatment; however thebiological metal ions copper, iron, and zinc in the CSF were found tobe very low at baseline and through treatment. Additionally, baselinelevels of glutathione and ergothioneine were found to be low in theplasma, whereas ergothioneine was also very low in erythrocytes.Altered mineral homeostasis in the CNS and impaired thiol redoxcouples in the blood may play important roles in NPC pathophysiol-ogy. Moreover, measurement of these biomarkers may providevaluable new insight for monitoring clinical management and newtargets for therapeutic strategies for NPC patients.

doi:10.1016/j.ymgme.2011.11.094

Verbal Memory and Hippocampal Volume in Individuals with MPS-I

Kelly King, Alia Ahmed, Brianna Yund, Kyle Rudser, Elsa Shapiro,University of Minnesota, Minneapolis, MN, USA

Children with Hurler syndrome, the severe form of mucopolysac-charidosis type I (MPS-I), experience decline in central nervous systemfunctioning after 12-months-old if left untreated. With hematopoieticcell transplant (HCT), thedecline is arrested but thepreparative regimennegatively affects the brain's white matter, complicating development.As individuals with the attenuated forms of MPS-I, Hurler Scheie andScheie syndromes, do not undergo HCT, they do not risk HCT's negativeeffects but alsodonot receive its beneficial effects.Wehypothesized thatverbal memory would be associated with the volume of the hippo-campus, a known memory center in the brain, and be more affected inthe severe group due to the disease severity and the long-term negativeside effects associated with HCT. Adjusting for age, we compared thehippocampal volumes (manually traced using Brains2) of MPS Isevere(n=10) and attenuated (n=13) participants ages 10 to 27-years withHopkins Verbal Learning Test – Revised (HVLT-R) scores. The groups didnot differ significantly in HVLT-R scores or in hippocampal volumes.However, there was an interaction between the severe and attenuatedgroups for the association of hippocampal volumewith both theHVLT-Rtotal learning and delayed scores. There was a positive associationwithvolume in the severe group (P<0.021) but not in the attenuated group.The lack of expected association between volume and memory in theattenuated group may reflect the cumulative build-up of storagematerial. As a result of HCT treatment, the donor-derived cells mayfacilitate storage material clearance in the severe group.

doi:10.1016/j.ymgme.2011.11.095

Characteristics Associated with Delays in Diagnosis of PompeDisease Among Patients Enrolled in the Pompe Registry

Priya Kishnani a, Hernán Amartino b, Christopher Lindberg c, TimothyMiller d, Joan Keutzer d, Amanda Wilson d, aDuke University Medical

Center, Durham, NC, USA, bHospital Alemán, Buenos Aires, Argentina,cNeuromuscular Centre, Sahlgrenska University Hospital, Gothenburg,Sweden, dGenzyme, a Sanofi company, Cambridge, MA, USA

Introduction: The rarity and variability of Pompe disease result indiagnostic delays.

Methods: The diagnostic gap (time from sign/symptom onset todiagnosis) among Pompe Registry patients in 3 onset categories wasexamined: Group A, onset ≤1 year of age with cardiomyopathy;Group B: onset ≤1 year without cardiomyopathy and >1 year to≤12 years; Group C: onset >12 years.

Results:GroupBhad the largest gap;GroupA, the shortest.Over time,the gap remained unchanged in Group A, while increasing in oldergroups, possibly reflecting increased awareness and identification ofpreviously undiagnosed patients with Pompe disease. Patients present-ing with respiratory and musculoskeletal signs/symptoms concurrentlyhad the shortest gap; those presenting with neither respiratory normusculoskeletal signs/symptoms had the longest. Independent pre-dictors of a long (>median) diagnostic gap were identified. Presentingsign/symptom class was the only significant independent predictor inGroupA. InGroupsB andC, age at symptomonset, year of diagnosis, andfirst sign/symptom class were significant independent predictors of along gap. With increasing age, Group B's probability of a long gapincreased, while Group C was slightly less likely to have a long gap.Group B and C patients diagnosed more recently had the highestprobability of a long gap, likely representing increased awareness ofPompe disease. Patients presenting with neither respiratory normusculoskeletal signs/symptoms had a high probability of a long gapcompared with patients presenting with respiratory and musculoske-letal signs/symptoms concurrently (all groups).

Conclusions: Despite reliable diagnostic methods, significantdiagnostic gaps in Pompe patients continue.

doi:10.1016/j.ymgme.2011.11.096

Presenting Signs and Symptoms Among Patients with PompeDisease Enrolled in the Pompe Registry

Priya Kishnani a, Hernán Amartino b, Christopher Lindberg c, AmandaWilson d, Joan Keutzer d, Timothy Miller d, aDuke University MedicalCenter, Durham, NC, USA, bHospital Alemán, Buenos Aires, Argentina,cNeuromuscular Centre, Sahlgrenska University Hospital, Gothenburg,Sweden, dGenzyme, a Sanofi company, Cambridge, MA, USA

Introduction: Recognizing Pompe disease can be challenging dueto the heterogeneity of disease presentation and overlap of signs/symptoms with other neuromuscular disorders.

Methods: This analysis identified the most common presentingsigns/symptoms reported for Pompe Registry patients. Patient onsetcategories were Group A: onset ≤1 year of age with cardiomyopathy;Group B: onset ≤1 year without cardiomyopathy and onset >1 yearto ≤12 years; Group C: onset >12 years. Signs/symptoms wereconsidered “presenting” based on occurrence within 1 month of thefirst recorded sign/symptom for Group A and within 1 year forGroups B and C. Signs/symptoms classifications were respiratorysigns/symptoms but not musculoskeletal signs/symptoms; muscu-loskeletal signs/symptoms but not respiratory signs/symptoms; bothrespiratory and musculoskeletal signs/symptoms concurrently; andneither respiratory nor musculoskeletal signs/symptoms.

Results: Of 1003 enrolled patients, 647 patients were eligible forinclusion. In all onset categories, musculoskeletal signs/symptomswere among the most frequent presenting signs/symptoms, inaddition to cardiomyopathy (part of the group definition) in GroupA. In addition to cardiomyopathy, hypotonia was the most commonpresenting sign/symptom in Group A. Proximal muscle weakness

Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69 S41