Characterization a New Model GM2-Gangliosidosis (Sandhoff 's
Natural history of infantile GM2 gangliosidosis — Survey of 97 patients
1
MPS I, II and VI have elevated HCIIT and DS:CS levels, whilst those with MPS III or IV do not. Comparison of DS:CS ratio and serum HCII-T biomarkers during treatment in patients with MPS I, II and VI showed that both biomarkers decrease in response to treatment with enzyme replacement and/or haematopoietic stem cell transplant. The HCII-T biomarker appears to be more responsive to acute perturbations in treatment and directly reflects serum DS levels, whilst urinary DS:CS ratio is more consistent and probably indicates chronic treatment outcome. HCII-T is a suitable biomarker for MPS I, II and VI, but is unlikely to be as informative for MPS diseases that do not store DS. Both HCII-T and DS:CS ratio decrease following treatment. HCII-T responds rapidly to treatment perturbations whilst DS:CS appears to indicate a more chronic effect. HCII-T measurement in appropriately stored DBS could allow development of newborn screening for MPS diseases. doi:10.1016/j.ymgme.2010.11.027 Natural history of infantile GM2 gangliosidosis — Survey of 97 patients Annette Bley a , Cynthia Tifft b , Susan Kahn c , Florian Eichler a , a Massa- chusetts General Hospital, Boston, MA, USA, b National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA, c National Tay Sachs and Allied Diseases Association, USA Q6 Objective: GM2 gangliosidoses are caused by inherited deficiency of lysosomal hexosaminidase and result in ganglioside accumulation in brain. Onset during infancy leads to rapid neurodegeneration and death before four years of age. We set out to quantify the rate of functional decline in infantile GM2 to evaluate the efficacy of future interventions. Methods: 237 patients with infantile GM2 gangliosidosis were contacted via questionnaires by the National Tay Sachs & Allied Diseases Association (NTSAD). This was supplemented by survival data from the NTSAD database and a literature survey. Results: Detailed retrospective surveys from 97 patients were available. Five patients who had received hematopoietic stem cell transplantation (HSCT) were evaluated separately. The remaining 92 patients were used for analysis of the natural history. The mortality of these patients was comparable to 103 patients from the NTSAD database and 121 patients reported in literature. Common symptoms at onset were developmental arrest (83%), startling (65%) and hypotonia (60%). All 55 patients who learned to sit without support lost the ability within a year. Individual functional measures correlated with each other but not with survival. Gastric tube placement was associated with prolonged survival. Conclusions: We describe the timing of regression in 97 cases of infantile GM2 gangliosidosis and conclude that survival is a poor measure of disease progression. However, functional measures are quantifiable and can inform power calculations and study design of future interventions such as gene therapy in GM2. doi:10.1016/j.ymgme.2010.11.028 Endothelial function in children and adolescents with mucopolysaccharidosis Elizabeth Braunlin a , Andrea Metzig b , Aaron Kelly b , a University of Minnesota Medical School, Minneapolis, MN, USA, b Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA Background: Although it is generally assumed that cardiovascular risk is heightened in the context of mucopolysaccharidosis (MPS) and reduced following hematopoietic stem cell transplantation (HSCT) or enzyme replacement therapy (ERT), this has never been formally evaluated due to limitations in the quantification of concentric arterial narrowing with coronary angiography. Therefore, we eval- uated endothelial function, using digital reactive hyperemia, in youth with MPS and healthy controls. Methods: Digital reactive hyperemic index (RHI) (EndoPAT, Itamar Medical, Caesarea, Israel) was measured in 12 children and adolescents (age 10.3±3.9 years old; 11 boys) with MPS and 9 age- and gender-matched (11.4 ± 4.0; 8 boys) healthy controls. An independent sample t-test was used to compare RHI between individuals with MPS and controls. Results: Children and adolescents with MPS (MPS type II: N =5; type I: N = 4; type 6 N = 3; treated with HSCT only: N = 3; treated with ERTonly: N = 8; untreated: N = 1) had significantly lower RHI compared to controls (MPS 1.22±0.19; controls 1.46±0.32; p < 0.05). Conclusion: These preliminary findings suggest that, children and adolescents with MPS, treated or not, have significantly lower endothelial function when compared to healthy controls. Further investigation into the long term implications of this difference is warranted. doi:10.1016/j.ymgme.2010.11.030 Glycan-based biomarkers for the mucopolysaccharidoses Jillian Brown a , Roger Lawrence b , Kia Langford-Smith