3. clinical outcome following 8-year enzyme replacement therapy in 884 children with type 1 gaucher...

Abstracts for the Lysosomal Disease Network’s WORLD Symposium

1. Genotype–phenotype associations in Juvenile neuronal ceroid lipofusci-

nosis (JNCL; CLN3)

Heather Adams a, Jonathan W. Mink a, Rachel Jordan b, Jennifer Kwon a,

Frederick J. Marshall a, Paul G. Rothberg a, Amy Vierhile a, Elisabeth A.

deBlieck a, David A. Pearce a, a University of Rochester Medical Center,

Rochester, NY, USA, b Massachusetts General Hospital, Boston, MA, USA

Objective: The most frequent mutation causing Juvenile neuronal cer-oid lipofuscinosis (JNCL) is a 1.02 kb deletion in the CLN3 gene (p12.1region of chromosome 16) removing exons 7 and 8, accounting forapproximately 80–85% of known mutations. Most remaining individualsare compound heterozygotes with one copy of the 1.02 kb deletion, andlimited reports suggest differential progression among these patients.

Methods: We evaluated mood and behavior with standardized childassessment tools and the Unified Batten Disease Rating Scale (UBDRS).

Results: We obtained information on 49 individuals with JNCL. Ofthese, 36 (73.5%) were homozygous for the common deletion, 12 werecompound heterozygotes and one subject had 2 copies of the R334H dele-tion. Homozygous subjects had worse motor function but also more var-iable motor function in comparison to compound heterozygotes over thecourse of the disease. Anxiety symptoms were also significantly worseamong patients homozygous for the 1.02 kb deletion.

Conclusions: Subjects homozygous for the 1.02 kb deletion had greatermood dysfunction and more variable motor function compared to com-pound heterozygotes. While these data are preliminary, they are consistentwith earlier reports of a milder clinical phenotype among compound het-erozygotes. At least 40 disease-causing mutations in CLN3 have beenidentified, but the function of the protein encoded by this gene is as yetunknown. Identification of genotype-phenotypic patterns in CLN3 mayhelp further our understanding of genomic and biochemical correlatesor modifiers of clinical disease, provide a focus for targeted interventionsto anticipate and manage symptoms, and improve models for future clin-ical trials.

doi:10.1016/j.ymgme.2007.10.013

2. Characterization of ovine GM1 gangliosidosis using immunofluoresence

Amelia Ahern-Rindell, University of Portland, Portland, OR, USA

GM1 gangliosidosis is a neurodegenerative, lysosomal storage dis-ease that results from a mutated GLB1 gene, which has been clonedin humans and a few other mammalian species. The GLB1 gene is alter-natively spliced to produce lysosomal beta-galactosidase and the elastinbinding protein (EBP). Beta-galactosidase removes terminal galactosemoieties from various macromolecules including GM1 ganglioside.EBP is involved in elastogenesis by chaperoning monomeric elastinout of the cell and assisting in its polymerization in the extracellularmatrix. A mutation in the shared coding region of the GLB1 genecan affect both beta-galactosidase and EBP. In attempting to character-ize a sheep model of GM1 at the molecular level, we have compared

normal and affected sheep fibroblasts for the presence or absence ofelastin fibers in their respective extracellular matrices. Using immunoflu-orescence with an elastin specific antibody, we have found no differencein elastin fibers in normal and GM1 affected sheep. This suggests thatthe mutation in these affected sheep is not in a location of the GLB1gene that adversely affects the function of EBP. However, to substanti-ate this finding, we have also used immunofluorescence with an EBPspecific antibody. Preliminary results suggest that there is less EBP inGM1 affected sheep compared to normal sheep. We have hypothesizedthat this reduction may be due to an accumulation of glycoconjugatesthat cause EBP shedding from the cell surface. Such shedding of EBPhas been seen in several Lysosomal Storage Diseases including GM1Gangliosidosis.

doi:10.1016/j.ymgme.2007.10.014

3. Clinical outcome following 8-year enzyme replacement therapy in 884

children with type 1 Gaucher disease (GD1)

Hans Andersson a, Paige Kaplan b, Kathrine Kacena c, John Yee c,a Hayward Genetics Center, Tulane University Medical School, New

Orleans, LA, USA, b Children’s Hospital of Philadelphia, University of

Pennsylvania School of Medicine, USA, c Genzyme Corporation,

Cambridge, MA, USA

Methods: Anonymized data from 884 children with GD1 in the Inter-national Collaborative Gaucher Group (ICGG) Gaucher Registry wereanalyzed for the effect of long-term enzyme replacement therapy (ERT)on hematological and visceral manifestations, linear growth and skeletaldisease. The parameters analyzed were hemoglobin, platelet counts, spleenand liver volumes, Z-scores for height and bone density, and reports ofbone pain and bone crises.

Results: The median height Z-score was �1.4 at baseline, but after8 years of therapy, median height was essentially normal. Anemia waspresent in over 50% at baseline and resolved in all patients after 8 yearsof therapy. Over 50% had platelet counts below 100 W 103/mm3 at base-line but over 95% had platelets counts above this level after 8 years of ther-apy. Hepatosplenomegaly decreased substantially over 8 years of therapy.Mean bone density Z-score was �0.34 at baseline, and normalized within6.6 years of therapy. Seventeen percent of patients reported bone crisisbefore treatment and in the first 2 years of treatment, but no bone criseswere reported after 2 years of ERT. Few patients (2.5%) without bone cri-ses before baseline had a crisis during treatment.

Conclusions: These data quantitate the benefit of continuous ERT inchildren with GD1: within 8 years of ERT, most clinical parameters stud-ied became normal or near normal. These data provide pediatricians ameasure of expected response in GD1 patients and offer the first long-termoutcomes for a large worldwide pediatric cohort.

doi:10.1016/j.ymgme.2007.10.015

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Molecular Genetics and Metabolism 93 (2008) S14–S46