- Email: [email protected]
Medical and treatment status correlates with central nervous system outcomes in mucopolysaccharidosis type VI
Molecular Genetics and Metabolism 108 (2013) S17–S102
Contents lists available at SciVerse ScienceDirect
Molecular Genetics and Metabolism j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y m g m e
Abstracts for the Lysosomal Disease Network's WORLD Symposium
1 A size comparison of beta-galactosidase isolated from fibroblasts from normal and GM1-affected sheep Amelia Ahern-Rindell, Masis Isikbay, University of Portland, Portland, OR, USA Research on lysosomal storage disorders (LSD) provides information about cellular dysfunction as well as how cells should normally work. Using animal models is an important aspect of this type of research for obvious reasons. The fatal LSD known as GM1-gangliosidosis (GM1) has been described in several mammalian species and many of the diseasecausing mutations identified. This study helps characterize what we think is a novel form of GM1 in sheep that manifests with a combined enzyme deficiency of beta-galactosidase and alpha-neuraminidase. GM1 is normally associated with a deficiency of beta-galactosidase, the lysosomal acid hydrolase coded for by the GLB1 gene. In humans, beta-galactosidase normally combines with 2 other proteins, alphaneuraminidase and protective protein cathepsin A to form a lysosomal multienzyme complex (LMC). Complex formation helps prevent premature degradation of beta-galactosidase and alpha-neuraminidase. Our working hypothesis for this ovine GM1 model is that affected sheep have a mutation that alters the structure of the beta-galactosidase protein such that it interferes with formation of the LMC leading to this unique, secondary deficiency of alpha-neuraminidase. This study used SDS-PAGE and Western Blotting to compare the beta-galactosidase from normal and GM1-affected sheep fibroblasts. Based on the relatively high homology between all mammalian GLB1 genes cloned to date, a feline anti-beta-gal antibody conjugated with horseradish peroxidase was used in an immunochemiluminescence assay. The results show no difference in size between the beta-galactosidase band obtained from normal and GM1-affected sheep, and that the 64 kDa protein visualized is comparable in size to the human betagalactosidase protein. doi:10.1016/j.ymgme.2012.11.015
2 Medical and treatment status correlates with central nervous system outcomes in mucopolysaccharidosis type VI Alia Ahmeda, Paul Harmatzb, Julian Raimanc, Suma Shankard, Kathleen Delaneya, Igor Nestrasila, Kyle Rudsera, Chester Whitleya, Elsa Shapiroa, a University of Minnesota, Minneapolis, MN, USA, bChildren's Hospital and Research Center Oakland, Oakland, California, USA, cHospital For Sick Children, Toronto, Canada, dEmory University, Atlanta, Georgia, USA 1096-7192/$ – see front matter.
Background: Mucopolysacchridosis type VI (MPS VI) is an autosomal recessive lysosomal disorder caused by a deficiency of enzyme arylsulfatase B. This is a progressive disorder presents with a spectrum of severity from mild to severe and leads to significant medical disability without treatment. hematopoetic cell transplant (HCT) was previously used as treatment but now enzyme replacement therapy (ERT) is the standard of care for MPS VI. Goal: To examine the effects of the medical phenotype and treatment on outcomes using quantitative MRI and neuropsychological data. This study examines the profile of medical involvement and initial correlations with cognitive and MRI measures. Method–Procedure: As a part of the LDN longitudinal study, 13 patients were recruited from 4 centers. Medical and treatment histories were collected according to case report forms developed for the study. A scoring system was devised to quantify abnormalities in each medical domain which were scored by a system of frequency and severity. Neuropsychological testing included IQ, attention and adaptive behavior. These results reflect baseline cross-sectional data. Data from unsedated 3 T brain MRI were traced manually (Brains2) and using automated segmentation (FreeSurfer). Results: Of 13 patients, 7 were female and 6 were male, 7 had ERT and 6 had HCT and their age range is 8 to 24 years. 2 of the HCT patients were unengrafted after HCT and both are now on ERT. Medical data: All patients had limited range of motion and ear infections, 12 of 13 patients had corneal opacity, cardiac valvular disease and hepatosplenomegaly. Only those patients who were treated with ERT had hydrocephalus (n = 4), shunts (n = 4), and cord compression (n = 5). Patients with more medical problems had higher ventricle volumes (may be due to hydrocephalus) and lower intelligence. Lower volumes were associated with lower IQ and attention. Corpus callosum volumes and attention were significantly related. Conclusion: Apparently ERT does not help to prevent hydrocephalus and cord compression in MPS VI. Medical problems are related to IQ and ventricle size. Mutation severity and detailed correlations with specific organ system involvement will be analyzed. doi:10.1016/j.ymgme.2012.11.016
3 Relationship of genotype, treatment and age with medical phenotype in mucopolysaccharidosis Type I Alia Ahmed, Renee Cooksley, Kyle Rudser, Chester Whitley, Elsa Shapiro, University of Minnesota, Minneapolis, MN, USA