d , Steven Le c , Charles Glass a , Patricia Dickson c , Brian Bigger d , Jeffrey Esko b , Brett Crawford a , a Zacharon Pharmaceuticals, Inc., San Diego, CA, USA, b University of California, San Diego, USA Q7 , c Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, USA Q8 6, d University of Manchester, UK Q9 The mucopolysaccharidoses (MPS) are caused by a deficiency in one of the enzymes responsible for the degradation of glycosami- noglycans (GAGs). Many biomarkers have been considered including enzyme activity, protein, mRNA, and measures of substrate accumu- lation. Quantification of substrate accumulation is a powerful approach given its ability to measure the disease causing material; however, historical methods to measure substrate in lysosomal storage disease have been hampered by the presence of endogenous and extremely heterogeneous substrate material. To overcome this challenge, the Sensi-Pro Assay was developed. In contrast to alternative substrate assays, this novel assay employs biochemical means to liberate and quantify only the common non-reducing ends (NREs) of the accumulating glycan fragments. These NREs provide a powerful biomarker because they are unique for each MPS class (each class has a distinct enzyme deficiency) and are not present in healthy normal subjects. To validate the method, we analyzed substrate in tissue and body fluid samples from MPS subjects. Samples of serum, plasma, urine, and cerebrospinal fluid were obtained from MPS patients, MPS animals, and normal subjects. The results demonstrate that the assay can sensitively detect GAG accumulation with substantial variation in GAG levels in samples from MPS subjects compared to normal subjects. Response to enzyme replacement therapy was also demonstrated, and sample sizes as low as 5 μl provided robust assay performance. These studies demonstrate that the assay can provide a biomarker to help diagnose, predict severity, and measure treatment response of MPS subjects in a variety of sample types and sizes. doi:10.1016/j.ymgme.2010.11.031 Abstracts / Molecular Genetics and Metabolism 102 (2011) S3–S47 S9
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Transcript of Natural history of infantile GM2 gangliosidosis — Survey of 97 patients
MPS I, II and VI have elevated HCIIT and DS:CS levels, whilst thosewith MPS III or IV do not. Comparison of DS:CS ratio and serum HCII-Tbiomarkers during treatment in patients with MPS I, II and VI showedthat both biomarkers decrease in response to treatment with enzymereplacement and/or haematopoietic stem cell transplant. The HCII-Tbiomarker appears to be more responsive to acute perturbations intreatment and directly reflects serum DS levels, whilst urinary DS:CSratio is more consistent and probably indicates chronic treatmentoutcome. HCII-T is a suitable biomarker for MPS I, II and VI, but isunlikely to be as informative for MPS diseases that do not store DS.Both HCII-T and DS:CS ratio decrease following treatment. HCII-Tresponds rapidly to treatment perturbations whilst DS:CS appears toindicate a more chronic effect. HCII-T measurement in appropriatelystored DBS could allow development of newborn screening for MPSdiseases.
doi:10.1016/j.ymgme.2010.11.027
Natural history of infantile GM2gangliosidosis— Surveyof 97 patients
Annette Bleya, Cynthia Tifftb, Susan Kahnc, Florian Eichlera, aMassa-chusetts General Hospital, Boston, MA, USA,
bNational Human Genome
Research Institute, National Institutes of Health, Bethesda, MD, USA,cNational Tay Sachs and Allied Diseases Association, USAQ6
Objective: GM2 gangliosidoses are caused by inherited deficiencyof lysosomal hexosaminidase and result in ganglioside accumulationin brain. Onset during infancy leads to rapid neurodegeneration anddeath before four years of age. We set out to quantify the rate offunctional decline in infantile GM2 to evaluate the efficacy of futureinterventions.
Methods: 237 patients with infantile GM2 gangliosidosis werecontacted via questionnaires by the National Tay Sachs & AlliedDiseases Association (NTSAD). This was supplemented by survivaldata from the NTSAD database and a literature survey.
Results: Detailed retrospective surveys from 97 patients wereavailable. Five patients who had received hematopoietic stem celltransplantation (HSCT) were evaluated separately. The remaining 92patients were used for analysis of the natural history. The mortality ofthese patients was comparable to 103 patients from the NTSADdatabase and 121 patients reported in literature. Common symptomsat onset were developmental arrest (83%), startling (65%) andhypotonia (60%). All 55 patients who learned to sit without supportlost the ability within a year. Individual functional measurescorrelated with each other but not with survival. Gastric tubeplacement was associated with prolonged survival.
