50. Early clinical markers of CNS involvement in MPS II

50. Early clinical markers of CNS involvement in MPS II

S18 Abstracts/Molecular Genetics and Metabolism 99 (2010) S8–S41 Sub-test F/48 yrs F/63 yrs M/25 yrs F/36 yrs F/41 yrs M/35 yrs Mean Memory ...

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


F/48 yrs

F/63 yrs

M/25 yrs

F/36 yrs

F/41 yrs

M/35 yrs


Memory Executive Visuospatial Verbal Attention Infoprocess Motorskills GCS

100.7 107.5 85.6 110.4 97 82.3 97.5 97.3

105.3 92.1 94.8 102.8 93.1 89.3 91.9 95.6

97.5 109.2 122 111.4 112.4 101.5 94.7 107

107.8 112.6 114.2 109.3 107.6 94.9 107.7 107.7

101.9 102.1 109.5 107.3 101.5 93.5 99.6 102.2

93 88.3 83.9 91.3 70 75 97.6 85.6

101.0 102.0 101.7 105.4 96.9 89.4 98.2 99.2

Conclusion: Unlike comparable Mindstreams testing in Gaucher disease and Late-onset Tay–Sachs disease, the domain most affected in patients with Fabry disease seems to be information processing. doi:10.1016/j.ymgme.2009.10.064

48. Endogenous glucocerebrosidase gene expression in Gaucher disease Deborah Elsteina, Eli Ben Chetrita, Carmit Yaroslawitza, Anna Tylki-Szyma skab, Barbara Czartoryskac, Gaya Chiccoa, Ari Zimrana, aShaare Zedek Medical Center, Jerusalem, Israel, bThe Childrens Memorial Health Institute, Warsaw, Poland, cInstitute of Psychiatry and Neurology, Warsaw, Poland Objectives: The original manufacturers recommended dose of enzyme replacement therapy (ERT) for Gaucher disease of 120 units/kg body weight/month is safe and effective. In Israel 30 units/kg/month with comparable safety and efficacy is used. Preliminary observations have raised concern that drug withdrawal/dose reduction after high dose is associated with a relatively rapid deterioration in disease parameters, findings not observed on lower doses. We speculated that this differential might be due to down-regulation of endogenous expression of the GBA gene induced by higher concentration of exogenous enzyme. Methods: There were four study groups: healthy controls (n = 20); untreated patients (n = 36); patients on low-dose ERT (n = 37); and patients on high-dose ERT (n = 27). RNA and cDNA levels were quantified. Results: High-dose ERT was not associated with down regulation of GBA gene expression. GBA gene expression was controls = 1; untreated patients = 0.37; patients on low-dose ERT = 0.24; and patients on high-dose ERT = 0.29. No statistically significant differences (p = 0.357). When treatment duration was assessed, i.e., patients treated <3 years (n = 33) versus 3 years (n = 31), there was statistically significant higher gene expression among patients treated <3 years (0.4 versus 0.167, p < 0.05). Conclusions: When using duration cut-off of 3 years, the timeframe within which most patients apparently achieve maximal ERT benefit and then evince a plateauing of clinical efficacy (as noted in results of international registry data), there was a significant difference noted in gene expression. Hypothetically this may suggest that down-regulation of endogenous enzyme activity impacts effectiveness of the exogenous treatment. doi:10.1016/j.ymgme.2009.10.065

49. Five-year safety and efficacy of velaglucerase alfa in Gaucher disease type 1: Experience in clinic and home settings Deborah Elsteina, Ari Zimrana, Gabriel M. Cohnb, Kiran Bhirangib, aGaucher Clinic, Shaare Zedek Medical Center, Jerusalem, Israel, bShire Human Genetic Therapies, Cambridge, MA, USA Background: This long-term study evaluated the safety and efficacy of velaglucerase alfa in patients with type 1 Gaucher disease. Methods: Ten of 11 adult patients who completed the Phase I/II study of velaglucerase alfa administered at 60 U/kg every other week, enrolled in a long-term extension study. After month-12, all patients began a step-wise dose reduction from 60 to 45 U/kg (13 weeks) and then to a 30 U/kg maintenance dose. Seven of 10 patients received home infusions at least once during the extension period. Eight patients (4 male, 4 female) have now received velaglucerase alfa treatment for 60 months. Results: Most adverse events were of mild to moderate severity and included arthralgia, back pain and pyrexia. At 60 months, the mean increase in hemoglobin concentration from baseline was +2.38 g/dL (95% CI: 1.60, 3.16; 21.3% change) and the mean increase in platelet count from baseline was +85.1 109/L (95% CI: 59.8, 110.4; 157.2% change). At 57 months, mean percent reduction in normalized liver volume from baseline was 38.8% (95% CI: 49.1, 28.5) and mean percent reduction in normalized spleen volume from baseline was 74.0% (95% CI: 89.3, 58.6). No patient developed antibodies to velaglucerase alfa. Conclusion: After 5 years, velaglucerase alfa continued to be generally well tolerated and demonstrated substantial and prolonged increases in hemoglobin concen-