Contents lists available at SciVerse ScienceDirect
Molecular Genetics and Metabolism j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y m g m e
Abstracts for the Lysosomal Disease Network's WORLD Symposium
1 A size comparison of beta-galactosidase isolated from fibroblasts from normal and GM1-affected sheep Amelia Ahern-Rindell, Masis Isikbay, University of Portland, Portland, OR, USA Research on lysosomal storage disorders (LSD) provides information about cellular dysfunction as well as how cells should normally work. Using animal models is an important aspect of this type of research for obvious reasons. The fatal LSD known as GM1-gangliosidosis (GM1) has been described in several mammalian species and many of the diseasecausing mutations identified. This study helps characterize what we think is a novel form of GM1 in sheep that manifests with a combined enzyme deficiency of beta-galactosidase and alpha-neuraminidase. GM1 is normally associated with a deficiency of beta-galactosidase, the lysosomal acid hydrolase coded for by the GLB1 gene. In humans, beta-galactosidase normally combines with 2 other proteins, alphaneuraminidase and protective protein cathepsin A to form a lysosomal multienzyme complex (LMC). Complex formation helps prevent premature degradation of beta-galactosidase and alpha-neuraminidase. Our working hypothesis for this ovine GM1 model is that affected sheep have a mutation that alters the structure of the beta-galactosidase protein such that it interferes with formation of the LMC leading to this unique, secondary deficiency of alpha-neuraminidase. This study used SDS-PAGE and Western Blotting to compare the beta-galactosidase from normal and GM1-affected sheep fibroblasts. Based on the relatively high homology between all mammalian GLB1 genes cloned to date, a feline anti-beta-gal antibody conjugated with horseradish peroxidase was used in an immunochemiluminescence assay. The results show no difference in size between the beta-galactosidase band obtained from normal and GM1-affected sheep, and that the 64 kDa protein visualized is comparable in size to the human betagalactosidase protein. doi:10.1016/j.ymgme.2012.11.015
2 Medical and treatment status correlates with central nervous system outcomes in mucopolysaccharidosis type VI Alia Ahmeda, Paul Harmatzb, Julian Raimanc, Suma Shankard, Kathleen Delaneya, Igor Nestrasila, Kyle Rudsera, Chester Whitleya, Elsa Shapiroa, a University of Minnesota, Minneapolis, MN, USA, bChildren's Hospital and Research Center Oakland, Oakland, California, USA, cHospital For Sick Children, Toronto, Canada, dEmory University, Atlanta, Georgia, USA 1096-7192/$ – see front matter.
Background: Mucopolysacchridosis type VI (MPS VI) is an autosomal recessive lysosomal disorder caused by a deficiency of enzyme arylsulfatase B. This is a progressive disorder presents with a spectrum of severity from mild to severe and leads to significant medical disability without treatment. hematopoetic cell transplant (HCT) was previously used as treatment but now enzyme replacement therapy (ERT) is the standard of care for MPS VI. Goal: To examine the effects of the medical phenotype and treatment on outcomes using quantitative MRI and neuropsychological data. This study examines the profile of medical involvement and initial correlations with cognitive and MRI measures. Method–Procedure: As a part of the LDN longitudinal study, 13 patients were recruited from 4 centers. Medical and treatment histories were collected according to case report forms developed for the study. A scoring system was devised to quantify abnormalities in each medical domain which were scored by a system of frequency and severity. Neuropsychological testing included IQ, attention and adaptive behavior. These results reflect baseline cross-sectional data. Data from unsedated 3 T brain MRI were traced manually (Brains2) and using automated segmentation (FreeSurfer). Results: Of 13 patients, 7 were female and 6 were male, 7 had ERT and 6 had HCT and their age range is 8 to 24 years. 2 of the HCT patients were unengrafted after HCT and both are now on ERT. Medical data: All patients had limited range of motion and ear infections, 12 of 13 patients had corneal opacity, cardiac valvular disease and hepatosplenomegaly. Only those patients who were treated with ERT had hydrocephalus (n = 4), shunts (n = 4), and cord compression (n = 5). Patients with more medical problems had higher ventricle volumes (may be due to hydrocephalus) and lower intelligence. Lower volumes were associated with lower IQ and attention. Corpus callosum volumes and attention were significantly related. Conclusion: Apparently ERT does not help to prevent hydrocephalus and cord compression in MPS VI. Medical problems are related to IQ and ventricle size. Mutation severity and detailed correlations with specific organ system involvement will be analyzed. doi:10.1016/j.ymgme.2012.11.016
3 Relationship of genotype, treatment and age with medical phenotype in mucopolysaccharidosis Type I Alia Ahmed, Renee Cooksley, Kyle Rudser, Chester Whitley, Elsa Shapiro, University of Minnesota, Minneapolis, MN, USA