Conclusions: We describe the timing of regression in 97 cases ofinfantile GM2 gangliosidosis and conclude that survival is a poormeasure of disease progression. However, functional measures arequantifiable and can inform power calculations and study design offuture interventions such as gene therapy in GM2.
doi:10.1016/j.ymgme.2010.11.028
Endothelial function in children and adolescents withmucopolysaccharidosis
Elizabeth Braunlina, Andrea Metzigb, Aaron Kellyb, aUniversity ofMinnesota Medical School, Minneapolis, MN, USA, bDepartment ofPediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
Background: Although it is generally assumed that cardiovascularrisk is heightened in the context of mucopolysaccharidosis (MPS) and
reduced following hematopoietic stem cell transplantation (HSCT) orenzyme replacement therapy (ERT), this has never been formallyevaluated due to limitations in the quantification of concentricarterial narrowing with coronary angiography. Therefore, we eval-uated endothelial function, using digital reactive hyperemia, in youthwith MPS and healthy controls.
Methods: Digital reactive hyperemic index (RHI) (EndoPAT, ItamarMedical, Caesarea, Israel) was measured in 12 children andadolescents (age 10.3±3.9 years old; 11 boys) with MPS and 9 age-and gender-matched (11.4±4.0; 8 boys) healthy controls. Anindependent sample t-test was used to compare RHI betweenindividuals with MPS and controls.
Results: Children and adolescents with MPS (MPS type II: N=5;type I: N=4; type 6 N=3; treated with HSCT only: N=3; treated withERTonly:N=8;untreated:N=1)had significantly lowerRHI comparedto controls (MPS 1.22±0.19; controls 1.46±0.32; p<0.05).
Conclusion: These preliminary findings suggest that, children andadolescents with MPS, treated or not, have significantly lowerendothelial function when compared to healthy controls. Furtherinvestigation into the long term implications of this difference iswarranted.
doi:10.1016/j.ymgme.2010.11.030
Glycan-based biomarkers for the mucopolysaccharidoses
Jillian Browna, Roger Lawrenceb, Kia Langford-Smithd, Steven Lec,Charles Glassa, Patricia Dicksonc, Brian Biggerd, Jeffrey Eskob, BrettCrawforda, aZacharon Pharmaceuticals, Inc., San Diego, CA, USA,bUniversity of California, San Diego, USA Q7, cLos Angeles BiomedicalResearch Institute at Harbor-UCLA Medical Center, USA Q86, dUniversity ofManchester, UK Q9
The mucopolysaccharidoses (MPS) are caused by a deficiency inone of the enzymes responsible for the degradation of glycosami-noglycans (GAGs). Many biomarkers have been considered includingenzyme activity, protein, mRNA, and measures of substrate accumu-lation. Quantification of substrate accumulation is a powerfulapproach given its ability to measure the disease causing material;however, historical methods to measure substrate in lysosomalstorage disease have been hampered by the presence of endogenousand extremely heterogeneous substrate material. To overcome thischallenge, the Sensi-Pro Assay was developed. In contrast toalternative substrate assays, this novel assay employs biochemicalmeans to liberate and quantify only the common non-reducing ends(NREs) of the accumulating glycan fragments. These NREs provide apowerful biomarker because they are unique for each MPS class (eachclass has a distinct enzyme deficiency) and are not present in healthynormal subjects. To validate the method, we analyzed substrate intissue and body fluid samples from MPS subjects. Samples of serum,plasma, urine, and cerebrospinal fluid were obtained from MPSpatients, MPS animals, and normal subjects. The results demonstratethat the assay can sensitively detect GAG accumulation withsubstantial variation in GAG levels in samples from MPS subjectscompared to normal subjects. Response to enzyme replacementtherapy was also demonstrated, and sample sizes as low as 5 μlprovided robust assay performance. These studies demonstrate thatthe assay can provide a biomarker to help diagnose, predict severity,and measure treatment response of MPS subjects in a variety ofsample types and sizes.
doi:10.1016/j.ymgme.2010.11.031
Abstracts / Molecular Genetics and Metabolism 102 (2011) S3–S47 S9