tration and platelet count, and substantial and prolonged decreases in liver and spleen volumes in type 1 Gaucher disease. doi:10.1016/j.ymgme.2009.10.066

50. Early clinical markers of CNS involvement in MPS II Maria Escolar, Joshua Holt, Poe Michelle, The Center for Development and Learning, University of North Carolina at Chapel Hill, Chapel Hill, USA Mucopolysaccharidosis II (MPS II) is an X-linked disorder caused by deficiency of iduronate-2-sulfatase, resulting in progressive accumulation of glycosaminoglycans within lysosomes. Enzyme replacement therapy (ERT) has been effective in reducing somatic disease but neurological diseases continues to progress. There is great optimism that intrathecal (IT) administration of enzyme will correct neurological symptoms. However, not all patients develop neurological disease. Therefore, early identification of those patients who will develop neurological disease will be critical to optimize the effect of therapy. The purpose of this study was to identify early clinical markers of CNS involvement in MPS II. We completed a retrospective review of clinical records of patients with MPS II referred to the Program for Neurodevelopmental Function in Rare Disorders. Each patient had longitudinal evaluations including medical and neurobehavioral assessments. Between December 2002 and August 2009, 52 patients with MPS II were evaluated and 134 patient encounters reviewed. Patient ages ranged from 2 months to 25 years with a mean age at initial visit of 71.8 56.4 months (range 2–300). Of the 52 subjects, 9 were found to have no CNS disease involvement and 43 exhibited neurologic deterioration. Over 100 MPS II related signs and symptoms were noted but only eight early clinical markers were identified to correlate strongly with later cognitive decline. There are eight early clinical markers of CNS involvement in MPS II. These markers in combination were present in all patients that developed neurologic decline. These markers are instrumental in identifying which children will benefit from early IT-ERT. doi:10.1016/j.ymgme.2009.10.067

51. Lipids and membrane microdomains in Gaucher disease Maria Fuller, Leanne Hein, Marten Snel, John Hopwood, SA Pathology at Womens and Childrens Hospital, 72 King William Road, North Adelaide, SA 5006, Australia Gaucher disease is an inborn error of lipid metabolism resulting from a deficiency of the lysosomal enzyme, acid-glucosidase, leading to the accumulation of glucosylceramide in affected cells. Although the enzymatic, genetic and molecular bases of Gaucher disease is well-characterised, the link between glucosylceramide accumulation and pathology remains poorly defined. Using cell models of Gaucher disease we have identified secondary lipid changes including ceramide, di- and trihexoslyceramide and the anionic phospholipid, bis(monoacylglycero)phosphate. These changes were found in different membrane microdomains and as such are likely to influence signaling pathways, contributing to the pathology in Gaucher disease. We have had success in normalising some of these changes with fatty acid supplementation. Currently we are investigating the spatial coordination of these lipid alterations in a conditional knockout mouse model of Gaucher disease using MALDI imaging mass spectrometry. Another avenue for these secondary lipid changes is their use as biomarkers for Gaucher disease. As they reflect the downstream biochemical changes these lipids are likely to more closely resemble the manifesting pathology. We have tested a plasmid lipid profiling approach to provide insight into the disease burden of individuals by direct measurement of the biochemical changes resulting from the disease and the subsequent correction of the blood biochemistry following treatment. Extending this concept, we are now developing a metabolomics approach to identify additional surrogate biomarkers of disease activity using a SYNAPT high definition exact mass time-of-flight mass spectrometer with data evaluation by principle component analysis. doi:10.1016/j.ymgme.2009.10.068

52. Long term outcome of haematopoietic stem cell transplantation (HCT) in 11 Hurler patients (MPS IH) Francesca Furlana, Attilio Rovellia, Paola Cortia, Graziella Uzielb, Pierluigi Russoa, Erik Sganzerlaa, Alessio Gambaa, Elena Piozzic, Maurizio De Pellegrind, Rossella Parinia, a Ospedale San Gerardo, Milano-Bicocca University, Monza, Italy, bIstituto Neurologico